Fishman's Pulmonary Diseases and Disorders - PART 09-14 by HD Derma

PART

IX Disorders of the Pulmonary Circulation

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80 The Pulmonary Circulation Alfred P. Fishman

I. PULMONARY HEMODYNAMICS Pulmonary Vascular Resistance Pulmonary Vascular Pressures Cardiac Output (Pulmonary Blood Flow) and Oxygen Delivery Pulmonary Blood Volume Induced Changes in Pulmonary Hemodynamics

IV. THE BRONCHIAL CIRCULATION The Bronchial Circulation in Disease

II. PULMONARY VASOMOTOR CONTROL Initial Tone Role of Nerves Prostacyclin and Other Arachidonic Acid Metabolites Nitric Oxide Endothelins Respiratory Gases and pH Other Vasoactive Substances

VI. ABNORMAL PULMONARY VASCULAR COMMUNICATIONS Systemic Artery-Pulmonary Vascular Communications

III. THE PULMONARY ARTERIAL MICROCIRCULATION IN GAS EXCHANGE Structure and Function of Intrapulmonary Vessels Effects of Inflation

The normal pulmonary circulation is a low-resistance, highly compliant vascular bed interposed between the two ventricles, lodged within the lungs and thorax. Its initial tone is low. Because of the way in which it is incorporated into the substance of the lung (Fig. 80-1), it can be greatly influenced by changes in airway and pleural pressures, on the one hand, and by the performance of the two ventricles, on the other. Because pulmonary vascular pressures are low, and because the thin-walled pulmonary vessels are closely apposed to the air-containing elements of the lungs, modest changes in external forces can exert rather large hemodynamic effects. Moreover, the pulmonary circulation is poorly equipped for self-regulation. Consequently, it is important to monitor and control perivascular pressures when observations are intended to distinguish between active and passive changes in vascular calibers.

V. THE FETAL AND NEONATAL PULMONARY CIRCULATIONS Regulation of the Fetal Pulmonary Circulation Postnatal Pulmonary Vasodilation The Ductus Arteriosus

VII. CONGENITAL PULMONARY ARTERIOVENOUS COMMUNICATIONS Clinical Manifestations Differential Diagnosis Treatment Prognosis

Passive influences can be quite subtle. For example, during each heartbeat, part of the ejectate from the right ventricle is retained with the pulmonary arterial tree, distending its walls, while the remainder flows through the pulmonary microvasculation toward the left side of the heart. How this stroke output is partitioned between the quantity retained and the quantity passing through to the pulmonary capillaries depends on a variety of influences: the intrinsic properties of the pulmonary arterial tree, the pressure drop along the length of the pulmonary arterial tree, the transmural pressures, and the resistance to outflow at the distal end of the arterial tree. A change in breathing pattern or cardiac performance—as may occur during a shift from rest to exercise—can passively affect the partition between the stored and pass-through components of the stroke volume as well as modify the peripheral transmission of the pressure and flow pulses.

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Figure 80-1 Incorporation of pulmonary arteriole into pulmonary parenchyma. The fascial sheath enables the vessel to slide in different directions within the lung tissue.

Until about 30 years ago, the predominant interest in the pulmonary circulation was on hemodynamics and gas exchange. Since then the focus has widened to include the nonrespiratory and water-exchanging functions of the lungs. Some of the nonrespiratory functions of the pulmonary circulation (e.g., the sieving of particulate matter) are simply mechanical; others are metabolic and endocrine, essential not only for the integrity of pulmonary structure and function (e.g., the generation of surfactant) but also as components of the neurohumoral and metabolic machinery of the body (e.g., the renin-angiotensin system) (Fig. 80-2). The pulmonary circulation is not the sole blood supply to the lungs: systemic arterial branches (the â&#x20AC;&#x153;bronchial circulationâ&#x20AC;?) ensure the vitality of the conducting airways of the lungs and of the structures that support the gas-exchanging apparatus. Ordinarily this blood supply is exceedingly small; however, it is capable of remarkable proliferation when the pulmonary blood is compromised or when the lungs are the seat of certain chronic inflammatory processes. Finally, both the structure and function of the pulmonary vessels can vary greatly, not only between species (Fig. 80-3) but sometimes also within species. For example, the pulmonary resistance vessels (small arteries and veins) of humans native to a high-altitude environment are more muscular than those native to a sea-level environment, apparently an adaptation to chronic hypoxia. Also, the pulmonary arterial pressor response to acute hypoxia can vary greatly from species to species. The fetus has thicker-walled media in its arteries and arterioles than does the adult, and these vessels respond more vigorously to vasomotor stimuli in the fetus than in the adult. In this chapter, unless otherwise stipulated, the designation normal pulmonary circulation signifies the pulmonary circulation in the normal adult who lives at sea level (Table 80-1).

Figure 80-2 Renin-angiotensin system. The lungs play a central role in control of systemic blood pressure because of the converting enzyme on the luminal aspect of pulmonary capillary endothelium. Strategic disposition of the enzyme and huge expanse of pulmonary capillary endothelium enable rapid and efficient conversion of angiotensin I to angiotensin II as blood courses through the lungs.

PULMONARY HEMODYNAMICS In clinical practice, thinking about the regulation of the pulmonary circulation centers around the concept of pulmonary vascular resistance (the hindrance offered by a vascular bed to the flow of blood through it). The hindrance changes during vasoconstriction or vasodilation. In the pulmonary circulation, the small pulmonary muscular arteries and arterioles are the only vessels that seem capable of appreciable vasomotor activity. Consequently, these precapillary vessels are generally referred to as resistance vessels and pictured as the principal sites of pulmonary vasomotor activity. Other contractile elements, such as perivascular contractile cells, are sometimes invoked to explain active changes in pulmonary vascular resistance, but as a rule, their effects are meager compared to the vasomotor activity of the small muscular arteries and arterioles.

Pulmonary Vascular Resistance Different approaches have been used to detect changes in pulmonary vascular resistance (PVR). However, clinicians rely

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The Pulmonary Circulation

Figure 80-3 Muscular pulmonary arteries (resistance vessels) in pulmonary circulation of various animal species. A. Dog (×500). B . Cat (×500). C . Human (×200). D . Rat (×800). A–D . Tunica media is relatively thin. E . Guinea pig (×200). F . Cow (×500). E and F. Elastic–van Gieson stain. (Micrographs courtesy of J. M. Kay.)

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Table 80-1 Representative Hemodynamic Values for Normal Adult Males at Rest and During Moderate Exercise

Cardiac output (L/min) Heart rate (beats/min) Right atrial pressure (mmHg) Pulmonary artery pressures (mmHg) Systolic Diastolic Mean Pulmonary wedge pressure (mmHg) Systemic arterial pressure (mmHg) Mean Pulmonary vascular resistance (units)

Rest

Exercise

6 80

16 130

4–6

6–8

20–25 10–12 14–18

30–35 11–14 20–25

6–9

10–12

120/180 90–100

150/95 110–120

0.70–0.95

0.60–0.90

heavily on calculations of PVR based on the following formula: P¯ PA − P¯ LA R= ¯˙ Q T

where R = PVR, either in R units or dynes·sec–1 cm5 P¯ PA − P¯ PV = drop in mean pressure between the pulmonary artery and left atrium, mmHg (pulmonary-wedge pressure, P¯ PW , is generally substituted for P¯ LA ) ¯ Q˙ T = mean pulmonary blood flow, ml/s The formula and units above express PVR in R (resistance) units. For the normal pulmonary circulation, the value for R is about 0.1 mmHg · L–1 min–1 . Some prefer to express PVR in dynes sec–1 · cm5 . To do so, the numerator of the equation is multiplied by 1332. The normal value is then around 100. All too often, for the sake of expediency in clinical studies, the pulmonary arterial pressure, per se, is substituted for the pressure difference in the numerator. This omission of the outflow pressure P¯ LA is then indicated by referring to the value calculated for resistance as the “total PVR.” Although this usage may be a practical expedient, the value calculated in this way is bereft of either physiological or physical meaning. A change in calculated PVR is generally used to infer that a change has occurred in the calibers of resistance vessels (i.e., in the muscular pulmonary arteries and arterioles). The

Figure 80-4 Effect of doubling blood flow through one lung on pulmonary arterial pressure in the main pulmonary artery (MPA). Bronchospirometric tracings of oxygen uptake before ( A) and after (B ) occlusion of the right pulmonary artery in a human subject. Oxygen uptake by the right lung ceases. C. Pulmonary arterial pressure. Inflation of the balloon (arrow) causes little change in pressure in the main pulmonary artery even though pulmonary blood flow has doubled.

next step is to judge whether the change is active or passive. This distinction can be difficult if both pulmonary vascular pressures and flows undergo large changes between control and test periods (e.g., in the transition from rest to exercise). In normal persons, in whom pulmonary arterial pressures undergo relatively small changes during exercise despite a doubling of cardiac output (Fig. 80-4), it seems reasonable to interpret a drop in resistance as reflecting pulmonary vasodilation as long as both rest and exercise studies are conducted while the patient is supine. If a shift is made during exercise to an upright position, however, the drop in resistance may reflect recruitment of new vessels in the uppermost parts of the lungs rather than dilation of vessels already open. In the pulmonary circulation of native residents at high altitude, the muscular media of the small pulmonary arteries and arterioles are thicker and precapillary smooth muscle extends further distally. Because of these anatomic features, PVR is ordinarily higher in native residents at altitude than in native residents at sea level. Alternative Approaches to PVR Physiologists advocate comparisons of the slopes and intercepts of pressure-flow curves, before and after a test stimulus, as a reliable approach (Fig. 80-5). Unfortunately, these curves are usually difficult to obtain in humans because of passive changes that accompany interventions (e.g., before and during assisted ventilation).

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Figure 80-5 Pulmonary vascular resistance (PVR) at rest and during exercise. Background is family of PVR curves as isopleths. During exercise, resistance decreases as cardiac output and the difference between pulmonary arterial and left atrial pressures (" P¯ ) increases.

A more sophisticated approach to the hindrance of blood flow through a vascular bed is the determination of vascular impedance. Instead of using mean pressures and flows, as in the traditional calculation of PVR, vascular impedance takes pulsability into account (Fig. 80-6). This use of pulsatile pressure and flows provides opportunity to gain information about the geometry and viscoelastic properties of the vessels, their dimensions, the sites of wave reflections, the occurrence of pulmonary vasomotor activity, and the relationship between the mechanical performance and energy expenditure of the right ventricle, on the one hand, and the pulmonary circulation, on the other.

Figure 80-6 Transformation of pulsatile pressures and flows in consecutive segments of the pulmonary circulation. Pressure contours between the pulmonary artery and vein undergo considerable transformation, so the pulmonary venous pressure closely resembles the left atrial pressure. In contrast, flow surges ahead under the impulse of the right ventricle, retaining its pulsatile contour in the pulmonary veins. (Based on data from Fishman AP: Pulmonary circulation, in Fishman AP, Fisher AB (eds), Handbook of Physiology, sec 3: The Respiratory System, Vol 1: Circulation and Nonrespiratory Functions. Bethesda, MD, American Physiological Society, 1985, pp 93–166, with permission.)

chapter under “The Pulmonary Arterial Microcirculation in Gas Exchange.” 3. If alveolar pressure in the portion of the pulmonary vascular bed under consideration exceeds left atrial pressure, conventional calculation of PVR as R=

Passive Modifiers of PVR Testing for active changes in pulmonary vascular caliber is always haunted by the prospect of overlooking passive changes. Among these, three warrant special mention: 1. An increase in pulmonary arterial or pulmonary venous pressure automatically causes resistance to fall, either by opening segments of the pulmonary microcirculation that were previously closed (recruitment) or by distending resistance vessels that are already open. 2. Lung volumes passively affect PVR: calculated PVR due to passive influences is lowest at end-expiration and increases as lung volumes move in either direction. This topic is considered in detail later in the

The Pulmonary Circulation

P¯ PA − P¯ LA ¯˙ Q T

is meaningless, since alveolar, rather than left atrial, pressure becomes the outflow pressure. This topic is considered later in terms of the zones of the lungs. Here it will suffice to indicate that in the upright lung, resistance to blood flow decreases automatically from top to bottom as, under the influence of gravity, dependent vessels open wider the distention of open vessels, and vessels previously closed are forced open (“recruited”).

Pulmonary Vascular Pressures During each respiratory cycle, all intrathoracic vessels are affected to some extent by the swings in pleural pressure.

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Whether blood pressure in the pulmonary circulation is referred to atmospheric or to pleural pressure depends on the use to which the results are to be put. For the calculation of PVR, mean blood pressures referred to atmosphere are used. In using left atrial pressure as the outflow pressure, care must be taken to ensure that left atrial pressure exceeds alveolar pressure—i.e., that zone 3 conditions prevail (see below). In contrast to referring pressures to atmosphere, as in the calculation of vascular resistance, the pressures that determine the caliber of vessels (i.e., the transmural pressures) are referred to the intrathoracic pressures that surround them: for the alveolar capillaries, this pressure is calculated as the difference between the luminal pressure in the pulmonary capillaries and the alveolar pressure; for the other pulmonary vessels, the transmural pressure is determined as the difference between luminal and pleural pressure. In practice, esophageal pressure is generally substituted for pleural pressure, and pleural pressure is taken to be equivalent to perivascular pressure. In Fig. 80-7, the pressure drop along the length of the pulmonary vascular tree is compared with that of the systemic circulation. Since pulmonary capillary pressures cannot be measured directly, they are generally estimated to be intermediate between the mean pulmonary arterial and pulmonary-

Figure 80-7 Pressure drop across the systemic (mesenteric) and pulmonary circulations. The decrements in pressures in the two vascular beds are strikingly different. Measurements were made by direct puncture of arterial and venous segments of the subpleural microcirculation. (Based on from Bhattacharya J, Nanjo S, Staub NC: Micropuncture measurement of lung microvascular pressure during 5-HT infusion. J Appl Physiol 52:634–637, 1982, with permission.)

wedge pressures. Pulmonary capillary flow can be recorded with a body plethysmograph and the nitrous oxide method. Pulmonary Arterial Pressures Ordinarily, the mean pulmonary arterial pressure averages about 10 to 12 mmHg (on the order of one-eighth of that in the systemic circulation). During systole, pulmonary arterial pressure increases abruptly from diastolic values of 5 to 10 mmHg to 20 to 30 mmHg. Aging is associated with a slight increase in pulmonary arterial pressures. The contour of the pulmonary arterial pressure resembles that recorded at the root of the aorta. Full-bodied pulmonary arterial curves are more apt to be recorded in pulmonary hypertensive states than when pressures are normotensive. Moreover, extrinsic mechanical influences deform contours when pulmonary arterial pressures are low. Left Atrial and Pulmonary-Wedge Pressures The drop in mean pressure between the pulmonary artery and left atrium is small—about 10 mmHg (about one-eighth of the pressure drop across the systemic circulation) (Fig. 807). Micropuncture of subpleural vessels suggests that most of the drop occurs in the pulmonary capillaries. In intact, unanesthetized humans, the mean left atrial pressure is about 5 to 10 mmHg. During a single respiratory cycle, swings in pressure occur on the order of 3 to 12 mmHg. Because the left atrium is relatively inaccessible in the intact human, pulmonary-wedge pressures are generally used as a substitute. The pulmonary-arterial-wedge pressure (Pw ) is recorded by advancing a cardiac catheter through the right side of the heart and pulmonary arterial tree until it is impacted in a small precapillary vessel. By this procedure, a stagnant column of blood is created to measure pressure at its junction with flowing blood (i.e., in large pulmonary veins in the vicinity of the left atrium) (Fig. 80-8). An alternative practical approach to estimating left atrial pressure is the inflation of a balloon in a segmental pulmonary artery for the recording of pressures distal to an occlusive balloon. The tracing obtained in this way resembles that of the Pw . Various criteria have been advanced to guarantee that a value obtained for Pw is a reliable measure of mean left atrial pressure: Pw less than mean pulmonary arterial and diastolic pressures, fully oxygenated blood withdrawn from the impacted catheter, the characteristic snap of the catheter as it is withdrawn from the wedge position, and the distinctive configuration of the wedge tracing. Unfortunately, even when all criteria are met, the Pw may fail to provide a measure of mean left atrial pressure if the catheter fails to be wedged properly or if the tip is wedged in an area where alveolar pressure exceeds pulmonary venous pressure (see “Zones of the Lungs”, later in the chapter), if pulmonary arterial vessels between the catheter tip and the left atrium are occluded, or if the airways or the parenchyma of the intervening lung is sufficiently abnormal to generate abnormal perivascular pressures (e.g., by fibrosis or obstructive airways disease).

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Figure 80-8 Meaning of pressure determined distal to an occlusive balloon. After the balloon is inflated, the pressure recorded is that which exists at the conjunction of flowing streams (two arrows) and the static pool beyond the occlusive balloon. Narrowing of pulmonary venule (PV) distal to the occlusive balloon, as by venoconstriction, does not affect the use of the postballoon pressure (or pulmonary-wedge pressure) as a measure of left atrial pressure until obstruction ensues that closes the channel to the left atrium. (From Marini JJ: Respiratory Medicine and Intensive Care. Baltimore, Williams & Wilkins, 1981.)

In brief, when used critically, the Pw , or the balloonocclusion pressure, usually provides a reliable measure of the mean left atrial pressure. However, because of the possibility that pulmonary venous constriction in various disease states may cause pulmonary capillary pressure to exceed left atrial pressure, it is not used as a measure of pulmonary capillary pressure.

Cardiac Output (Pulmonary Blood Flow) and Oxygen Delivery Averaged over several respiratory cycles, the outputs of the two ventricles are approximately the same; although the output of the left ventricle is slightly greater than that of the right ventricle because of the admixture of bronchial venous to pulmonary venous blood, this “anatomic venous admixture” is about 1 to 2 percent of the total left ventricular output. As noted above (Fig. 80-4), doubling of the cardiac output can be accommodated in the capacious pulmonary vascular bed with virtually no increase in mean pulmonary arterial pressure. In humans, the cardiac output is generally determined by some application of the indicator dilution or Fick principle. For either, reliable determinations require a steady state; the time required to achieve a steady state is generally shorter

The Pulmonary Circulation

for the indicator dilution techniques. Also, in practice, indicator dilution techniques are easier to apply. As a result, indicator dilution techniques are quite popular. However, the indicator dilution technique is not as reliable as the Fick technique unless carefully done, and it is apt to be misleading when cardiac output is low (as in heart failure). Other techniques for determining the cardiac output, such as those designed to determine pulmonary capillary blood flow, are neither easy to perform nor reliable. In order to compare values obtained from subjects of different dimensions, cardiac output is generally expressed in terms of body surface area (i.e., as cardiac index). In normal adults lying quietly at rest, supine and in the postprandial state, the cardiac index averages about 3.12 L/min/m2 (SD ± 14). The primary mission of the coordinated interplay of the respiration, circulation, and blood is to deliver oxygen to tissues and organs in accord with their metabolic needs (Fig. 80-9) and to carry off the carbon dioxide that they generate in the course of metabolism. In the steady state, cardiac output is matched to metabolic rate: cardiac output (blood flow) increases by 600 to 800 ml per min per 10-ml increase ˙ 2 ). During heart failure, when blood in oxygen uptake ("VO flow fails to increase normally, the oxygen uptake is sustained by circulatory and ventilatory adjustments in the parameters shown in Fig. 80-9. Oxygen delivery is defined as the product of cardiac out˙ put and the arterial O2 content (QT× CaO2 ). An increase in O2 requirement by the tissues (as during exercise) is ordinarily met by increasing the cardiac output, widening the arteriovenous O2 difference, or both. In contrast to the roughly linear relation between oxygen uptake and cardiac output during exercise, the relation between oxygen uptake and the arteriovenous oxygen difference is hyperbolic. The relative contribution of an increase in cardiac output and a widening of the arteriovenous oxygen difference to satisfying the tissue requirements for oxygen depends on how the increase in metabolism is induced (by exercise, increase in body temperature, hormones, or drugs). As noted above, the “oxygen delivery” to the tissues is equal to the product of the cardiac output and the arterial O2 content (Q˙ T × CaO2 ). Polycythemia enhances O2 delivery by increasing the O2 -carrying capacity of the blood; but if the increase becomes excessive, complications such as thromboembolism, induced by an increase in red cell mass, tend to nullify the advantages of polycythemia for gas exchange. In states of low cardiac output or arterial hypoxemia, O2 delivery can be enhanced by increasing the oxygen content of arterial blood (e.g., by breathing O2 -enriched inspired air or by mechanical ventilation). In unanesthetized human subjects, the treadmill and bicycle ergometer are the conventional devices for achieving calibrated and reproducible levels of exercise. The hemodynamic effects of anxiety, caused by lack of familiarity with the procedure, may dominate the response, not only at rest but also during moderate exercise. For this reason, values of cot VO2 at rest are often lower after exercise than before (i.e.,

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Figure 80-9 The Morgan-Murray diagram showing the interplay of the respiration and circulation in satisfying the O2 requirement at rest and during exercise. At rest (inner rectangle), the oxygen uptake V˙ O2 is provided by a cardiac output of about 5 L/min and corresponding values for O2 transport by the blood and diffusing capacity. The increase in O2 uptake (V˙ O2 ) during exercise (outer rectangle) is met by an increase in blood flow, O2 transport in the blood, and the diffusing capacity of the lungs (EX). A similar diagram can be drawn for O2 delivery to the tissues.

after the threat of the unknown is gone). Quantification of the level of exercise is accomplished either by determining oxygen uptake or by assessing the workload. Tachycardia and the respiratory exchange ratio are often more reliable indices of anxiety than are clinical signs and symptoms. Intrapulmonary Distribution of the Cardiac Output ˙ to alveolar ventilation (VA) ˙ is a Matching the blood flow (Q) prime prerequisite for efficiency in gas exchange. A powerful stimulus for rearrangement of local pulmonary blood flow is acute alveolar hypoxia (as might be caused by a local inflammatory process). The classic demonstration of the vasoconstrictor property of acute hypoxia is considered in detail in a subsequent section (“Pulmonary Vasomotor Control”).

Pulmonary Blood Volume In normal humans, the pulmonary blood volume is about 10 percent of the total circulating blood volume. As a rule, it is measured by a variant of the indicator-dilution principle. In the hypothetical adult male weighing 70 kg, this value is approximately 400 to 500 ml. This volume is of interest on several pathophysiological accounts: (1) as a determinant of the mechanical behavior of the lungs, (2) as a reservoir that provides the preload for the left ventricle, (3) as a supply of hemoglobin for alveolar-capillary gas exchange, (4) as a source of water and macromolecules that engage in alveolar-capillary exchange, (5) as a potential mechanism for increasing pulmonary capillary pressures and promoting pulmonary edema, and (6) as a potential mechanism for evoking dyspnea. Changes in pulmonary blood volume are at the expense of the air volumes. Thus, the vital capacity decreases in acute pulmonary congestion. The pulmonary blood volume varies with body position: it increases when the subject lies down

and decreases when he or she stands; it is readily enlarged by intravenous infusions, by immersing the body in water, by inflation of an antigravity suit, by negative-pressure breathing, and by displacement of blood from the systemic circulation (as during systemic vasoconstriction). Conversely, the pulmonary blood volume decreases when the subject stands on his or her head, after a large venesection (one that decreases cardiac output), during positive-pressure breathing or the Valsalva maneuver, and during systemic vasodilatation. In normal subjects, the pulmonary blood volume appears to be subdivided equally among the pulmonary arteries, capillaries, and veins. In the hypothetical 70-kg man, the pulmonary capillary blood volume can only be estimated: values range from 100 to 200 ml, depending on the method. Upon sitting up, the pulmonary capillary blood volume shares in the overall decrease in pulmonary blood volume; during exercise, as cardiac output goes up, pulmonary capillary blood volume also increases. More of the increase in volume is accomplished by recruiting new capillaries from the reserve than by dilating open vessels. As capillary blood volume enlarges as a result of recruitment and dilation, the endothelial surface area gas and fluid exchanges enlarge correspondingly.

Induced Changes in Pulmonary Hemodynamics Mechanical Ventilation From the hemodynamic point of view, the best-analyzed types of mechanical ventilation are positive-pressure ventilation and positive end-expiratory ventilation.In the former, airway pressures increase during inflation, returning promptly to atmospheric during expiration; in the latter, raised airway pressure is sustained throughout the breathing cycle. Terminology used in clinical practice generally focuses on the positive endexpiratory pressure (PEEP), and the designation generally

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refers to continuous positive pressure ventilation rather than solely to positive end-expiratory pressure. In normal humans, the imposition of PEEP at a level of 5 cm H2 O has several hemodynamic consequences: stroke volume, cardiac output, and central blood volume decrease while heart rate is unaffected. Pulmonary arterial pressures (referred to as atmospheric pressures) increase, and the increase in alveolar pressure causes pulmonary-wedge pressures to exceed left atrial pressures. At higher levels of PEEP, these hemodynamic effects are exaggerated. Stiffening of the lungs by pulmonary edema requires higher levels of PEEP to produce the same effects (e.g., 15 to 40 cm H2 O instead of 5 cm H2 O). At these levels, however, the risk of barotrauma to the lungs also increases markedly. The cardiac output falls when normal lungs are subjected to PEEP, but how this decrease is effected remains enigmatic. At least three mechanisms have been proposed: the traditional one implicates a decrease in venous return (preload) to the right ventricle. The second entails a decrease in left ventricular preload and impairment of both right and left ventricular performance. The third attributes a negative inotropic effect to PEEP mediated by way of cardiovascular inhibitory mechanisms in the brain and the local release of prostaglandins. Clearly, the use of PEEP triggers an intricate resetting of regulatory mechanisms that seems to involve mechanical, reflex, and local humoral mechanisms. Which mechanism dominates at any given time may well depend on the experimental and clinical setting. Exercise The changes in pulmonary vascular pressures, flows, and resistances brought about by light exercise are indicated in Table 80-1. Despite the respiratory swings and the shifts in midposition of the lung during exercise that complicate accurate measurement of pressures, the hemodynamics are quite consistent: at the start of the exercise, the pulmonary arterial mean pressure (referred to atmosphere) increases abruptly

The Pulmonary Circulation

by 3 to 5 mmHg. As exercise continues, a plateau is reached, generally at 1 to 2 mmHg less than peak values; the increase in systolic pressure is greater than the increase in diastolic pressure. Because of the increase in pulsatility and in mean pulmonary arterial pressure, perfusion of the apices improves. Direct determinations of left atrial pressure during exercise in intact humans or dogs have not been reported. The pulmonary-wedge pressure is generally little affected by mild exercise, but intensification of the exercise tends to increase it. The concept of pulmonary capillary â&#x20AC;&#x153;stress failureâ&#x20AC;? has been advanced as a limiting factor for maximal exercise.

PULMONARY VASOMOTOR CONTROL In the normal pulmonary circulation at sea level, vascular tone is low (i.e., the pulmonary vascular bed is virtually fully dilated) (Fig. 80-10). It is considerably higher in the native resident at high altitude, in whom comparable increments in pulmonary blood flow elicit larger increments in pulmonary arterial pressures.

Initial Tone The low initial tone in the pulmonary circulation at sea level is attributed to a balance in favor of vasodilation due to substances released by pulmonary vascular endothelium (Fig. 80-11). The predominant mediators in this balance are the vasodilator substances prostacyclin and nitric oxide, on the one hand, and endothelin-1, on the other. The vasodilators are released promptly in response to shear stresses, whereas endothelin-1 is released slowly and is active in more prolonged control of vascular tone. Ion channels feature prominently in setting pulmonary vascular tone. Paramount among these are several different K+ channels that are present on vascular smooth muscle:

Figure 80-10 Effect of initial tone on vasodilator responsiveness. Administration of acetylcholine while the subject is breathing room air (upper panels) elicits no vasodilator response because of the low initial tone. During hypoxia, when tone is increased by vasoconstriction, administration of acetylcholine causes a considerable drop in pulmonary arterial pressures. (From Fritts HW, Harris P, Clauss RH, et al: The Effect of Acetylcholine on the Human Pulmonary Circulation Under Normal and Hypoxic Conditions. J Clin Invest 37:99â&#x20AC;&#x201C;110, 1958.)

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Figure 80-11 The balance between vasodilator and vasoconstrictor mediators. A. Under normal conditions, breathing ambient air at sea level, the balance favors vasodilation. B . During hypoxia, the balance is tilted to vasoconstriction.

adenosine triphosphate (ATP)-sensitive, Ca2+ -activated, and nonspecific, voltage-gated K+ channels. Activation of these channels causes an increase in K+ efflux and membrane hyperpolarization, followed by relaxation of smooth muscle.

Role of Nerves Vasomotor responses can be elicited from the isolated lung devoid of all nervous connections and perfused by artificial fluids. This capability underscores the primary role played by vasomotor mechanisms intrinsic to the lungs in effecting vasomotor control. However, the predominance of intrinsic control in normal subjects or in patients studied in clinical settings does not exclude the possibility that extrinsic influences, such as sympathetic nerves, can contribute important elements of control should the occasion arise (e.g., the “fight or flight reaction” associated with a terrifying experience). The sympathetic innervation to the pulmonary circulation includes α- and β-adrenergic receptors on pulmonary vascular smooth muscle. α-Adrenergic receptors appear to predominate. The α-adrenergic receptors (e.g., norepinephrine) are constrictor, whereas the β-adrenergic receptors (e.g., isoproterenol) are dilator. In the normal resting adult at sea level, adrenergic activity is modest and αadrenergic influences predominate. Cholinergic activity does not appear to be implicated at any time in the control of the pulmonary circulation. Nervous connections from without the lungs can mediate certain reflex effects on the pulmonary circulation. A systemic depressor reflex is evoked by an abrupt, large increase in pulmonary arterial or venous pressure and elicits modest bradycardia and systemic hypotension; sectioning the vagi abolishes this reflex. The outputs of the two ventricles are automatically adjusted by reflex mechanisms that avoid flooding

of the lungs. Stimulation of systemic baro- and chemoreceptors elicits reflex changes in pulmonary vascular tone. Reflex pathways also exist within the lungs. For example, the juxtacapillary reflex (“J” reflex) is elicited by deformation of the terminal airways (as by edema) to evoke tachypnea, bronchoconstriction, and reluctance to exercise. The Bainbridge reflex is triggered by distention of the pulmonary venoatrial junction and elicits reflex tachycardia. Occasionally, persons with pulmonary hypertension (as do deteriorating experimental preparations) show swings in pulmonary arterial pressure “vasomotor waves” reminiscent of Traube-Hering and Mayer waves. Imbalance in central vasomotor control has been held responsible for their genesis. Finally, it has been proposed that CO2 -sensitive receptors within the lungs can augment ventilation. These reflex patterns demonstrate that even though predominant control of the pulmonary circulation resides within the lungs per se, potential exists for activating a complicated system of extrinsic controls, by either disease or experimental conditions.

Prostacyclin and Other Arachidonic Acid Metabolites Prostacyclin, a metabolic product of arachidonic acid metabolism (Fig. 80-12), has been identified as a major determinant of initial tone in the pulmonary circulation. Arachidonic acid is metabolized via two major enzymatic pathways: cyclooxygenase and lipoxygenase. The cyclooxygenase pathway gives rise to the prostaglandins and thromboxane A2 . The lipoxygenase pathway produces the leukotrienes and the 5-, 12-, and 15-hydroxy-eicosatetraenoic acids. A separate series of reactions involves a cytochrome P450 pathway, which produces oxygenated metabolites of arachidonic acid. Arachidonic acid (eicosanoic acid), a 20-carbon polyunsaturated fatty acid, is the precursor of the

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Figure 80-12 The arachidonic acid cascade illustrating the two pathways and a few metabolic products capable of pulmonary vasomotor activity. (Based on data from Fishman AP: Pulmonary circulation, in Fishman AP, Fisher AB (eds), Handbook of Physiology, sec 3: The Respiratory System, Vol 1: Circulation and Nonrespiratory Functions. Bethesda, MD, American Physiological Society, 1985, pp 93–166, with permission.)

prostaglandins (Fig. 80-12). It is released from tissue by deacylation of cellular phospholipids. Upon release, it is metabolized by either the cyclooxygenase or lipoxygenase enzyme systems. Because the arachidonic acid metabolites released from membrane lipids are both organ-specific and cell-specific, and because experimental conditions strongly influence the metabolism of arachidonic acid, either the cyclooxygenase or lipoxygenase pathway may predominate. Administered arachidonic acid need not have the same metabolic consequences as that generated endogenously. Nor are physiological and pharmacologic doses and patterns of release apt to be identical. Therefore, it is difficult to predict which pathway will dominate or how experimental circumstances are influencing the biologic effects. As a rule, arachidonic acid injected intravenously elicits pulmonary vasoconstriction largely because of the predominant effect of thromboxane A2 , even though prostacyclin, a potent vasodilator, is also released; leukotrienes do not appear to be operative in this circumstance. Pharmacologic interruption of one pathway has been used to uncover the effect of metabolites produced by the other. For example, indomethacin, which inhibits prostaglandin synthetase, is a popular agent for blocking the cyclooxygenase pathway in order to disclose the actions exerted by metabolites of the lipoxygenase pathway. Diethylcarbamazine, which interferes with the lipoxygenase pathway, serves the same purpose for the cyclooxygenase pathway. However, specificity of these and other inhibitors for particular sites in the arachidonic acid cascade is rarely complete. Moreover, alternative pathways in the metabolism of arachidonate provide opportunity for subtle experimental quirks to channel the cascade into one pathway or another, thereby covertly shaping the vasomotor response of the pulmonary circulation, not only to prostaglandins (exogenous as well as endogenous) but also to inapparent neurohumoral influences and to biologically active molecules. Finally,

The Pulmonary Circulation

considerable species variation exists in the intensity of the vasomotor response to particular products of arachidonic acid metabolism. Considerable diversity of biologic effects exists among the prostaglandins: (1) certain metabolic products of the cyclooxygenase pathway are pulmonary vasoconstrictors , PGE2 , thromboxane A2 ), whereas others are (e.g., PGF2α pulmonary vasodilators (e.g., PGE1 , PGI2 ); PGE2 , which constricts the adult pulmonary vascular bed, dilates the neonatal pulmonary vascular bed; (2) leukotrienes, generated by the lipoxygenase pathway, include potent pulmonary vasoconstrictors; and (3) suspicion is high that the prostaglandins act as intermediaries in pulmonary vasomotor responses to other agents, such as the kallidins, histamine, and isoproterenol. Prostacyclin (PGI2 ) is both a potent pulmonary (and systemic) vasodilator and an antithrombogenic agent. It is formed in pulmonary vascular endothelium (Fig. 80-13) by the action of prostacyclin synthetase on the prostaglandin endoperoxide PGH2 . Shear stress of the endothelium and bradykinin seem to be powerful stimuli for the release of prostacyclin from endothelium. Thromboxane A2 is a potent pulmonary vasoconstrictor and a powerful stimulus for platelet aggregation. Prostacyclin antagonizes the effects of thromboxane A2 . An imbalance has been found between the excretion of thromboxane and of prostacyclin metabolites in pulmonary hypertension.

Nitric Oxide Although the original view of endothelium as a passive lining of blood vessels had long been appreciated to be an oversimplification, particularly with respect to the exchange of water and biologic molecules, full understanding of its biologic role began with the demonstration in isolated aortic preparations that the vasodilation elicited by acetylcholine required the presence of an intact endothelial layer (Fig. 80-14). Subsequently, endothelium-derived relaxing factor (EDRF) was pinpointed as the mediator, followed by the identification of nitric oxide as EDRF. In 1995, largely in recognition of its ubiquitous biologic role as an intercellular messenger in signal transduction in a wide variety of mammalian cells, nitric oxide (NO) was elevated from its lowly status as a gaseous air pollutant to the vaunted position of “molecule of the year”—an endogenous, ubiquitous regulator of a wide range of physiological processes. Although NO is a highly reactive molecule, in minute (physiological) quantities it is safe, transmitting signals and serving diverse biologic functions, such as the regulation of blood pressure. It is short-lived because of its interactions with oxygen. NO also reacts with superoxide radical (O2– ) and with ferrous hemoproteins, such as guanylate cyclase and hemoglobin. Because of its chemical properties, NO is less specific and less controllable than almost any other transmitter or hormone. Cigarette smoke contains up to 1000 ppm of NO. Silo-filler’s disease, an interstitial pneumonitis, is caused by exposure to high levels of NO and NO2 .

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Figure 80-14 Influence of endothelium on responses of different vessels to acetylcholine (ACH). Increasing concentrations of acetylcholine were applied to rings of femoral, saphenous, splenic, and pulmonary arteries (circles) that had previously been contracted with norepinephrine. Vessels in which endothelium was intact (solid curves) responded with increasing vasodilation. In vessels without endothelium (dashed curves), virtually no vasodilation occurred. (From De Mey JG, Vanhouette PM: Heterogeneous behavior of the canine arterial and venous wall. Importance of the endothelium. Circ Res 51:439â&#x20AC;&#x201C;447, 1982, with permission.)

Figure 80-13 Cross-section of alveolar capillary from human lung lined by endothelium (EN). Endothelial nucleus is striking. Alveolar-capillary barrier is organized into thick (right) and thin (left) portions. Thick side includes considerable interstitial space (IN), containing connective-tissue elements (e.g., fibers [cf]). In contrast, interstitial space on thin side is obliterated by fusion of basement membranes, which forms a minimal air-blood barrier. C = capillary containing three red corpuscles in its lumen; EP = alveolar epithelium; F = fibroblast. (Courtesy of E. Weibel.)

NO is synthesized in endothelial cells from one of the guanidium nitrogens (l-arginine) by the enzyme nitric oxide synthase (NOS) (Fig. 80-15). Two major forms of NOS enzymes produce NO: constitutive isoforms, in endothelium and neurons, release small quantities of NO, in bursts, to signal adjacent cells; and inducible isoforms, in macrophages, release large amounts of NO continuously and serve to eliminate bacteria and parasites. NOS are a family of complex

cytochrome P450-like hemoproteins. NO synthase can be inhibited by methylene blue and by l-N-monomethylarginine, an l-arginine analog. Among its biologic functions is the regulation of pulmonary vascular tone. Its release is triggered by both physical factors, such as endothelial shear stress, and biochemical influences, such as bradykinin, histamine, and catecholamines. The NO produced by pulmonary endothelial cells is transported by the hemoglobin in the red blood cells to systemic arterioles, where it causes muscle relaxation. The cysteine residue of hemoglobin is active in the transport of NO to the peripheral blood vessels. The NO conveyed to the periphery enters the vascular smooth-muscle cell by diffusion to activate adenylate cyclase, leading to an increase in cyclic guanosine monophosphate (cGMP), which, in turn, causes muscle relaxation (vascular dilation) (Fig. 80-16). Inhaled NO is currently being investigated as a therapeutic pulmonary vasodilator. It is administered by airway and is rapidly removed by hemoglobin in blood. The apparatus for delivering NO by inhalation is cumbersome. Because it is administered by inhalation, it has opportunity en route to interact with the wide variety of cells that comprise the epithelial lining, autonomic neurons, smooth muscle, and interstitium.

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Figure 80-15 Synthesis of nitric oxide (NO) by vascular endothelium. 1. The enzyme nitric oxide synthase (NOS) synthesizes NO from L-arginine. 2. NO diffuses to the smooth muscle cell, where it activates the enzyme guanylate cyclase via cyclic GMP to smooth-muscle relation.

Endothelins Endothelins (ET-1, ET-2, and ET-3) are a family of short (21 amino acids) peptides. Of the three, ET-1 is the only one produced by endothelial cells. It is a powerful vasoconstrictor

Figure 80-16 Electron micrograph of small muscular pulmonary artery from human lung showing endothelium (EN) and single layer of smooth muscle (SM). Thick endothelial cytoplasm and wealth of organelles (inset) comprising mitochondria (M), endoplasmic reticulum (ER), lipid droplet (Li), specific granules (asterisks), microtubules (mt), and many vesicles (arrows). Crosssectioned smooth-muscle cells show central nucleus, mitochondria, sarcoplasmic reticulum (SR), membrane-bounded caveolae (arrows), filamentous matter with dense bodies (db), and cell-tocell contacts (circle). cf = collagen fibrils; el = elastic fibers; bars = 0.5 m. (Courtesy of E. Weibel.)

and stimulant of cell growth. ET-1 is produced, on physiological demand, from a larger precursor molecule (ECE), which is being intensively investigated for its potential as an avenue for inhibiting endothelin formation in various disease states. Three endothelin receptors (ETA, ETB, and ETC) have been cloned. ETA receptors on vascular smooth muscle are responsible for vasoconstriction and growth promotion; ETB receptors on endothelium are related to release of prostacyclin or NO. Binding of ET-1 to ETA receptors initiates a cascade leading to vasoconstriction by way of phospholipase C and resulting in an increase in intracellular calcium ion concentration. Binding of endothelins to ETB receptors stimulates vasodilation. In addition to its direct effects on vascular tone, ET-1 has a wide range of biologic actions, including constriction of extravascular smooth muscle, mitogenesis, and release of other mediators, such as prostacyclin, NO, and atrial natriuretic peptide. The lungs remove large amounts of endothelin from circulating blood. Within the lungs, endothelins are present in the parenchyma and pulmonary vessels. They are powerful bronchoconstrictors. Release of endothelins is stimulated by such receptor-mediated stimuli as epinephrine, angiotensin II, arginine vasopressin, thrombin, transforming growth factor-Î˛ and interleukin-1, and also by hypoxia. The endothelin-receptor antagonist bosentan prevents and reverses pulmonary hypertension in rats. Because of the diversity of their effects and widespread distribution in the body, the role of the endothelins is being explored in a wide variety of diseases, such as hypertension, arteriosclerosis, Raynaudâ&#x20AC;&#x2122;s disease, ulcerative colitis, and renal failure.

Respiratory Gases and pH Acute Hypoxia The classic demonstration of the pressor effect of acute hypoxia on the pulmonary circulation was made by Euler and Liljestrand on the open-chest cat (Fig. 80-17). In the ensuing half-century, acute hypoxia has proved to be a pulmonary vasoconstrictor in virtually all species indigenous to sea level. The authors not only documented the role of alveolar hypoxia in eliciting the pulmonary pressor response but also

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Figure 80-17 The classic recordings by Euler and Liljestrand showing the effects of acute hypoxia on the pulmonary arterial (PA) and left atrial (LA) pressures in the open chest cast (labels added). At the far right, breathing 10.5 percent O2 caused a considerable rise in pulmonary arterial pressure without a corresponding increase in left atrial pressure. (Labels added at bottom of figure.) (Based on data from Euler US, Liljestrand G: Observations on the pulmonary arterial blood pressure in the cat. Acta Physiol Scand 12:301–320, 1946, with permission.)

appreciated that local hypoxia (as by disease) might automatically redirect blood flow to better-ventilated parts of the lung by eliciting local vasoconstriction.Finally, they anticipated recent studies on the effect of shear on release of endothelial mediators by identifying as a subject for research the response of pulmonary vessels to large increases in pulmonary blood flow. In human subjects, acute hypoxia causes an increase in pulmonary arterial pressure, does not affect left atrial pressure, and usually produces little increase in cardiac output. The pressor response starts within seconds, generally reaching its peak by 3 min, and attenuates gradually as hypoxia continues. Severe acidosis augments the hypoxic pressor response. The site of pulmonary vasoconstriction in response to acute hypoxia is predominantly at the precapillary level, involving the small muscular arteries and arterioles (Fig. 80-18). Acute hypoxic vasoconstriction can be relieved by a variety of bronchodilators and vasodilators, such as inhalation anesthetics. Endothelial-derived vasodilators appear to be particularly effective. For example, prostacyclin administered intravenously can blunt or abolish the hypoxic pressor response. Similarly, inhalation of NO inhibits hypoxic vasoconstriction, whereas inhibitors of NOS augment the hy-

poxic pressor response by blocking the endogenous synthesis of NO. The mechanisms of the hypoxic-pressor response have been investigated for years along two dominant lines: the first postulates a direct effect of hypoxia on the smooth-muscle cells of vascular media; the second proposes the release of a chemical mediator within the lungs during acute hypoxia (e.g., ET-1 by pulmonary vascular endothelium). Although both continue to have their proponents, the cumulative evidence favors the view that the hypoxic pressor effect is exerted directly on pulmonary vascular smooth muscle. Moreover, the many vasoactive substances that have been investigated as possible mediators of this effect (i.e., the postulated “indirect” effect) are actually modulators rather than mediators. The direct effect has been explored along three lines: the sensing mechanism, the transduction mechanism, and the effector mechanism. Of these three components of the hypoxic pressor response, the most settled is the effector mechanism (i.e., an increase in cytosolic calcium concentration). For insights into the sensing and transducing mechanisms, investigators have turned to the type I cell of the carotid body that, like the pulmonary myocyte, is stimulated by hypoxia. In both types of cells, hypoxia has been found to inhibit an outward potassium current, thereby causing membrane depolarization and entry of calcium into the cells by way of voltage-dependent calcium channels. Also in both types of cells, changes in the redox status of the oxygen-sensitive potassium channel or channels may control current flow, so that the channel is open when oxidized and closed when reduced. Still unsettled is the type(s) of potassium channel that responds to hypoxia and how the ionic exchanges through these channels are gated. One attractive hypothesis being tested is that hypoxia is sensed by a hemoprotein in the membrane of the smooth-muscle cell—which, in turn, activates the responsive potassium channel(s). Chronic Hypoxia With few exceptions, such as the yak (a native resident at high altitude), chronic hypoxic pulmonary hypertension is a feature of life at high altitude. The exceptions are due to genetic influences that are manifested by variability in the hypoxic pressor response among species and even among strains. Chronic hypoxia elicits anatomic changes in the small pulmonary arteries and arterioles. These changes have been designated “pulmonary vascular remodeling.” These structural changes are characterized by proliferation of the smooth muscle in the vessel walls, causing thickening and peripheral extension of smooth muscle in the media of small muscular arteries and arterioles. Concomitantly, elastin and collagen are synthesized and deposited in the extracellular matrix and adventitia. The end result is an increase in resistance to blood flow and a decrease in distensibility of the pulmonary resistance vessels. The stimuli for remodeling include not only hypoxia but also mechanical forces, such as increase in blood flow, which expose endothelial cells to increased shear stress and activate platelets to release promotors of smooth-muscle

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Figure 80-18 Direct visualization of the vasoconstrictor effect of acute hypoxia. During breathing of 5 percent O2 in N2 , the pulmonary precapillary vessels, is attenuated by vasoconstriction, whereas the pulmonary veins undergo no appreciable change. (Courtesy of Dr. I. Ninomiya, National Cardiovascular Research Institute, Osaka, Japan.)

cell proliferation. Various genes are expressed in the process of hypoxic-induced vascular remodeling, some attributable to the hypoxia per se and others evoked by the vasoconstrictor response. Agents that block hypoxic pulmonary vasoconstriction also block the development of chronic hypoxic pulmonary hypertension and the remodeling response. In essence, a variety of influences, including mechanical factors, growth factors, and mediators, appear to be active in pulmonary vascular remodeling. With respect to both acute and chronic hypoxia, one tantalizing enigma is the reason why hypoxia causes pulmonary vessels to constrict and systemic vessels to dilate. Considerable data about the pulmonary circulation at altitude have been gathered at Morococha, Peru (an altitude of 4540 m), where an ambient PO2 of about 80 mmHg is associated in adults with a mean pulmonary arterial pressure of about 28 mmHg (about twice the average value of 12 mmHg in sea-level residents [Lima], even though cardiac output and pulmonary-wedge pressures are the same) (Fig. 80-19). During moderate exercise, mean pulmonary arterial pressure increases considerably: quadrupling the oxygen uptake intensifies arterial hypoxemia and doubles both the cardiac output (from 3.65 to 7.49 L/min/m2 ) and the pulmonary arterial pressure (from 41/15, 29 mmHg, to 77/40, 60 mmHg). In persons suffering from chronic mountain sickness, in which severe arterial hypoxemia and hypercapnia are secondary to alveolar hypoventilation, pulmonary arterial pressures are much higher. Genetic factors seem to in-

fluence human susceptibility to pulmonary hypertension at altitude. When native residents of high altitudes take up residence at sea level, pulmonary arterial pressure and PVR decrease somewhat, although not to normal (Fig. 80-20). PVR remains high because of anatomic changes in the pulmonary arterial tree elicited by the chronic hypoxia (i.e., by hypertrophy and hyperplasia of the small muscular arteries and arterioles, accompanied by extension of muscle peripherally into precapillary vessels that are ordinarily nonmuscular). In the face of this restructuring of precapillary vessels, the pulmonary capillaries and veins remain unchanged. Polycythemia, because it increases blood viscosity, contributes to the pulmonary hypertension associated with chronic hypoxia. At sea level, the anatomic lesions of hypoxic pulmonary hypertension gradually revert toward normal. Nonetheless, 2 years after moving to sea level, the native high-altitude dweller still shows an inordinate increase in pulmonary arterial pressure, in response to a modest increase in pulmonary blood flow, presumably a consequence of persistent muscularization of the small pulmonary arteries. Children born and raised at altitude undergo more gradual involution of pulmonary arterial pressures than do those born at sea level. Therefore, up to the age of 5 years, children raised at altitude have uniformly higher pulmonary arterial pressures (around 58/32, 44 mmHg) than do older children at altitude (41/18, 28 mmHg).

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Figure 80-19 Schematic representations of respiratory and circulatory measurements in humans at altitude (14,900 feet). The three circles within each rectangle illustrate normal values for the 1-year resident (left circles), the native resident (middle circles), and the native mountain-sick resident (right circles). The facial expressions are intended to indicate the degree of acclimatization.

Acute Hypercapnia Although Euler and Liljestrand found an increase in pulmonary arterial pressure during CO2 breathing, it has since been shown that there is little response to inspired CO2 if pH is maintained at near-normal levels (they did not measure

Figure 80-20 Return of pulmonary artery pressures to normal after prolonged residence at sea level.

pH). For example, enrichment of inspired air with tolerable concentrations of CO2 (5 to 7 percent) has little effect on the human pulmonary circulation, presumably because the increase in ventilation minimizes change in blood pH. However, if the ventilatory response is limited (e.g., during anesthesia), a distinct pressor response is evoked as arterial blood becomes acidotic (i.e., as pH falls to 7.2 or less). The combination of moderate to severe acidosisâ&#x20AC;&#x201D;no matter how inducedâ&#x20AC;&#x201D;and acute hypoxia elicits a greater response than either alone (i.e., the pressor response to acute hypoxia and acute hypercapnia combined is synergistic). Blood pH Just as severe acidosis elicits pulmonary vasoconstriction, so does severe alkalosis cause pulmonary vasodilatation. The interplay between hypoxia and acidosis is believed to be of considerable importance in areas of alveolar hypoventilation in which the combination of local acidosis and hypoxia promotes the diversion of blood flow to better ventilated parts of the lungs.

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Other Vasoactive Substances

The Pulmonary Circulation

A variety of endogenous and exogenous substances have been used to alter the tone of the pulmonary resistance vessels, predominantly the small pulmonary arteries and arterioles.

tently elicit pulmonary vasoconstriction. Epinephrine, which possesses α- and β-adrenergic effects, not only evokes less vasoconstriction on a weight-for-weight basis but can also, depending on the preparation, cause vasodilatation.

Vasodilators

Angiotensin II

Acetylcholine

As noted above, acetylcholine is a powerful pulmonary vasodilator when pulmonary vascular tone is high (Fig. 80-10). Observations on the role of endothelium in determining the responses of different vessels to acetylcholine marked the beginning of current interest in EDRF and led to the identification of NO as an agent that mimicked the EDRF effects.

Angiotensin II, an octapeptide formed in the lungs by the action of converting enzyme from angiotensin I and decapeptide (Fig. 80-2), generally but not invariably elicits pulmonary vasoconstriction. Small doses (0.03 µg/kg/min, administered intravenously) suffice to increase pulmonary arterial pressure without discernible effect on the systemic circulation. Histamine

Bradykinin

This pulmonary vasodilator is a member of a family of vasoactive polypeptides. It is inactivated by the same converting enzyme(s) in the lungs that convert(s) angiotensin I to II. Although it is consistently a powerful systemic vasodilator, it is not as predictable as a pulmonary vasodilator, usually evoking pulmonary vasodilatation. The biologic role of bradykinin in regulating the pulmonary circulation is unclear. The possibility has been raised that the origin of bradykinin in the pulmonary vascular endothelium constitutes a source of vasodilator agent for the systemic circulation. Although angiotensin II and bradykinin share a dependency on converting enzyme for their genesis, they act differently on vascular smooth muscle: angiotensin acts without intermediaries, whereas vasoactive prostaglandins are involved in the effects of the kallidins. Indeed, at least in some of the species, the variability in the vasoactive effects of bradykinin and the kallidins has been attributed to variations in the extent to which different prostaglandins are engaged as mediators of the vasodilator response. Isoproterenol

In the normal pulmonary circulation, isoproterenol usually evokes a barely detectable drop in pressure; the modest response has been attributed to low initial tone due either to the paucity of β-adrenergic receptors or to the low level of their activity in the normal state. The vasodilator response is much more impressive in animal preparations in which initial tone is high and in some patients with pulmonary hypertension. It has been suggested that the pulmonary vasodilator effect of isoproterenol when pulmonary vascular tone is high depends not only on pulmonary vascular adrenergic receptors but also on vasodilator prostaglandins. One complicating feature in the use of isoproterenol as a pulmonary vasodilator is its powerful inotropic effect on the heart. Vasoconstrictors Catecholamines

Norepinephrine and phenylephrine, potent stimulators of the α-adrenergic system in the pulmonary circulation, consis-

Histamine (in doses of 10–5 g, given intravenously over a 2-min period) elicits more variable responses. Although species difference and the type of experimental preparation seem to influence the outcome, as a rule, histamine (like hypoxia) appears to be a powerful pulmonary vasoconstrictor and systemic vasodilator. At one time, it was suspected that histamine was an important local mediator in the regulation of the pulmonary circulation. However, this belief appears to have been discounted. Discrepant effects of histamine on the pulmonary circulation can be rationalized in terms of H1 and H2 receptors and their blocking agents: chlorpheniramine to block H1 receptors selectively, metiamide to block H2 receptors. The use of these agents suggests that pulmonary vasoconstriction is mediated by H1 receptors and vasodilatation by H2 receptors. Serotonin

Interest in the effects of serotonin (5-hydroxytryptamine, 5HT) on the pulmonary circulation was stimulated by reports that individuals who ingested appetite suppressants that interact with 5-HT are at increased risk of developing idiopathic pulmonary arterial hypertension (IPAH). The first reports, in the 1960s, related the appetite suppressant aminorex to an outbreak of IPAH; a subsequent report, in the 1980s, implicated fenfluramine in a similar role. These clinical observations were supported by the occurrence of pulmonary hypertension in fawn-hooded rats, which have an inherited defect in platelet storage. Fenfluramine, difenfluramine, and aminorex act by inhibiting serotonin reuptake, triggering 5-HT release and interacting with 5-HHT and 5-HT receptors. In addition to its vasomotor effects, 5-HT exerts mitogenic effects on smooth-muscle cells. Serotonin occurs in the mast cells of some species but not others. It is synthesized in the enterochromaffin cells of the gut from dietary tryptophan. The serotonin released by these cells is largely removed by the liver, the excess being almost completely removed by the endothelial cells of the pulmonary circulation (Fig. 80-21). Any serotonin that escapes the metabolic machinery of the liver and lungs is stored as dense granules in circulating platelets. In addition to direct effects on vessels, airways, and platelets, serotonin enhances

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(3) SEROTONIN REMOVAL COMPLETED

(2) SEROTONIN PARTIALLY REMOVED

(1) SEROTONIN INTO PORTAL VEIN

Figure 80-21 Handling of serotonin by the gutliver-lung axis. During a single passage, serotonin is partly removed by the liver. Removal is completed by the lungs.

vasoconstriction and platelet aggregation produced by other vasoactive agents, such as norepinephrine and angiotensin II. Two separate binding sites have been identified for serotonin: S1 receptor binding sites that are labeled by serotonin and S2 receptor binding sites that are labeled by serotonin antagonists (e.g., spiperone and ketanserin). The physiological and pharmacologic effects of serotonin (vasomotor activity, bronchoconstriction, platelet aggregation) appear to be related to the binding of serotonin to the S2 receptor; no such effects have been attributed to binding to the S1 receptor. The distinction between S1 receptors and S2 receptors holds great promise for reexamining the role of serotonin in the bronchoconstriction and pulmonary vasoconstriction evoked by pulmonary embolism. In contrast to histamine, which seems to affect both pulmonary arterial and venous components, serotonin seems to constrict predominantly the precapillary vessels.

THE PULMONARY ARTERIAL MICROCIRCULATION IN GAS EXCHANGE The pulmonary circulation is designed to operate in concert with alveolar ventilation for the sake of gas exchange. Certain aspects of this interplay warrant special mention: (1) the lungs receive the entire cardiac output; (2) the pulmonary blood flow is about the same as the alveolar ventilation; and (3) although the respiratory and circulatory processes are

phasic, the rates are entirely different (i.e., about 15 breaths and 80 heartbeats per minute at rest). Therefore, matching of air and blood for optimal arterialization of mixed venous blood requires delicate tuning of operations that are not in phase, either at rest or during exercise; no vasomotor nerves or neurohumoral substances are at hand to make the speedy and fine adjustments of alveolar blood flow to alveolar ventilation. Matching of air and blood for optimal gas exchange involves about 300 million alveoli that bear myriad capillary segments in their walls. The interposition of pulmonary capillaries between contiguous alveoli provides an enormous surface area for gas exchange, about 100 m2 at rest, which increases further during exercise. The volume of blood in the capillaries at any one instance is approximately 100 to 200 ml, and red blood cells pass from one end of the gas-exchanging network to the other in about 0.75 s. Four aspects of the distribution of the pulmonary circulation have attracted special attention with respect to gas exchange: (1) gas-exchanging vessels, (2) effects of gravity, (3) interplay among pressures influencing vascular calibers, and (4) effects of inflation.

Structure and Function of Intrapulmonary Vessels Depending on the perivascular pressures to which they are exposed, three types of intrapulmonary vessels have been distinguished: alveolar, corner, and extra-alveolar (Fig. 80-22).

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Figure 80-22 Schematic representation of the effects of a deep breath on the relative calibers of alveolar capillaries, ‘‘corner vessels,” and extra-alveolar vessels. Top: At end-expiration, the alveolar capillaries (containing red cells) are wide-bored. The relative sizes of corner vessels and of extra-alveolar vessels are also shown. Deep inspiration narrows the alveolar vessels and widens extra-alveolar vessels, leaving inner vessels virtually unchanged in caliber. Bottom: The same phenomenon is shown for alveolar and extra-alveolar vessels. A = end-expiration; B = end-inspiration.

Alveolar Vessels Alveolar vessels are capillaries that are contained within the walls that separate adjacent alveoli. They are surrounded by interstitium that varies in thickness and in the nature and content of cells, collagen, and elastic fibers. The appearance of the alveolar capillaries depends heavily on the route of fixation. Thus, fixation via the airways—which removes the surfactant lining—causes the capillaries to bulge into the alveoli, whereas fixation by perfusion—so that the lung remains air-filled—eliminates these deformations, widens capillaries unnaturally, and does away with alveolar pleats and folds. As the lung expands, alveolar walls unfold, and the connectivetissue elements surrounding them are rearranged. The calibers of the alveolar capillaries depend on the level of lung inflation, and they undergo compression (without change in wall thickness) when alveolar pressures increase. It is clear from the above that impressions of alveolar morphology are meaningful only when full account is taken not only of the route of fixation but also of the way in which the lung was handled during fixation. As the lungs expand, largely because of the surfactant lining of the alveoli, the alveolar pericapillary pressure is less than the alveolar pressure but higher than the pressure surrounding extra-alveolar vessels. This difference between the interstitial pressures to which alveolar and extra-alveolar vessels are exposed is exaggerated at high levels of lung inflation. Corner Vessels Corner vessels (Fig. 80-22) are located at sites where three alveoli abut; there they are contained within pleats in the alveolar walls beneath sharp curvatures in the overlying alveolar film of surfactant. They are neither extra-alveolar vessels (see above)—in that they lack a surrounding sleeve of connec-

tive tissue—nor conventional components of the pulmonary microcirculation. Their location and anatomic arrangement within pleats seem to offer considerable protection against fluctuations in alveolar pressure. Indeed, blood flow persists in these vessels when alveolar pressure exceeds pulmonary arterial pressure by 10 cm H2 O. Originally pictured as arteriovenous anastomoses, they are now viewed as preferential channels through which blood flow continues in the face of wide swings in alveolar pressure. Extra-Alveolar Vessels Extra-alveolar vessels are, by definition, small vessels that are not affected by changes in alveolar pressure but do enlarge during lung inflation (Fig. 80-22). The definition is far more precise for physiologists than for anatomists, since the designation extra-alveolar vessel appears to include diverse components of the pulmonary microcirculation—notably veins, venules, arteries, and precapillaries. Despite the morphologic diversity, the key to the physiological behavior of the extra-alveolar vessels appears to be the connective-tissue sheath that they share. Surrounding the extra-alveolar vessels is an interstitial space that is bounded by extensions of the fascial sheaths that envelop the trachea and esophagus. Within the perivascular interstitial space lies loose areolar tissue, collagenous fibers, and lymph vessels that drain lymph from the lung parenchyma; in pulmonary edema, excess fluid (and protein) accumulates within this space. The sheaths extend farther peripherally along the pulmonary arteries than the bronchi; for pulmonary arteries, and probably for pulmonary veins, the perivascular sheaths continue peripherally to vessels on the order of 100 µm in diameter. Dilatation of extra-alveolar vessels during inflation is a consequence of a drop in the surrounding interstitial pressure.

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Figure 80-23 Blood flow in the upright lung as a function of vertical height. (Based on data from Glazier JB, Hughes JMB, Maloney JE, et al: Measurements of capillary dimensions and blood volume in rapidly frozen lungs. J Appl Physiol 26:65–76, 1969, with permission.)

The degree to which extra-alveolar vessels widen during inflation depends on their initial calibers which, in turn, vary with lung volume. During deflation to levels below functional residual capacity (FRC), small arteries and veins tend to close, possibly because of inherent vascular tone abetted by alveolar hypoxia in the poorly expanded regions. At this time, the site of maximum resistance to blood flow shifts proximally in the arterial tree. Effects of Gravity A variety of techniques have been used to test the influence of gravity on the topographic distribution of blood delivered to the lungs. Among these have been the intravenous injection of a polysoluble gas (e.g., xenon), the inhalation of a very soluble gas (e.g., carbon dioxide), and the intravenous injection of microaggregated albumin, followed by radiographic determination of the distribution of radioactivity. Although interpretation of the results of these different methods is often complicated by individual peculiarities of the techniques, coupled with the different types of information that they provide, the results do suggest that in the upright lungs, blood flow decreases steadily from the bottom to the top (Fig. 80-23), that gravity is the compelling force, and that there is an interplay among pulmonary arterial, alveolar, and pulmonary venous pressures. As a consequence of these influences, in a relaxed, seated subject—particularly one with an elongated thorax— the apices are apt to be poorly perfused, especially in states of pulmonary hypotension or increased alveolar pressure.

Interplay among Pressures Influencing Vascular Calibers In 1960, Banister and Torrance, in West, demonstrated that the level of alveolar pressure could influence pressure-flow relationships in the pulmonary circulation and drew an analogy between the behavior of the pulmonary arterial, pulmonary venous, and alveolar pressures and that of a Starling resistor (Fig. 80-24). The crucial point of their demonstration was that when alveolar pressure (chamber pressure) exceeded venous (downstream) pressure, the driving pressure bee arterial minus alveolar pressure and not arterial minus venous pressure. Permutt and colleagues compared this behavior to that of a waterfall, where height does not influence the flow of water over its brink. Zones of the Lungs Recognition of the effects of alveolar pressure on pressureflow relationships in the pulmonary circulation, coupled with the formulation of the behavior of pulmonary microvessels in terms of the Starling resistor, paved the way for a model of the topographic distribution of blood flow in the lungs under the influence of gravity. As a result, it is now common to use “zones” of blood flow in the lungs as operative shorthand for specifying the interplay of pulmonary arterial, alveolar, and pulmonary venous pressures (Fig. 80-25). In the normal, upright lung (estimated height of 25 cm at FRC), about 15 cm is above the left atrium and about 10 cm is below. Assuming that the mean pulmonary arterial pressure Figure 80-24 Principle of a Starling resistor. Thin-walled collapsible tube traverses a closed chamber (A) in which pressure can be varied at will. Fluid flows from reservoir (R ) into collecting vessel (striped area), traversing collapsible tube en route. When outflow pressure exceeds chamber pressure (left), flow is determined by difference between inflow and outflow pressure. However, when chamber pressure exceeds outflow pressure, so that collapsible tube closes (arrow), flow is determined by difference between inflow and chamber pressure. (From West JB, Dollery CT: Distribution of blood flow and the pressure-flow relations of the whole lung: J Appl Physiol 20:175, 1965, with permission.)

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Figure 80-25 Zones of the lung. Topographic distribution of pulmonary blood flow according to relationship among pulmonary arterial pressure (Ppa), pulmonary venous pressure (Ppv), and alveolar pressure (P A ). Because of effect of surface tension, P A is more accurately pericapillary pressure. Zone 1 (apex): P A > Ppa > Ppv. There is no flow (except through corner vessels) because collapsible vessels close when pericapillary pressure exceeds the pressure inside the vessels. Vessels that close are capillaries and other alveolar vessels up to ∼30 m in diameter. Zone 2: Ppa > P A > Ppv. Driving pressure is Ppa – P A . This difference increases down lung, and so does flow. Zone 3: Ppa > Ppv > P A . Driving pressure is Ppa – Ppv. Although Ppa – Ppv does not change down lung, Ppa and Ppv continue to increase from top to bottom. Flow down zone 3 is less than in zone 2. Zone 4 (appears at residual volume): This region of decreased flow appears during forced exhalation and has been attributed to either an increase in interstitial pressure at lung bases or closure of small airways at low lung volumes as the increase in P A creates either zone 1 or zone 2 conditions. (From West JB, Dollery CT: Distribution of blood flow and the pressure-flow relations of the whole lung: J Appl Physiol 20:175, 1965, with permission.)

measured at the level of the left atrium is around 15 cm H2 O and that left atrial pressure is about 7 cm H2 O, the top few centimeters of the lung will be hypoperfused during most of the cardiac cycle, except for flushes of blood during the peak ejection phase of systole. This zone has been designated as zone 1. In the next-lower zone (zone 2), blood flow increases regularly with distance down the lung. Below zone 2 is another zone of increasing blood flow, zone 3. Finally, a zone 4 may exist near the base; in this zone, blood flow decreases instead of increases. In this zone, although most alveolar capillaries appear to be attenuated or collapsed, extra-alveolar vessels in the alveolar corners often remain open, once again emphasizing that the extra-alveolar vessels are exposed to different forces than are the alveolar vessels. As noted previously, persistence of blood flow through parts of zone 1 presumably occurs via (corner) vessels.

flow pressure is alveolar pressure and the driving force is the pulmonary arterial-alveolar pressure difference. This hemodynamic situation, in which flow is independent of downstream pressure, has been likened to a “vascular waterfall.” Under the influence of gravity, the pulmonary arterial pressure increases by about 1 cm H2 O per centimeter of distance down the lung, whereas alveolar pressure remains unchanged; the driving pressure and, therefore, the blood flow increase down the zone. Changing relationships between alveolar and luminal pressures then shift outflow pressures from alveolar to pulmonary venous and then back. Flow through the capillaries of zone 2 is pictured as intermittent, as through “sluice gates” that open when pulmonary venous pressures exceed alveolar pressures and close when alveolar pressures exceed pulmonary venous pressures. Zone 3

Zone 1

In the vertical lung, blood flow in zone 1, where alveolar pressure exceeds arterial pressure (PA > Ppa), is minimal (Fig. 80-25). The apices of upright lungs would be deprived of pulmonary blood flow were it not for the pulsatility of pulmonary arterial blood flow; a flush of blood during systole perfuses the apices even though mean pulmonary arterial pressure is too low to sustain blood flow to the apices. Zone 2

In zone 2, pulmonary arterial pressure exceeds alveolar pressure which, in turn, exceeds pulmonary venous pressure (Ppa > PA > Ppv) (Fig. 80-25). In this constellation of pressures, blood flow is no longer determined by the usual pressure drop across the pulmonary circulation. Instead, the out-

It is only in this zone that conventional calculations of PVR are valid: since pulmonary venous pressure is greater than alveolar pressure (Ppa > Ppv > PA ), blood flow is determined by the arteriovenous difference in pressure (since both exceed alveolar pressure) (Fig. 80-25). Resistance to blood flow in zone 3 is less than in zone 2. The driving pressure here remains fixed down to the bottom of the lung because the effect of gravity causes arterial and venous pressures to decrease equally per centimeter of distance as the lung base is approached. Despite the constant driving pressure, flow increases toward the bottom of the lung as resistance decreases. In contrast to zone 2, where the increase in blood flow from top to bottom of the zone is predominantly due to recruitment of vessels that were previously closed in zone 3, a comparable increase in blood flow is effected largely by distention of patient microvessels (i.e., capillaries).

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Zone 4

The upright lung includes in its most dependent part, where vascular pressures are highest, an area of decreased blood flow (Fig. 80-23). The zone of reduced flow (zone 4) disappears on deep inflation. This paradox of high vascular pressures and low blood flow is not explicable in terms of the three-zone model, in which pulmonary arterial and pulmonary venous pressures are related to alveolar pressures in predicting distribution of blood flow. The mechanism is believed to reside in the extra-alveolar rather than in the alveolar vessels. Indeed, at residual volume, owing to the increase in perivascular pressure and mechanical distortion of extra-alveolar vessels, the distribution of blood flow throughout the lung is attributable to extra-alveolar vessels. It is worth emphasizing that zones are a functional rather than an anatomic concept; instead of being fixed topographically, they vary in vertical height according to shifts in the relationships between pulmonary arterial, pulmonary venous, and alveolar pressures. For example, positive-pressure breathing enlarges zone 2 at the expense of zone 3, and zone 1 at the expense of zone 2. Awareness of the functional nature of these relationships affects the interpretation of changes in calculated PVR; for vessels in zone 2, because alveolar pressure rather than pulmonary venous pressure is the outlet pressure, the conventional calculation of PVR is meaningless; oppositely, for vessels in zone 3, the calculation is meaningful because pulmonary venous pressure rather than alveolar pressure determines the quantity of blood flow. A change in body position reorients the zones of the lungs. For example, the supine position places more of the lung in zone 3 and virtually eliminates zone 1 (Fig. 80-25).

Effects of Inflation It was pointed out above (“Pulmonary Vascular Resistance”) that at either very high or low levels of lung inflation—no matter how accomplished—PVR increases. Inflation of the collapsed, isolated lung with negative pressure first decreases resistance and then increases resistance as high levels of inflation are reached. These observations can be reconciled by attributing the high resistance at high levels of inflation (alveolar pressure held constant) to narrowing of alveolar capillaries and the high resistance during lung collapse to closure, narrowing, and kinking of alveolar capillaries and extra-alveolar vessels. Distention and Recruitment The extent of the alveolar capillary network is quite variable, and the number, size, and shape of the open capillaries depend on the method of fixation for histological examination as well as on the experimental circumstances. But some uncertainty still persists about the relative roles played by recruitment (opening of new capillaries) or distention (increase in the caliber of patient capillaries) in enlarging the capillary network. Not very long ago, pulmonary capillary distention was discounted, largely on the basis of extrapolation from the behavior of systemic capillaries. However, attempts to draw

analogy between the distensibility of systemic and pulmonary capillaries appear predestined to fail because pulmonary capillaries are suspended in a sea of air and not embedded in tissue. Indeed, it has now been amply shown that pulmonary vascular calibers do increase appreciably as transmural pressures are raised. But it has also become evident that the relationship between vascular calibers and transmural pressure is far from simple. Moreover, there is no consensus about the extent to which the alveolar capillary bed is distensible. How recruitment is affected remains unsettled. When blood flow is minimal (as in zone 1), only a few capillaries are open; these are predominantly “corner vessels” lodged within septal pleats. As transmural pressures increase, the extent of the open capillary bed enlarges, primarily by recruitment in zone 2 and by dilatation in zone 3. Some believe that as pulmonary arterial pressure increases, critical opening pressures of different arterioles are successively overcome to open new arteriolar domains to blood flow. Others favor the view that capillaries control their own destinies—i.e., that capillaries per se, rather than arterioles, are responsible for opening new portions of the capillary bed, and that both distensibility and recruitment occur at the capillary level. Despite lingering doubts about the mechanisms at work in the operation of recruitment and distensibility under different conditions, a few generalizations can be made: (1) pulmonary capillaries are more distensible than systemic capillaries, presumably owing to the lack of supporting connective tissue in the lung; (2) both recruitment and distensibility are more affected by changes in pulmonary arterial than in pulmonary venous pressure; and (3) recruitment is the predominant mechanism for enlarging the capillary bed in the apices of the lungs in response to pulsatile flow, whereas recruitment and distensibility probably both contribute—although to different degrees, depending on the circumstances—in the more dependent parts of the lungs.

THE BRONCHIAL CIRCULATION Although popular usage has firmly entrenched the designation bronchial, the term is inadequate on two accounts: (1) the systemic blood supply to the lungs originates not only from bronchial arteries but also from the aorta and other intrathoracic arteries, and (2) the systemic arterial blood is delivered not only to the walls of the bronchi but also to the adventitia or large vessels and structures of the lungs. In the normal lung, the bronchial circulation has the features of a nutrient circulation: it is modest in size (1 to 2 percent of the cardiac output), carries arterialized blood, and is distributed primarily to the airways, blood vessels, and supporting structures of the lungs up to the respiratory bronchioles. Beyond this point, the pulmonary circulation takes over as the nutrient circulation. One likely function of the bronchial circulation is to air-condition the inspired air. For example, the disposition and architecture of the submucosal bronchial venous plexus seem to constitute an anatomic arrangement that could properly adjust the temperature and

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water content of air passing to and fro in the airways. The nutrient function also comes into play in lung transplantation, where survival of the graft depends critically on an adequate blood supply. Venous return from the bronchial circulation is via either bronchial or pulmonary veins. From the hilar structures and large bronchi, bronchial venous blood is returned to the right atrium via systemic veins; from more peripheral airways and the substance of the lung, bronchial venous blood is returned to the left atrium by two routes: via bronchopulmonary capillary anastomoses and by “bronchopulmonary veins” that connect bronchial capillaries to small pulmonary veins. The direction taken by bronchial venous outflow is determined by the relative pressures at the outlet of the two systems. For example, an increase in left atrial pressure detours bronchial venous drainage toward the right, rather than the left, atrium. In some animals, functioning communications exist not only between the bronchial and pulmonary capillary circulations but also between the bronchial arteries and other systemic arteries. Certain features of the bronchial circulation merit special attention: (1) although difficult to demonstrate and of doubtful functional significance, microscopic anastomoses between bronchial and pulmonary arteries do appear to exist at the precapillary level in the normal lung; (2) the bronchial arteries proliferate remarkably in certain types of lung disease, liver disease, and congenital heart disease, often in association with clubbing of the digits; (3) the mechanisms responsible for the proliferation of the bronchial circulation are unclear, but certain influences, such as cortisone, retard its expansion, whereas growth hormone stimulates it; (4) the bronchial veins in the submucosa of the airways form a large plexus that runs the entire length of the tracheobronchial tree, sending off communicating branches to a corresponding venous plexus on the other side of the tracheal muscle; (5) the bronchial venules respond to certain vasoactive agents, notably histamine and bradykinin, as do other systemic venules; and (6) the bronchial venous circulation is involved in the pathogenesis of experimental pulmonary edema produced in the dog and sheep by histamine, endotoxin, and bradykinin.

The Bronchial Circulation in Disease In the normal lung, the minute bronchial circulation operates covertly. But if the pulmonary circulation to an area is compromised or lost—as by ligation or an embolus—the bronchial circulation proliferates far beyond local metabolic need for viability and function (Fig. 80-26). The stimulus for proliferation is unclear. Expansion of the bronchial arterial circulation is clinically marked in two major categories of disease: (1) those producing severe curtailment of pulmonary atresia and (2) a chronic inflammatory bronchopulmonary process, such as bronchiectasis, old inflammatory cavities, chronic lung abscess, and lung cancer. Because clubbing of the digits, occasionally accompanied by hypertrophic osteoarthropathy, is also common in these disorders, question is often raised about the relationship between clubbing of the digits and expansion of the collateral circulation to the

The Pulmonary Circulation

Figure 80-26 Schematic representations of bronchial circulation in bronchiectasis and right ventricular failure. Top: Bronchial arteries (BA). In chronic suppurative diseases of the lungs, bronchial arteries undergo considerable proliferation. Bottom: Bronchial veins (BV). Proximal bronchial veins drain into either the right atrium (RA) or left atrium (LA), depending on pressure levels in these two cardiac chambers. Normally most bronchial venous outflow from the lungs enters the right atrium (thicker curved arrow). However, in right ventricular failure, bronchial venous drainage to the left atrium increases.

lungs. In contrast to the disorders of the lungs associated with bronchial arterial blood is chronic mitral stenosis, in which hemoptysis usually originates from bronchial veins underlying the tracheobronchial mucosa. An expanded bronchial arterial circulation can also constitute a hemodynamic burden (a left-to-right shunt). But rarely, as in widespread bronchiectasis, do the connections between the bronchial and pulmonary arteries enlarge sufficiently to cause cardiac embarrassment. If a wedged pulmonary arterial catheter lodges in the vicinity of bronchopulmonary arterial anastomoses, the pulmonary-wedge pressure is apt to be misleading. As noted above, bronchial venous blood that drains into the left atrium contributes to anatomic venous admixture. Another source of anatomic venous admixture occurs in some patients with cirrhosis of the liver, in whom abnormal anatomic connections allow the passage of portal venous blood into the pulmonary venous system. Occasionally, in a patient with hepatic cirrhosis, the portalpulmonary blood flow becomes quite extensive (about 5

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to 15 percent of the cardiac output). These anastomotic channels occasionally enlarge sufficiently to be demonstrable during life with use of indicators or angiography. More often, the quantity of blood shunted from the portal to pulmonary venous system is too small to be measured reliably. Since primary carcinoma of the lungs often receives much of its blood supply from systemic arteries, particularly if the neoplasm obstructs blood flow to the pulmonary artery, attempts have been made to deliver chemotherapeutic agents to the cancerous site via a bronchial artery. This approach has proved ineffective. Also, in patients in whom life-threatening hemoptysis complicates a carcinoma of the lungs, particulate matter has been injected as bronchial arterial emboli in the hope of occluding the feeder bronchial artery. Unfortunately, selective embolization is, at best, only transiently effective.

THE FETAL AND NEONATAL PULMONARY CIRCULATIONS Before birth, the lungs play no role in gas exchange; this function is served by the placenta. For the sake of their nutrition and role as a metabolic organ, the lungs are provided with a modest blood flow, and most of the blood returning to the right side of the heart is directed toward the systemic circulation via the foramen ovale and ductus arteriosus. As a result of this diversion, the lungs before birth receive about 10 to 15 percent of the right ventricular output. After birth, as the lungs assume gas-exchanging functions and fetal connections close, the entire output of the right ventricle perfuses the lungs. In the fetus approaching term, pulmonary arterial and aortic pressure levels are virtually identical; during gestation, blood pressures in both circuits increase in parallel, while pulmonary blood flow increases dramatically. At the same time, PVR decreases progressively as the number of minute vessels increases. Near term, the small muscular arteries, which constitute the â&#x20AC;&#x153;resistanceâ&#x20AC;? vessels, are well endowed with smooth muscle. After birth, the media of the small muscular arteries regress rapidly. However, prolonging hypoxia, as by exposing the newborn to a continued decrease in inspired Po2 for 2 weeks, not only retards the normal involution of pulmonary vascular smooth muscle but also leads to the development of new muscle in peripheral precapillary vessels that would otherwise be expected to be devoid of muscle.

Regulation of the Fetal Pulmonary Circulation Compared to the adult pulmonary circulation, the fetal circulation affords much more vascular resistance, a higher initial tone, and, as has been noted above, a greater vascular reactivity; reactivity increases with gestational age.

Also, in contrast to the adult pulmonary circulation, the fetal pulmonary circulation manifests a considerable reactive hyperemia. The three categories of endothelial-derived substances (prostaglandins, endothelins, and NO) play an important role in regulating fetal and transitional pulmonary vascular tone. Disturbances in their interplay may culminate in persistent pulmonary hypertension of the newborn. It seems likely, however, that other mediators as well as abnormal developmental changes, entailing growth of vascular smooth muscle and the extracellular matrix, are involved in failure after birth of normal involution of the fetal circulation.

Postnatal Pulmonary Vasodilation Ventilation of the lungs with air causes a marked drop in PVR. Two factors are concerned: predominant is the increase in Po2 ; a much lesser role is played by physical expansion of the lungs. The mechanism by which relief of hypoxia exerts its vasodilator effect in the fetus is not settled. However, the prostaglandins seem to play a key role. This prospect stems from two types of observations: (1) distention of the lungs of adult animals results in the release of prostaglandins, particularly those of the E series; and (2) indomethacin blunts the continued drop in PVR that would be expected to continue for 10 to 20 min after the initial fall. Moreover, in the fetus, prostaglandin synthetase inhibitors enhance the pulmonary pressor response to acute hypoxia. The role of other vasodilators (e.g., NO) remains to be defined. Attention has been called repeatedly in this section to the marked reactivity of the fetal pulmonary circulation. The purposes served by the marked pulmonary vasoreactivity are not certain. But since the increase in fetal PVR does direct the bulk of the pulmonary arterial inflow to the placenta, brain, and myocardium, the capability for marked pulmonary vasodilatation may be importantly involved in the circulatory rearrangements after birth. Fetal hypoxia, no matter how induced, elicits intense pulmonary vasoconstriction. The magnitude of the response increases as gestation advances, consistent with the idea that pulmonary vascular smooth muscle grows increasingly responsive to hypoxia as gestation advances. In contrast to that in the adult, the sympathetic nervous system contributes significantly to initial tone and to the pressor response to acute hypoxia. As in the adult, acidosis elicits pulmonary vasoconstriction and greatly enhances the pulmonary pressor response to acute hypoxia; the more severe the acidosis, the greater the pressor and enhancing effects.

The Ductus Arteriosus Despite its embryologic origin (as the distal segment of the left sixth aortic arch) and its location as a bridge between the pulmonary artery and the descending aorta, the ductus arteriosus leads a vasomotor life of its own, independent of the two circulations that it bridges (Fig. 80-27). For example, immediately after birth (i.e., at the switch from the hypoxic

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Figure 80-27 Relationship between ductus arteriosus and systemic vessels and the aorta. Acute hypoxia constricts pulmonary arteries but dilates the ductus arteriosus and systemic arteries.

environment in utero to the air-filled, oxygen-rich environment of independent neonatal life), the ductus arteriosus contracts vigorously to the point of self-obliteration of its lumen; at the same time, the pulmonary circulation vasodilates. Closure of the ductus arteriosus immediately after birth depends heavily on prostaglandins in its walls. Conversely, premature closure of the ductus arteriosus (i.e., before birth), as may be caused by transplacental passage of indomethacin taken by the mother, may either cause fetal pulmonary arterial hypertension or interfere with the morphologic development of the pulmonary vascular bed. The vasomotor responses of the ductus arteriosus to prostaglandins and to inhibitors of the cyclooxygenase pathway have been turned to clinical advantage: on the one hand, PGE2 or PGE1 has been used to maintain patency of the ductus arteriosus in newborns and in patients with congenital heart disease, who need continued communication between the pulmonary and systemic circulations; on the other hand, indomethacin, an inhibitor of the prostaglandin synthetase element of the cyclooxygenase pathway, has been used to promote closure of a persistent ductus arteriosus in premature infants.

ABNORMAL PULMONARY VASCULAR COMMUNICATIONS

The Pulmonary Circulation

Acquired Communications Acquired systemic artery-pulmonary communications are much more common than congenital communications. Most are traumatic or iatrogenic and hemodynamically constitute a left-to-right shunt between an intrathoracic systemic artery (coronary, intercostal, or internal mammary) and the pulmonary circulation. Because of the large pressure gradient, flow through such connections can be large, but rarely sufficient to cause left ventricular failure. The characteristic physical finding is a continuous murmur over the site of communication and radiographic evidence either of the vessels operative in the communication (e.g., enlarged pulmonary vessels) or of adjacent local effects (e.g., pleural thickening). Selective angiography reveals the nature of these communications. Rarely does cardiac overload due to left ventricular failure become manifest. Instead, most patients remain asymptomatic. Other acquired systemic artery-pulmonary vascular communications may complicate intrathoracic neoplasms or chronic inflammatory disorders. Their predominant clinical importance lies in the risk of brisk bleeding. Bronchiectasis is the most common cause of bleeding from such communications. If extensive, bronchial artery-pulmonary arterial inflow may replace pulmonary arterial blood in perfusing an affected lobe or an entire lung. Bronchopulmonary Sequestration Bronchopulmonary sequestration refers to a part of the parenchyma of the lung that has either incomplete or no connection with the airways and is supplied by an aberrant artery from the aorta or one of its branches. Sequestrations are further categorized as either intra- or extralobar: intralobar sequestrations have the same pleural covering with the adjacent lung, whereas extralobar sequestrations have their own pleural lining (i.e., separate from that of adjacent lung tissue). Embryology

Bronchopulmonary sequestrations are held to be developmental abnormalities of the embryonic foregut. In this respect, they resemble bronchogenic cysts. Sequestration is believed to begin in an accessory lung bud that originates distal to the normal lung bud. Whether the sequestration will be intralobar or extralobar appears to depend on the stage of embryologic development at which this anomaly occurs: if the accessory bud forms before the pleura is formed, the bud remains within the pleura and results in an intralobar sequestration; if it forms after the pleura has formed, it causes an extralobar sequestration that is covered by its own pleura. Both types of sequestrations, but particularly extralobar sequestrations, are often associated with other congenital anomalies of the foregut.

Systemic Artery-Pulmonary Vascular Communications

Clinical Manifestations

Communications between a systemic artery and the pulmonary circulation may be acquired or congenital.

Bronchopulmonary sequestration is suspected in a patient with recurrent infiltrates about a single chronically affected

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area containing cystic spaces in a basilar segment of a lower lobe. A clue to the diagnosis may be provided by the presence of a continuous bruit over the chest or axilla on the afflicted side due to shunting of blood from systemic artery to pulmonary vein in the intralobar sequestration.

CONGENITAL PULMONARY ARTERIOVENOUS COMMUNICATIONS Congenital pulmonary arteriovenous communications between the pulmonary arteries and veins can occur as lesions confined to the lungs or as part of the entity hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber disease). In hereditary hemorrhagic telangiectasia, about 15 percent of affected family members have pulmonary arteriovenous fistulas, although about 50 percent of patients with pulmonary arteriovenous fistulas have evidence of other mucocutaneous telangiectases or a family history of hereditary hemorrhagic telangiectasis. Pulmonary arteriovenous fistulas are local lesions that do not disturb the adjacent pulmonary tissue (i.e., there is no associated atelectasis, bronchiectasis, or pneumonia). Generally, the pulmonary artery supplies all the afferent blood, although occasionally, when it occurs in association with hereditary hemorrhagic telangiectasia, some of the afferent supply may be from a bronchial artery or from other systemic arteries. The lesions are multiple in one-third of the cases and are most frequently found in the lower lobes adjacent to the visceral pleura, although they can also be deep in the parenchyma. Grossly, the lesions appear as thin-walled aneurysmal sacs connecting the artery and the vein. Thrombotic masses may be present within the aneurysmal sac. Microscopically, the sac walls contain various amounts of muscle, fibrous tissues, and occasionally small amounts of calcium. The pulmonary arteriovenous fistulas act as bypass routes, allowing mixed venous blood to escape arterialization in the lungs. Despite the hypoxic stimulus, pulmonary hypertension has not occurred; however, the chronic arterial hypoxemia does evoke erythrocytosis and polycythemia.

Clinical Manifestations Most patients with pulmonary arteriovenous fistulas are asymptomatic and come to medical attention because of an abnormal shadow found on routine radiography; some complain of dyspnea. Epistaxis is present in 50 percent of patients, usually in association with hereditary hemorrhagic telangiectasia. These patients may also have gastrointestinal bleeding, strokes, brain abscesses, or seizures. Most cases are diagnosed in the third or fourth decade of life. On physical examination, the relatively few patients with dyspnea usually are cyanotic and clubbed. One-third of all patients with pulmonary arteriovenous fistulas also

have mucocutaneous telangiectases. A characteristic feature of pulmonary arteriovenous fistula is an extracardiac murmur or bruit. Because pulmonary blood flow increases during inspiration, the intensity of the murmur increases during inspiration and decreases during expiration. Similarly, the Valsalva maneuver, by transiently decreasing pulmonary blood flow, decreases flow through the fistula and decreases or eliminates the murmur. As expected, the MÂ¨uller maneuver (forced inspiration with a closed glottis after full expiration) does the opposite (i.e., increases the murmur). Occasionally, for unexplained reasons, the murmur may be atypical and either increase with expiration or be heard only during diastole. The most important laboratory examination is chest radiography. A solitary fistula takes the form of a coin lesion or a bunch of grapes in the peripheral lung fields (Fig. 80-28). Fewer than 5 percent of pulmonary arteriovenous fistulas contain calcium demonstrable by radiography. Usually, feeding and draining vessels connect the lesion to the hilus. Tomography is useful in demonstrating the continuity of the hilar vessels and the fistula. Fluoroscopy usually demonstrates the pulsating nature of the mass. Angiography is not usually needed to make the diagnosis, but it can be used to demonstrate the vascular nature of the lesion and to determine the exact number of fistulas present. Patients with a significant shunt will have a secondary polycythemia, although if there has been significant bleeding, some patients may actually be anemic. The arterial PO2 is invariably decreased and does not increase appreciably with 100 percent O2 . Local complications of pulmonary arteriovenous fistulas are due to rupture of the aneurysmal sacs, with bleeding either into the bronchi, causing hemoptysis, or into the pleura, where it produces a hemothorax. Thrombosis within the pulmonary arteriovenous fistula is common and is occasionally the cause of bland and septic emboli to the central nervous system. Strokes and seizures may result from telangiectases in the central nervous system.

Differential Diagnosis The radiographic shadows may simulate bronchiectasis, tuberculosis, or other granulomatous disease, solitary pulmonary nodules, or metastatic carcinoma. The murmur or bruit must be differentiated from valvular or congenital heart disease. The cause of the cyanosis may erroneously be attributed to congenital heart disease. The normal white blood count, platelets, and spleen help to identify the polycythemia as secondary to hypoxia and not to polycythemia vera.

Treatment The only available treatment for pulmonary arteriovenous fistulas is excision. Because of the vascular nature of the lesion, wedge resection and lobectomy have been the procedures of choice. Since adjacent lung parenchyma is normal, an attempt is made to preserve as much lung as possible. However, because as many as one-third of the patients have

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Figure 80-28 Pulmonary arteriovenous fistulas in a pregnant 24-year-old woman with hereditary hemorrhagic telangiectasia. A. Before pregnancy. Small, nodular densities are seen at both bases and in the left hilus. The shunt was estimated to be 49 percent of the cardiac output. B . Arteriogram before pregnancy, demonstrating arteriovenous fistulas of both lower lobes. C . Seven months pregnant, the patient was admitted to the hospital with hemoptysis and left hemothorax. The enlargement of the arteriovenous fistulas is striking. The pregnancy was terminated. D . Two weeks after termination of pregnancy. The nodular densities have decreased in size. (Courtesy of M. Rossman.)

multiple fistulas, recurrence is possible after surgery. Therefore, in all patients with cyanosis and polycythemia, hemoptysis, or rapidly increasing lesions for whom surgery is considered, preoperative pulmonary arteriogram is necessary so that all the fistulas can be identified. Generally, all symptoms due to the pulmonary arteriovenous fistulas are reversed if surgery is successful.

Prognosis Because the anomaly is uncommon, the natural history is not well understood. Whereas some pulmonary lesions enlarge rapidly, others remain stable or enlarge slightly over a period of years. Serious complications are just as likely to be pulmonary (hemoptysis or hemothorax in about 10 percent) as neurologic (about 10 percent).

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SUGGESTED READING Abenhaim L, Moride Y, Brenot F, et al: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335:609–616, 1996. Barman SA, Pauly JR: Mechanism of action of endothelin-1 in the canine pulmonary circulation. J Appl Physiol 79:2014– 2020, 1995. Chen S-J, Chen Y-F, Meng QC, et al: Endothelin–receptor antagonist bosentan prevents and reverses pulmonary hypertension in rats. J Appl Physiol 79:2122–2131, 1995. Eddahibi S, Adnot S: Anorexigen-induced pulmonary hypertension and the serotonin (5-HT) hypothesis: Lessons for the future in pathogenesis. Respir Res 3:9, 2002. Fishman AP: Hypoxia on the pulmonary circulation: How and where it acts. Circ Res 38:221–231, 1976. Herve P, Launay JM, Scrobohaci ML, et al: Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249–254, 1995. Luscher TF, Wenzel RR: Endothelin and endothelin antagonists: Pharmacology and clinical implications. Agents Actions Suppl 45:237–253, 1995. Lynn RJ: Inhaled nitric oxide therapy. Mayo Clin Proc 70:247– 255, 1995.

MacLean MR, Herve P, Eddahibi S, et al: 5-hydroxytryptamine and the pulmonary circulation: Receptors, transporters and relevance to pulmonary arterial hypertension. Br J Pharmacol 131:161–168, 2000. Marshall BE, Hanson CW, Frasch F, et al: Role of hypoxic pulmonary vasoconstriction in pulmonary gas exchange and blood flow distribution. Intensive Care Med 20:291– 297, 379–389, 1994. Naeije R, Eddahibi S: Serotonin in pulmonary arterial hypertension. Am J Respir Crit Care Med 170:209–210, 2004. Weir EK, Archer SL: The mechanism of acute hypoxic pulmonary vasoconstriction: The tale of two channels. FASEB J 9:183–189, 1995. Weir EK, Archer SL, Reeves JT: Nitric Oxide and Radicals in the Pulmonary Vasculature. Armonk, NY, Futura Publishing, 1996. West JB, Mathieu-Costello O: Stress failure of pulmonary capillaries as a limiting factor for maximal exercise. Eur J Appl Physiol 70:99–108, 1995. Yamaguchi K, Asano K, Takasugi T, et al: Modulation of hypoxic pulmonary vasoconstriction by antioxidant enzymes in red blood cells. Am J Resp Crit Care Med 153:211– 217, 1996. Ziegler JW, Ivy DD, Kinsella JP, et al: The role of nitric oxide, endothelin, and prostaglandins in the transition of the pulmonary circulation. Clin Perinatol 22:387–403, 1995.

81 Pulmonary Hypertension and Cor Pulmonale Darren B. Taichman

Alfred P. Fishman

I. GENERAL ASPECTS Pulmonary Hypertension Cor Pulmonale II. CLASSIFICATION OF THE PULMONARY HYPERTENSIVE DISEASES III. PATHOLOGICAL CHANGES IN PULMONARY HYPERTENSION Anatomic Alterations Histopathological Changes Pathobiologic Mechanisms Vasoconstrictive Mechanisms Mechanisms of Idiopathic Pulmonary Arterial Hypertension IV. CLINICAL EVALUATION OF PULMONARY HYPERTENSION Patient History in Pulmonary Hypertension and Cor Pulmonale Physical Examination Diagnostic Studies

GENERAL ASPECTS Pulmonary Hypertension Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than 25 mmHg at rest, or greater than 30 mmHg with exercise. Pulmonary hypertension can be due to diseases predominantly confined to the pulmonary vasculature, as in pulmonary arterial hypertension, or can occur in association with diseases in which the primary disturbance is in respiratory function or in the left heart. Disturbances of respiratory function that cause pulmonary hypertension include

V. GENERAL ASPECTS OF DISEASE MANAGEMENT Exercise and the Avoidance of Deconditioning Oxygen Therapy Infection Fluid Management and Diuretics Digitalis and Theophylline Dysrhythmias Pulmonary Vasodilators in non-PAH Forms of Pulmonary Hypertension Phlebotomy VI. EPIDEMIOLOGY AND TREATMENT OF INDIVIDUAL PULMONARY HYPERTENSIVE DISEASES Pulmonary Arterial Hypertension Pulmonary Hypertension Associated with Left Heart Disease or with Extrinsic Restriction of Pulmonary Venous Flow Pulmonary Hypertension Associated with Hypoxemic Lung Disease Chronic Thromboembolic Pulmonary Hypertension Cor Pulmonale

parenchymal lung diseases that impair gas exchange and elicit chronic hypoxia (e.g., chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis) and impaired movement of air due to processes outside of the lungs (e.g., impairment of the respiratory muscles or the drive to breathe). Examples of cardiac dysfunction that result in pulmonary hypertension include left ventricular failure due to ischemic cardiomyopathy or mitral valvular stenosis. The generally accepted definition of pulmonary arterial hypertension calls for a mean pulmonary arterial pressure greater than 25 mmHg at rest or 30 mmHg with exercise, a pulmonary capillary occlusion pressure or left ventricular end diastolic pressure that is less than

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15 mmHg, and an increase in pulmonary vascular resistance greater than 3 Wood units (240 dynes/sec/cm−5 ) without significant respiratory or cardiac dysfunction. When the primary pathophysiological derangement appears to originate within the pulmonary circulation without an identifiable risk factor, idiopathic pulmonary arterial hypertension (IPAH) is considered to be present.

Cor Pulmonale Cor pulmonale is an enlargement of the right ventricle due to derangements in the structure or function of the respiratory system (Fig. 81-1). The enlargement may represent hypertrophy or dilation or both. It results from an increase in afterload imposed by pulmonary hypertension. The frequency of cor pulmonale is linked to the diseases that cause pulmonary hypertension (e.g., chronic obstructive pulmonary disease, interstitial lung diseases, sleep-disordered breathing). Cor pulmonale accounts for as many as 20 percent of hospital admissions for heart failure and for a significant proportion of all cardiac disease.1 It may occur acutely, following a pulmonary embolus or an acute exacerbation of chronic obstructive pulmonary disease. Cor pulmonale may reverse readily after treatment of the precipitating problem. Cor pulmonale is a complication of pulmonary hypertension. Treatment is directed at the process that caused the pulmonary hypertension.

CLASSIFICATION OF THE PULMONARY HYPERTENSIVE DISEASES Table 81-1 presents a current clinical classification of the pulmonary hypertensive diseases. This classification has evolved over the years. In the current classification, the group of patients formerly designated as “primary pulmonary hypertension” is demarcated from the group with known causes (e.g., due to chronic disease of the left heart or to hypoxic pulmonary disease). Sclerosis of the pulmonary arteries (Uber sklerose der lungen arterie) without identifiable cause was first described by Ernst von Romberg in 1891.2 Thereafter, until the 1950s, when cardiac catheterization was widely adopted for hemodynamic studies, Dresdale, Schultz, and Michtom described a hypertensive vasculopathy of the pulmonary circulation that involved pulmonary vasoconstriction, high pulmonary arterial pressures, and a pulmonary vasodilator response to injection of an agent that had been used as a systemic vasodilator (tolazoline).3 No cause for the pulmonary hypertension could be identified and the term primary pulmonary hypertension (PPH) was coined. Subsequent classifications schemes for diseases causing pulmonary hypertension have been adopted by international consensus panels. Current classifications have evolved from systems based primarily on histopathological findings to a

model that relies on hemodynamic and clinical characteristics (Table 81-1). In this classification, the group of patients with pulmonary arterial hypertension (PAH) is separate from the group with known causes of pulmonary hypertension (e.g., due to chronic left heart or respiratory disease and hypoxia). This grouping recognizes similarities in the histological and many clinical features of patients with identifiable genetic causes of PAH (i.e., those with familial PAH), collagen vascular or other diseases known to be associated with PAH (associated PAH), and patients in whom no known associated entity or genetic cause has been found. This last group is referred to as having idiopathic PAH (IPAH), in place of the previously (and often loosely) used term primary pulmonary hypertension (PPH). Abandonment of the term primary is important as a means of discouraging use of the confusing and clinically inappropriate term secondary pulmonary hypertension. Use of such “primary” and “secondary” groupings may inappropriately suggest clinical similarities among the many very different diseases previously referred to as secondary PH (e.g., between patients with COPD and those with congenital heart disease). It may also promote a failure to recognize important similarities in clinical features (including appropriate treatment) between what was previously called primary PH and entities inappropriately labeled secondary (e.g., patients with congenital heart disease or HIV infection).

PATHOLOGICAL CHANGES IN PULMONARY HYPERTENSION Anatomic Alterations The pulmonary vasculature reacts to chronic elevations in pressure in only a limited number of histologically recognizable patterns, regardless of the cause.4,5 Accordingly, the histopathological changes seen are qualitatively similar regardless of the clinical classification of the disease. While quantitative differences occur in the distribution of histological changes between portions of the vasculature, neither the qualitative nor quantitative patterns in individual patients reliably indicates the etiology of the pulmonary hypertension. Indeed, both qualitative and quantitative differences in pathological findings have been noted even between members of the same kindred of patients with familial PAH.6 In the normal lung the muscle in the precapillary arteries thins progressively as the capillary bed is approached. A variety of lesions of these small muscular pulmonary arteries and arterioles can lead to pulmonary hypertension. Some lesions, such as those induced by chronic hypoxia, entail thickening of small muscular arteries and promote peripheral extensions of vascular smooth muscle. Others, such as thrombotic disease, encroach on pulmonary vascular lumens by intimal thickening and clotting. A third category consists of intimal fibrosis at the mouths of small pulmonary arteries, commonly in association with plexiform lesions.

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Figure 81-1 Cor pulmonale in experimental pulmonary arterial hypertension in the dog. A. Normal heart. B . Chronic cor pulmonale secondary to severe pulmonary arterial hypertension. C . Cross section of normal heart to show thin wall of the right ventricular cavity. D . Cross section of heart with chronic cor pulmonale to show hypertrophy of the right ventricular myocardium and enlargement of the right ventricular cavity. (Courtesy of Dr. B. Atkinson.)

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Table 81-1 Clinical Classification of Pulmonary Hypertension∗ Group 1. Pulmonary arterial hypertension (PAH) Idiopathic PAH Familial PAH Associated with (APAH): Collagen vascular disease Congenital systemic to pulmonary shunts (large, small, repaired, or nonrepaired) Portal hypertension HIV infection Drugs and toxins Other (glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Group 2. Pulmonary venous hypertension Left-sided atrial or ventricular heart disease Left-sided valvular heart disease Group 3. Pulmonary hypertension associated with hypoxemia COPD Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Group 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Pulmonary embolism (tumor, parasites, foreign material) Group 5. Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) ∗ Clinical

classification of the pulmonary hypertensive states as adapted at the 2003 World Symposium on Pulmonary Arterial Hypertension in Venice, Italy. Note that the diseases are segregated into “groups” (e.g., group 1 being diseases considered forms of pulmonary arterial hypertension as distinct from group 3 diseases being disorders in which pulmonary hypertension is associated with hypoxic respiratory states. Source: Adapted from Simonneau G, et al: J Am Coll Cardiol 43:5S–12S, 2004; Rubin LJ: Chest 126:7S–10S, 2004.

Anatomic Changes Seen in All Forms of Pulmonary Hypertension All causes of pulmonary hypertension can result in similar derangements of elastic and muscular pulmonary vessels: intimal atheromas, medial hypertrophy, and remodeling of muscular arteries. Intimal atheromas are confined to the elastic pulmonary arteries. Compared with the atherosclerotic changes found in the hypertensive systemic circulation, atheromas in the pulmonary circulation tend to be shallow and nonobstructing.7,8 Similar changes occur in the nonhypertensive pulmonary circulation as part of normal aging, particularly at the branching points of large elastic arteries.

Medial hypertrophy occurs in the muscular and elastic arteries and involves an abnormal increase in smooth muscle cell mass and reduplication of the elastic laminae. Pulmonary hypertension can also cause arterial dilation, which can obscure the changes of medial hypertrophy and, when severe, may compress adjacent airways (causing recurrent pneumonia) or the laryngeal nerve (resulting in hoarseness, the Ortner sign). Persistent pulmonary hypertension, regardless of cause, can lead to the development of cor pulmonale with hypertrophy of the right ventricle, right ventricular dilation, and right ventricular failure (see Fig. 81-1).

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Figure 81-2 Medial hypertrophy. As compared with a normal vessel (A), hypertrophy of smooth muscle cells (arrow) is seen in the pulmonary artery of a patient with pulmonary arterial hypertension (B). Extension of muscle (arrow) into normally nonmuscularized small intra-acinar pulmonary vessels is another prominent feature of pulmonary arterial hypertension (C). (Courtesy of Dr. GG Pietra and reproduced from Taichman DB, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

Histopathological Changes In addition to the changes described above seen in all types of pulmonary hypertension, distinctive histopathological patterns are found in pulmonary arterial hypertension. These patterns include constrictive lesions of the intima, remodeling of the media and adventitia, as well as complex lesions affecting the histological appearance of the entire vessel wall.4,9,10 Constrictive lesions include medial hypertrophy involving an increase in the number and size of smooth muscle

cells. Extension of smooth muscle cells into vessels normally only partially muscularized or nonmuscularized is a common and often prominent feature of precapillary vessels11 (Fig. 81-2). Marked smooth muscle hypertrophy can eventually cause medial atrophy, fibrosis, and the subsequent thinning of the media and dilation of the vessel lumen. Intimal thickening occurs with or without associated medial hypertrophy and in three patterns: concentric laminar, eccentric, and concentric nonlaminar (Fig. 81-3). Concentric laminar intimal thickening is a distinctive lesion composed of onionskin-like

Figure 81-3 Intimal thickening in pulmonary arterial hypertension. A. Concentric laminal intimal thickening (â&#x20AC;&#x2DC;â&#x20AC;&#x2DC; onion skinningâ&#x20AC;?) with marked narrowing of the vessel lumen in a patient with focal fibrosis associated with systemic sclerosis. Nonlaminar intimal thickening can be concentric (B) or eccentric (C). (Courtesy of Dr. GG Pietra and reproduced from Taichman DB, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

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layers of fibroblasts, myofibroblasts, and smooth muscle cells. Although such onion skinning is characteristic of the plexogenic arteriopathy previously thought to be a unique feature of idiopathic (primary) pulmonary arterial hypertension, this finding can be seen in other forms of PAH as well. Intimal thickening may be cellular and may involve fibrosis, and has been referred to as concentric laminar intimal fibrosis (CLIF). Eccentric and concentric nonlaminar intimal thickenings are collections of fibroblasts and connective tissue matrix. They have been described as resulting from the organization of thromboembolic material, although this has not been proved. Eccentric lesions are confined to one segment of the intima, while concentric thickenings obliterate the entire vessel lumen. Complex lesions involve the entire vessel wall and include plexiform and dilation lesions. Although uncommon, the plexiform lesion is so distinctive a finding of the small muscular arteries that pathologists once favored the designation plexogenic pulmonary hypertension as the anatomic hallmark of IPAH12 (Fig. 81-4). However, these lesions are not unique to IPAH since they also occur in the lungs of patients with severe PAH associated with left-to-right cardiac shunts, HIV infection, liver cirrhosis, and scleroderma. Although not pathognomonic, the plexiform lesion has been the focus of many studies of the cellular and molecular pathogenesis of PAH.13−16 They contain collections of proliferating endothelial and smooth muscle cells, together with myofibroblasts and matrix proteins that can partially or completely occlude the vessel lumen. Narrowing or complete obliteration of the parent vessel by intimal thickening is a frequent associated finding, as is destruction of its media. Plexiform lesions often coexist with other obliterative vascular changes such as concentric laminar intimal thickening.5 Dilation lesions are thin-walled vessels frequently occurring distal to plexiform lesions (Fig. 81-4B) and are possibly the site of rupture when pulmonary hemorrhage occurs in patients with PAH.

Figure 81-4 Plexiform and dilation lesions. A. A plexiform lesion (arrow) characterized by small channels of blood and granulation tissue. B. Dilation lesions (arrows) consist of thin-walled sinusoidal channels. Such lesions are found distal to plexiform lesions. (Courtesy of Dr. GG Pietra and reproduced from Pietra GG, et al: J Am Coll Cardiol 43912:25S–32S, 2004.)

Arteritis marked by the infiltration of acute and chronic inflammatory cells within the intima and media can also be found associated with complex lesions and may lead to vessel necrosis. The pulmonary veins can also be affected in pulmonary arterial hypertension (Fig. 81-5). Fibrous tissue occludes veins of various sizes in pulmonary occlusive venopathy (POV), and can appear as loosely organized and edematous or dense and sclerotic fibrous tissue.17,18 The lumen may have multiple channels, and the interstitium populated by large numbers of hemosiderin-laden macrophages. Dilation and fibrosis of the pulmonary lymphatics is another prominent feature of POV. Pulmonary microvasculopathy (PM) is a rare histological pattern marked by angioproliferative lesions. Numerous layers of small vessels containing many erythrocytes occlude capillaries and occasionally invade the surrounding interstitium and airways.19−22 In situ thrombosis of small vessels (both arterial and venous) is frequently noted in all forms of PAH (Fig. 81-6). These occur in the absence of findings to suggest an embolic source of the thrombotic material.23−35 No single histological feature distinguishes between the clinical PAH diagnoses. Each of the arterial and venous changes described can be seen in varying proportions in all clinical forms of PAH. For example, while the pathological designation pulmonary occlusive vasculopathy is the predominant histological finding in the clinical diagnosis of pulmonary veno-occlusive disease, arterial changes are seen in approximately one-half of the patients.26 Similarly, pulmonary microvasculopathy is a pathological term describing the predominant histological findings in patients with the clinical manifestations of pulmonary capillary hemangiomatosis. Widespread pulmonary interstitial disease commonly encroaches on the small pulmonary vessels, compressing and entrapping them in the fibrotic process (Fig. 81-7). In some

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Figure 81-5 Pulmonary obstructive venopathy (POV) and pulmonary microvasculopathy (PM). A. Biopsy from a patient with pulmonary veno-occlusive disease with changes of POV, including the near total obstruction of pulmonary veins lymphatic dilation capillary congestion (black arrows) and the accumulation of hemosiderin-laden macrophages (white arrows). B. Higher power shows obstruction recanalization of a vein together with medial hypertrophy and thickened elastic laminae (white arrow). C. Biopsy from a patient with pulmonary capillary hemangiomatosis revealing capillary proliferation and the accumulation of hemosiderin-laden macrophages (arrows) within the alveoli and interstitium. D. Widened alveolar septa with more than one capillary (arrows) are seen as in an intra-acinar artery with medial hypertrophy (A). (Courtesy of Dr. GG Pietra and reproduced from Taichman DB, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006. Panel A originally from Pietra GG, et al: J Am Coll Cardiol 43912:25Sâ&#x20AC;&#x201C;32S, 2004.)

interstitial diseases, such as progressive systemic sclerosis, the parenchymal disease and the pulmonary vascular disease, can evolve independently. For example, in the CREST syndrome (calcinosis, Raynaudâ&#x20AC;&#x2122;s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia), a variant of scleroderma, pulmonary hypertension sometimes stems solely from obstructive vascular disease of the small muscular arteries, unaccompanied by pulmonary fibrosis. In other connectivetissue disorders, such as lupus erythematosus, combinations of interstitial disease and intrinsic vascular abnormalities contribute to pulmonary hypertension.

Pathobiologic Mechanisms The pathogenetic mechanisms leading to pulmonary hypertension have been sorted into six categories (Table 81-2): (a) passive, due to obstruction to pulmonary venous outflow (e.g., fibrosing mediastinitis, mitral stenosis, or left heart failure); (b) hyperkinetic, due to abnormally high pulmonary blood flow (e.g., left-to-right shunts); (c) obstructive, due to pulmonary thromboembolic disease; (d) obliterative, due to curtailment of the pulmonary vascular bed by parenchymal proliferative disease; (e) vasoconstrictive, due to hypoxic

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Figure 81-6 In situ thrombosis within preacinar muscular arteries with organization and recanalization; also seen is eccentric intimal thickening. (Courtesy of Dr. GG Pietra and reproduced from Taichman DB, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

vasoconstriction; and (f) idiopathic (i.e., without discernible cause). Over time, distinctions between categories tend to become blurred (e.g., thrombosis may complicate obliterative vascular disease). Also, by the time pulmonary hypertension becomes manifest clinically, the pulmonary arterial tree has undergone considerable remodeling that limits its extent and distensibility. The anatomic curtailment of the pulmonary vascular tree involves thickening of the vascular walls of the small muscular pulmonary arteries and arterioles, partial or complete

obliteration of their vascular lumens, and peripheral extensions of vascular smooth muscle toward the capillary bed as described above.27 As a result, there is little capacity for distention and modest increments in pulmonary blood flow can elicit inordinate increments in pulmonary arterial pressures (Fig. 81-8). This situation is in marked contrast to that of the normal pulmonary circulation,in which an amputation of considerable lung volumes rarely suffices, per se, to raise pulmonary arterial pressures to pulmonary hypertensive levels. In the dog, more than two-thirds of the lungs must be ablated before pulmonary arterial pressures increase to hypertensive levels; in humans, occlusion of one major pulmonary artery, as by unilateral pneumonectomy, has little effect on pulmonary arterial pressures. Even in the individual with extensive pulmonary emphysema, as in Îą1 -antitrypsin deficiency, the striking decrease in the number of minute vessels in the emphysematous areas rarely suffices to elicit pulmonary hypertension. In contrast, widespread occlusion of the pulmonary vascular bed by multiple pulmonary emboli often causes pulmonary hypertension by obliterating large segments of the pulmonary arterial tree and increasing resistance to blood flow. Pulmonary vasoconstriction, as by acute or chronic hypoxia, may add to the increase in pulmonary vascular resistance.28

Vasoconstrictive Mechanisms: Hypoxia, Hypercapnia, and Acidosis

Figure 81-7 Interstitial pulmonary fibrosis in a patient with systemic sclerosis (scleroderma). In addition to the thickening and fibrosis of the interstitial spaces is the entrapment of vessels by fibrotic material. (Courtesy of Dr. G.G. Pietra.)

In some instances, pulmonary vasoconstriction can play an essential role in the pathogenesis of pulmonary hypertension. Hypoxia is by far the most powerful vasoconstrictor encountered clinically; acidosis is next, but is much less powerful.29,30 Both exert their vasomotor effects directly on the pulmonary vessels. Although these â&#x20AC;&#x153;powerfulâ&#x20AC;? vasoconstrictors

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Table 81-2 Pathogenetic Mechanisms of Pulmonary Hypertensionâ&#x2C6;&#x2014; Mechanism

Examples

Passive

Pulmonary venous hypertension

Mitral stenosis, left atrial myxoma fibrosing mediastinitis pulmonary veno-occlusive disease

Hyperkinetic

Increased pulmonary blood flowâ&#x2C6;&#x2014;

Left-to-right intracardiac shunts

Obstructive

Thromboembolic pulmonary vascular disease

Widespread pulmonary thrombosis of minute vessels, multiple pulmonary emboli

Obliterative

Inflammatory and/or proliferative pulmonary vascular disease

Interstitial lung disease, pulmonary arterial hypertension, schistosomiasis

Venoconstrictive

Hypoxia

Chronic bronchitis and emphysema (COPD)

Idiopathic

Unknown

Dietary pulmonary hypertension, porto-pulmonary hypertension, HIV infection

â&#x2C6;&#x2014; Most

categories overlap to some extent. For example, increased pulmonary blood flow is usually coupled with anatomic changes in the resistance vessels to produce pulmonary hypertension.

generally elicit only modest increments in pulmonary arterial pressure in the normal adult, acute hypoxia can elicit striking pulmonary pressor effects in the fetus and newborn and in some individuals with pulmonary hypertension. In chronic hypoxia, sustained pulmonary vasoconstriction

elicits structural changes within a matter of weeks. This remodeling is characterized by thickening of the media of the small pulmonary arteries and arterioles (Fig. 81-9) and peripheral extension of muscle into minute pulmonary vessels that are normally devoid of muscle.31 Acute hypercapnia has no direct pressor effect on the pulmonary circulation. However, it can contribute to pulmonary hypertension via the acidosis that hypercapnia elicits.

Mechanisms of Idiopathic Pulmonary Arterial Hypertension

Figure 81-8 Schematic pulmonary arterial blood pressure-flow curves for the normal and pulmonary hypertensive circulations. At high levels of pulmonary hypertension small increments in pulmonary blood flow elicit inordinate increments in pressure.

The initiating mechanisms of idiopathic and other forms of pulmonary arterial hypertension are obscured by the fact that the pulmonary hypertension itself may represent an end stage of the disease process. Abnormalities that initiate this process are difficult to trace once the anatomic changes are in place and by the time a sufficient amount of the normal vasculature has been curtailed to cause symptoms prompting clinical evaluation. This often long and quite variable interval between the original insults thought to initiate the pulmonary vascular disease and the onset of clinical signs and symptoms has been a major obstacle. In some patients, the insult appears to be present life-long (as in the case of congenital heart disease). In others, the inciting event is traceable to a few months or years of ingesting anorectic agents.32,33 Investigations using cells or tissues from patients with pulmonary hypertension have identified many cellular and molecular abnormalities. However, neither the experiments with cells or tissues nor animal models reproduced the changes of human PAH. Although alterations in ion channels,

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Figure 81-9 Normal and thickened pulmonary resistance vessels. A. Pulmonary arteriole showing thin muscular media double elastic lamina and widely patent lumen (40 µm). Aldehyde-fuchsin-elastic (×560). B. Pulmonary arteriole from pulmonary hypertensive dog showing marked thickening of the media decrease in lumen size and perivascular fibrosis (40 µm). Aldehyde-fuchsin-elastic (×560). (Courtesy of Dr. B. Atkinson.)

growth factors, and vasoactive proteins, together with gene mutations, have been identified as contributing to the abnormal endothelial, platelet, hemostatic, and smooth muscle function involved in the pathogenesis of PAH, distinguishing between initiating and secondary events remains problematic. It seems likely that instead of a single etiological factor, PAH can result from a number of abnormalities of pulmonary vascular cell function, initiated by one or more possible insults. The propensity of such abnormalities to produce disease appears to be determined by both the intensity and duration of these derangements, as well as an individual’s genetic predisposition to abnormal vascular responses. The development of pulmonary arterial hypertension involves disruptions in the normal balance of vasoconstriction and vasodilation, in the control of cellular proliferation, and thrombosis. Abnormalities in the expression of numerous vasoactive mediators cause, or result from, changes in en-

dothelial, smooth muscle and platelet function, and result in a thickened vessel wall and markedly narrowed or even completely obliterated lumen (Fig. 81-10). Some mechanisms for this combination of uncontrolled vasoconstriction, cell proliferation, and thrombosis are highlighted here.

Imbalance of Vasoactive Mediators Relative deficiencies of factors with vasodilatory properties and a simultaneous excess in those promoting vasoconstriction have been noted in both animal models and patients with PAH (Fig. 81-11). In addition to vasoconstriction/dilation, these same factors influence cell proliferation and thrombosis. Deficiencies in the production of the potent vasodilators nitric oxide (NO) and prostacyclin have been identified and both substances have been used in treating PAH. NO and prostacyclin are normally produced by vascular endothelial

Figure 81-10 Schematic representation of the pathogenesis of pulmonary arterial hypertension in which multiple factors contribute to vascular changes that produce an increase in resistance and an impaired cardiac output. (Histological images courtesy of Dr. GG Pietra and reproduced from Snow JL, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

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Figure 81-11 Imbalance in vasoconstrictor and vasodilator mediators found in patients with pulmonary hypertension. Urinary expression of vasoconstrictor (thromboxane) metabolites are increased, whereas vasodilator (prostacyclin) metabolites are decreased as compared with normal. (Originally adapted from Christman BW, et al: N Engl J Med 327:70–75, 1992; Snow JL, et al: Histopathology of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

cells, and each promotes the formation of cyclic nucleotides (cGMP and cAMP) by smooth muscle cells, thereby eliciting vascular relaxation and vasodilation. In addition, both prostacyclin and NO inhibit smooth muscle cell proliferation and platelet aggregation. The overexpression of NO synthase by transgenic animals protects against the development of hypoxia-induced pulmonary hypertension, whereas mice that lack the gene for this enzyme develop severe pulmonary hypertension upon exposure to mild hypoxia.34−36 In rats, monocrotaline-induced pulmonary hypertension can be prevented, and even reversed, with the administration of endothelial progenitor cells that overexpress human eNOS.37 In patients with PAH, the chronic administration of prostacyclin analogues improves hemodynamics, exercise capacity and survival. Vasoactive intestinal protein (VIP) also promotes vasodilation, inhibits smooth muscle proliferation and platelet aggregation. Its levels are reduced in patients with PAH. In a preliminary study of eight patients with IPAH, treatment with inhalations of VIP improved hemodynamics and exercise capacity.38 In addition to deficiencies in vasodilators in patients with PAH, excesses occur of other mediators that are capa-

Pulmonary Hypertension and Cor Pulmonale

ble of promoting vasoconstriction, smooth muscle proliferation, or platelet aggregation. Among these is thromboxane, an arachidonic acid metabolite produced by endothelial cells and platelets. Thromboxane causes vasoconstriction, platelet aggregation, and is a smooth muscle mitogen. Increased thromboxane metabolites have been demonstrated in the urine of patients with PAH.39 Attention was called to the effects of serotonin (5-HT) on the pulmonary circulation by the epidemic of pulmonary arterial hypertension in patients who ingested the appetite suppressants aminorex and fenfluramine.30 These agents increase plasma 5-HT levels by inducing the release of serotonin from platelets and interfering with its reuptake.40 The hypothesis that serotonin may play a role in the pathogenesis of pulmonary hypertension was supported by the occurrence of pulmonary hypertension in fawn-hooded rats that have an inherited defect in the storage of serotonin by platelet and the observed increase in circulating serotonin in a patient with platelet storage disease and PAH.41 Serotonin causes vasoconstriction and is a smooth muscle mitogen. A key regulator of 5-HT action is the serotonin transporter (5-HTT), the expression of which is above normal in the platelets and the pulmonary arteries of patients with IPAH. Overexpression of the 5-HTT gene in recombinant mice worsens hypoxia-induced pulmonary hypertension,42 whereas loss of the gene’s function is protective against hypoxia or monocrotaline-induced disease.43,44 A polymorphism in the 5-HTT gene that increases its activity may confer increased susceptibility for the development of pulmonary hypertension in patients with COPD. Although some studies have suggested a similar role in IPAH,45 larger data sets have not found such an association.46 Endothelin-1 (ET-1) is one of the most potent endogenous vasoconstrictors known. Levels of ET-1 are increased in the blood and tissues of patients with idiopathic and other forms of PAH and correlate with the severity of the disease.47−49 In addition to its vasoconstricting properties, ET-1 is mitogenic for both smooth muscle cells and fibroblasts.50,51 Its administration or overexpression in animal models has been shown to result in fibrosis, inflammation, and platelet aggregation.52,53 ET-1 binds to receptors for endothelin A (ETA ) and B (ETB ) on the surface of smooth muscle cells resulting in potent vasoconstriction. ETB receptors on vascular endothelial cells increase the production of NO, resulting in vasodilatation. ETB receptors are also active in the clearance of endothelin. The net effect of endothelin’s vasoconstricting or dilating actions may be both site and context dependent. Both the distribution and relative expression of the ETA or ETB receptors differ according to vessel location in normal lung tissue, and are altered in patients with IPAH.54,55 Indeed, both selective ETA and dual ETA /ETB inhibition ameliorates the hemodynamic derangements and clinical outcome of patients with PAH.56−58 Vascular tone may also be altered in PAH by changes in the expression of voltage-gated K+ (Kv) channels. Their activation normally allows an efflux of K+ and resultant changes in intracellular Ca2+ that promote vasodilation. Gene expression of Kv family members is downregulated by

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hypoxia-induced pulmonary hypertension in rats,59,60 whereas induction of their expression can reverse the hemodynamic effects.59,61 The expression of specific Kv channels is decreased in the lungs of patients with IPAH62−64 possibly contributing to heightened vasoconstriction. Kv channels may also be involved in the effects of certain drugs. The anorexigens dexfenfluramine and aminorex inhibit smooth muscle Kv1.5 activity, thereby causing pulmonary vasoconstriction.65 In contrast, the enhanced activity of Kv channels may be a mechanism by which sildenafil promotes vasodilation in addition to its activity as an inhibitor of phosphodiesterase.59 One final way by which decreased activity of Kv1.5 channels might promote the development of PAH is by inhibiting apoptosis, thus enabling unchecked smooth muscle cell proliferation. Apoptosis requires a loss in cell volume as well as the function of specific caspases, both of which require appropriate K+ movement via Kv channels.66,67 Increased expression of another ion channel (transient receptor potential channels) that permits the influx of Ca2+ for smooth muscle proliferation has been found in the lungs of patients with IPAH. As for the changes in Kv channels, it is not clear whether altered expression of these transient receptor potential channels in IPAH represents a primary event or a secondary effect of other mechanisms in the evolution of disease.68 Genetic Changes and Altered Cell Growth Recent advances in molecular genetics have identified two genes involved in the pathogenesis of both idiopathic and familial pulmonary arterial hypertension. Bone morphogenetic protein receptor II (BMP-RII) and activin receptor kinase-like 1 (ALK1) are receptors of the transforming growth factorbeta (TGFβ) superfamily. This family of receptors is involved in diverse cell growth and differentiation processes in multiple systems. Engagement of a BMP receptor with its ligand normally results in the activation of intracellular mediators (Smads) and their translocation to the cell nucleus and regulation of the transcription of target genes. The resulting activation of some genes and the inhibition of others varies according to the BMP pathway and tissue involved. BMP signaling is essential to both normal vascular development and the maintenance of the normal adult pulmonary vasculature, presumably by regulating the growth and apoptosis of endothelial and smooth muscle cells. Loss of such regulation gives rise to pulmonary hypertension.69 Germline mutations in BMP-RII have been identified in up to 60 percent of patients with familial PAH, and in some patients with idiopathic PAH,70−74 as well as in PAH associated with anorexigens,75 congenital heart disease,76 and pulmonary veno-occlusive disease.77 Mutations in ALK-1 confer susceptibility to the development of PAH in patients with hereditary hemorrhagic telangiectasia.78,79 BMP-RII is normally found primarily on endothelium and to a lesser extent smooth muscle cells. The expression of BMP-RII is reduced and its function is abnormal in patients with various types of PAH, particularly in patients with mu-

tations of the BMP-RII gene.80 The ability of BMP to inhibit smooth muscle proliferation and induce apoptosis is suppressed in cells isolated from smaller pulmonary vessels in patients with IPAH (e.g., 1 to 2 mm, where occlusive vascular pathological changes predominate).81−83 Growth factors known to promote the maturation and stabilization of the developing vasculature have also been implicated in the pathogenesis of PAH. Increases in angiopoietin 1 and its ligand TIE2 correlate with disease severity in patients with multiple forms of PAH.84 These patients had no known mutations in either BMP-RII or ALK1, but the increased levels of angiopoietin inhibited the expression of another member of the TGFβ family (BMP-R1A) that is required for normal signaling through BMP-RII. How angiopoietin becomes increased in these patients is not clear. Interestingly, in an animal model of PAH induced by monocrotaline, the overexpression of angiopoietin is actually protective.85 Whether this discrepancy represents differences in studying human versus animal tissues or the differing insults to the vasculature involved is not yet clear. Another modulator of development, vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase receptors are increased in the pulmonary vasculature of patients with PAH. Increased VEGF expression has been reported within plexiform lesions14,86 in which its proangiogenic properties are hypothesized to mediate disordered endothelial cell proliferation.87 Whether such changes are primary, secondary, or indeed detrimental is not entirely clear. Like elevations in angiopoietin, increments in the expression of VEGF, which are believed to be deleterious in some situations, might be beneficial in others that promote the development of pulmonary hypertension. In animal models of hypoxia, the inhibition of VEGF signaling results in proliferative vascular abnormalities88 and promotion of VEGF signaling is protective against the development of monocrotalineinduced PH.89

In Situ Thrombosis Thrombosis is common in the small vessels of patients with PAH. The thrombosis occurs without evidence of a remote (embolic) source of the thrombus,23−25,90 suggesting a local imbalance of pro- and anticoagulant forces. In addition are pro-coagulant factors, including abnormal von Willebrand factor activity, increase in plasma fibrinopeptide-A and increases in the half-life of fibrinogen91,92 and plasminogen activator inhibitor type-1.93 Endothelial cell-dependent fibrinolytic activity is also decreased in most patients with IPAH. Activation and altered function of the endothelium leading to a shift from anti- to procoagulant activities may be due to the effects of shear stress associated with elevated pressure and/or flow. In addition to altered endothelial cell activity, platelets also promote thrombus formation by releasing vasoactive and mitogenic factors such as thromboxane metabolites and serotonin. These, as well as other platelet-derived products (e.g., platelet-derived growth factor, TGFβ and VEGF) probably also contribute to the remodeling of vessel walls seen in PAH.

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Changes in the Extracellular Matrix The normal turnover of extracellular matrix (ECM) proteins is accelerated with remodeling of the vasculature in pulmonary arterial hypertension.94,95 The expression of tenascin-C (TN-C), for example, is increased in both experimental pulmonary hypertension induced by either monocrotaline in rats or increased blood flow in swine.96−98 Indeed, inhibition of TN-C expression by antisense RNA ameliorates monocrotaline-induced pulmonary vascular lesions.99 Increased levels of this ECM protein are also seen in the pulmonary arteries of patients with PAH.100−101 TN-C might contribute to the pathogenesis of PAH by modulating the effects of receptor tyrosine kinases, such as epidermal growth factor and fibroblast growth factor-2, on the proliferation and survival of pulmonary artery smooth muscle.102

CLINICAL EVALUATION OF PULMONARY HYPERTENSION Patient History in Pulmonary Hypertension and Cor Pulmonale The symptoms of pulmonary hypertension are nonspecific (Table 81-3). Except for mild breathlessness—often attributed to being out of shape—pulmonary hypertension is generally asymptomatic until severe. Because of the nonspecific nature of the symptoms, under-recognition of the disease by healthcare providers, and confusion with other conditions are common. As a result, there is often a significant delay between the onset of symptoms and the diagnosis of PAH. By one estimate, an average of 2.5 years elapse between the development of symptoms and the diagnosis of IPAH. Most

Table 81-3 Clinical Manifestations of Pulmonary Hypertension Symptom

Frequency∗

Dyspnea

60–90

Fatigue

Chest pain

Near syncope

Syncope

Leg edema

Palpitations

∗ In

percent of patients.

Pulmonary Hypertension and Cor Pulmonale

patients present with progressive dyspnea and significantly advanced disease. Symptoms due to pulmonary hypertension are generally difficult to dissociate from the symptoms of underlying pulmonary or cardiac disease. In idiopathic pulmonary arterial hypertension, the first symptoms generally occur during exertion, usually as dyspnea and, less often, chest pain, dizziness, or syncope.103 Dyspnea on exertion is by far the most common presenting complaint. Often, because of the lack of other signs or symptoms, it is attributed to physical deconditioning or anxiety. The mechanism responsible for the dyspnea of pulmonary hypertension is unclear. Other initial complaints, particularly easy fatigability and chest discomfort, are often dismissed as neurotic. Angina-like or nondescript chest pain is common in patients with severe pulmonary hypertension and generally attributed to right ventricular overload and myocardial ischemia. Chest pain might also occur if the left main coronary artery is compressed by an enlarged pulmonary artery.104 In time, right-sided heart failure evolves. Syncope, or light-headedness on exertion, are less common but more ominous complications of pulmonary hypertension. These symptoms occur in patients with severe pulmonary hypertension and a fixed low cardiac output. The cause is inadequate cerebral blood flow due to the combined failure to increase cardiac output and the diversion of systemic blood flow to the exercising muscles. Syncope may also occur at rest in association with the onset of bradycardia, presumably vagal in origin. Hoarseness, due to paralysis of the left recurrent laryngeal nerve, may result from trapping of the nerve between the aorta and the dilated left pulmonary artery (a form of Ortner syndrome). If the right ventricle should fail, the typical manifestations appear. Lower extremity swelling is common as are abdominal complaints of fullness, often described as a sensation of bloating, early satiety, tender hepatomegaly, ascites, and even abdominal pain. Symptoms of right ventricular failure and the presence of syncopal events herald a worse prognosis. Hemoptysis in pulmonary hypertension is usually due to pulmonary venous congestion. In contrast, in mitral stenosis is usually attributed to bleeding from bronchial veins. Occasionally, hemoptysis occurs in other forms of pulmonary hypertension and may originate in alveolar capillaries, precapillaries, and elsewhere in the pulmonary arterial tree. Not infrequently, suspicion of pulmonary hypertension is raised by the presence of a known etiology for pulmonary hypertension (e.g., systemic sclerosis or mitral stenosis) or serendipitous discovery of right ventricular enlargement by an electrocardiogram or chest radiograph taken for other reasons (Fig. 81-12). Initial recognition of the presence of pulmonary hypertension also frequently occurs in the patient without symptoms when an echocardiogram is performed in the evaluation of a murmur heard upon auscultation of the heart. Alternatively, echocardiographic evidence of pulmonary hypertension may be found when the study is obtained as routine evaluation of a patient complaining of any of a number of chest symptoms, including dyspnea.

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Figure 81-12 Radiographic changes in idiopathic pulmonary hypertension. As compared to a chest radiograph 14 months earlier (A) enlargement of the cardiac silhouette has occurred in a 30-year-old man in association with increasing dyspnea (B). Decrease in the cardiac silhouette occurred in response to chronic pulmonary vasodilator therapy.

Patients with severe pulmonary hypertension are prone to sudden death and its occurrence may be the first (and last) indication of disease. Death has occurred unexpectedly during normal activities, cardiac catheterization, and surgical procedures, and after the administration of barbiturates or anesthetic agents. In a few instances, bradycardia leading to cardiac arrest has preceded sudden death. Patients should be asked about important symptoms that might suggest the cause of pulmonary hypertension (Table 81-4). These include symptoms of collagen vascular disease (e.g., dysphagia, skin or joint changes, Raynaudâ&#x20AC;&#x2122;s phenomenon), sleep apnea (e.g., witnessed apneic events, daytime hypersomnolence), risks for thromboembolism or HIV infection, liver disease, or anorectic agent use. A history of tobacco abuse and chronic sputum production, or a known history of asthma with poor control may afford important clues to the presence of obstructive airways disease and hypoxia as the cause of pulmonary hypertension. A prior history of recognized interstitial lung disease or any other cause of chronic hypoxia should be noted. A careful family history should be taken including asking about relatives who suffer(ed) poorly understood cardiopulmonary conditions.

Physical Examination Until the right ventricle fails, preoccupation with the underlying pulmonary disease may divert attention from the presence of pulmonary hypertension and the development of right ventricular enlargement (cor pulmonale). Each pathogenetic sequence that culminates in cor pulmonale leaves its own

imprint on the clinical manifestations. For example, COPD is usually associated with hyperinflation of the lungs, which shifts the position of the heart and makes heart sounds less audible. Another example is interstitial lung disease, which is accompanied by rapid shallow breathing. In mild to moderate pulmonary hypertension physical examination is apt to be unrevealing unless suspicion has been aroused that pulmonary hypertension may be present. Right ventricular enlargement is an important clue but notoriously difficult to detect on physical examination in its early stages. Evidence of pulmonary hypertension such as prominent closure of the pulmonary valve is apt to be overlooked or discounted, especially in younger people; recognition of tricuspid insufficiency or a right ventricular gallop is often delayed until pulmonary hypertension has become severe and has led to heart failure. Once pulmonary hypertension is suspected, the physical examination can offer important signs. When symptoms first become manifest, a large a wave generally can be detected in the jugular venous pulse. Auscultation usually discloses splitting of the second heart sound with accentuation of the pulmonic component. A sharp systolic ejection click over the region of the pulmonary artery is usually heard. As pulmonary hypertension persists, enlargement of the right ventricle becomes evident as a palpable cardiac impulse near the left sternal border and in the hypogastrium. An important sign of cor pulmonale is a right-sided (ventricular), diastolic (S3 ) gallop. In timing, it coincides with the third heart sound; it is accentuated by inspiration. Less helpful is the right atrial gallop (S4 ), which occurs immediately before the first heart sound and represents an accentuation of the normal atrial

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Table 81-4 Evaluation of Patients with Pulmonary Hypertension Detection of pulmonary hypertension

Detailed history and physical examination

Essential testing

Pulmonary function testing Overnight oximetry Lung (V/Q) scan Blood serologies (e.g., CBC, liver function, renal function, HIV, ANA, antiphospholipid antibodies) Oxygen desaturation study

Electrocardiogram Chest radiograph Echocardiogram (at rest, to consider repeat with exertion)

6-Minute walk test Right cardiac catheterization Contingent testing

Transesophageal echocardiogram Computed tomogram of chest Polysomnogram Pulmonary angiogram Blood studies (BNP, clotting studies, genetic testing) Lung biopsy

Suspicion of pulmonary hypertension and possible causes/associations Exclude other causes of cardiopulmonary symptoms Evaluate for presence of pulmonary hypertension, assess chamber sizes and function, valvular abnormalities, contrast (“bubble”) study to evaluate possible shunt Exclude instrinsic lung disease Screen for sleep disordered breathing Exclude thromboembolism Exclude collagen vascular disease, liver disease, infection and other possible causes of pulmonary hypertension Assess need for supplemental oxygen (rest and exertion) Establish baseline Confirm diagnosis, assess other cardiac causes (shunt); consider left heart catheterization) Assess patent foramen ovale (PFO) Characterize valvular function Assess interstitial lung disease, adenopathy Diagnosis and treatment of sleep-disordered breathing Assess presence and location of clot and suitability for pulmonary thromboendarterectomy Exclude subtle interstitial lung disease vasculitis and other uncommon diseases (PVOD, PCH) to assist planning

Source: Adapted from: Barst RJ, et al: J Am Coll Cardiol 43:40S–47S, 2004.

sound; it suggests an increase in the filling pressure of the right side of the heart. In time, tricuspid insufficiency develops. It is manifested by a holosystolic murmur, best heard in the fourth interspace to the left of the sternum; the murmur characteristically increases in intensity during inspiration (as do the third and fourth heart sounds). A prominent v wave appears in the jugular pulse, and distended neck veins pulsate with each heartbeat. The onset of right ventricular failure is often marked by discomfort in the right upper quadrant due to hepatic engorgement as well as edema at the lower extremities. The liver often also shows expansive pulsations that are synchronous with the heartbeat. Hydrothorax and ascites are uncommon, even after right ventricular failure has progressed to the stage of hepatomegaly and pedal edema. Systemic arterial hypoxemia is often present. Assessment of possible oxyhemoglobin desaturation during activ-

ity is an important component of the patient evaluation; if desaturation is noted, formal exercise testing to titrate oxygen therapy should be pursued promptly. Late in the disease, many patients develop peripheral cyanosis secondary to a reduced cardiac output and peripheral vasoconstriction; central cyanosis also occurs in some patients because of right-to-left shunting through a patent foramen ovale. The physical examination should focus on the presence of additional signs to indicate a possible cause of pulmonary hypertension. Abnormal lung sounds might include wheezing suggesting airways obstruction, or crackles suggesting either pulmonary edema or interstitial disease. Additional findings suggestive of lung disease include hyper-resonance to percussion or hyperinflation of the thorax (barrel chest) suggestive of COPD; kyphoscoliosis may cause a restrictive pattern. Skin changes such as rash or telangiectasias are clues to the presence of collagen vascular disease; so are digital

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ulcers in patients with the CREST variant of systemic sclerosis. The presence of digital clubbing may indicate congenital heart disease, certain forms of chronic hypoxic lung disease (e.g., cystic fibrosis or certain interstitial lung diseases) or pulmonary veno-occlusive disease.105 A narrow posterior oropharynx, macroglossia, and a large neck size may suggest obstructive sleep apnea (OSA).

Diagnostic Studies Diagnostic testing is used to confirm the presence of pulmonary hypertension, identify the etiology, assess severity and prognosis, and help to identify appropriate therapy (see Table 81-4). When pulmonary hypertension is suspected, the echocardiogram is the appropriate first test.103,106 Indeed, as noted, evidence of pulmonary hypertension on an echocardiogram is often what first brings the issue to attention. A carefully performed Doppler examination is able to quantify the tricuspid regurgitant jet in the majority of cases.107 A modified Bernoulli equation is used to estimate the right ventricular systolic pressure (RVSP = 4v2 + right atrial pressure; where v = tricuspid jet velocity in meters per second) and is assumed to equal the pulmonary artery systolic pressure when the pulmonic valve is normal. Normal RVSP has been reported as 28 Âą 5 mmHg. Echocardiographic evaluations during exercise are an additional consideration when estimates of RVSP at rest are normal and suspicion of pulmonary hypertension is high (e.g., dyspnea in a patient with systemic sclerosis and no other obvious cause). Echocardiographic measurements taken at peak exercise may reveal inordinate increases in pulmonary arterial pressures, perhaps signaling the presence of earlier disease. Normative echocardiographic values of RVSP during exercise have not been well established. The echocardiogram can also reveal important information about cardiac structure and function. It enables evaluation for a patent foramen ovale and intracardiac or intrapulmonary shunting of blood (e.g., using a bubble contrast). Echocardiography can also help to rule out related anatomic abnormalities, such as acquired or congenital mitral valve disease or a left atrial myxoma. Left ventricular hypertrophy, diastolic noncompliance, decreased systolic function, or focal hypokinesis as well as mitral or aortic valvular defects are essential observations when evaluating the likely cause of pulmonary hypertension. Dilation and decreased function of the right ventricle are indications of the functional importance and severity of pulmonary hypertension. Taken together, an evaluation of right ventricular contraction, relaxation, and ejection can yield functional information with prognostic value in patients with PH.108 The presence and size of a pericardial effusion are poor prognostic signs.109â&#x2C6;&#x2019;112 Flattening of the interventricular septum occurs with advanced dilation and failure of the right heart, and the leftward movement of the septum may denote impairment of left ventricular filling. While the correlation between echocardiographic estimates of PASP and measurements taken at right heart catheterization are generally good, it must be remembered

that there is significant variability. Confirmation by cardiac catheterization is required when the presence of pulmonary hypertension will influence the approach to treatment. For example, in the setting of some patients with severe COPD in whom an echocardiogram reveals evidence of pulmonary hypertension, confirmation by right heart catheterization might not influence medical therapy. If, on the other hand, surgical intervention for the COPD is a consideration (e.g., for lung transplantation or lung volume reduction), confirmation of the presence of pulmonary hypertension by cardiac catheterization is important. When the diagnosis is thought to be pulmonary arterial hypertension, diagnostic catheterization confirms the diagnosis and is useful in guiding therapy. Cardiac catheterization in evaluation of pulmonary hypertension is described in the following sections. Once evidence of pulmonary hypertension has been established by echocardiography, testing for possible causes is in order. Pulmonary function tests, a ventilation-perfusion scan and overnight oximetry are essential to screen for possible underlying obstructive or restrictive lung disease, occult thromboembolism, and sleep-disordered breathing, respectively. Blood tests including HIV antibody, rheumatologic serologies (e.g., ANA), liver function tests, and a complete blood count are essential. A plain chest radiograph (together with the pulmonary function tests) may suggest the presence of parenchymal lung disease; in such patients further evaluation with CT is usually warranted. Early in the evolution of pulmonary hypertension, the chest radiograph appears normal. In time, the central pulmonary arteries become increasingly prominent as the peripheral vessels become attenuated, and the cardiac silhouette enlarges (Fig. 81-13). An electrocardiogram should be obtained and may indicate signs

Figure 81-13 Prominent central pulmonary arteries in conjunction with the marked pruning of the peripheral tree reflect marked pulmonary hypertension in a patient with a history of multiple pulmonary thromboemboli.

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Figure 81-14 Twenty-six-year-old woman in whom the first evidence of idiopathic pulmonary arterial hypertension was by electrocardiography. The record shows marked right axis deviation and dominant R waves over the right precordium consistent with right ventricular hypertrophy.

of ischemic heart disease or conduction abnormalities. The electrocardiogram almost invariably shows some evidence of right ventricular overload, usually in conjunction with right atrial impairment (Fig. 81-14). Arrhythmias are uncommon until late in the course of the disease, when they may contribute to syncopal episodes. Baseline testing should also include assessments of exercise tolerance and whether supplemental oxygen is required. A 6-minute walk test is a useful means of assessing exercise capacity and prognosis, and serial testing can be useful in evaluating the response to therapy. Measurements of arterial oxyhemoglobin saturation both at rest and during exercise are important to be sure that adequate oxygenation is maintained and, if not, to titrate with supplemental oxygen accordingly. Cardiac catheterization is required in most cases to confirm the diagnosis of pulmonary hypertension, test for important cardiac causes and, in appropriate patients, perform vasodilator trials to determine therapy. Except in those considered to be at very low risk of coronary artery disease, many centers first perform left heart catheterization in all patients. In addition to coronary angiography, measurement of the LVEDP is important to exclude left atrial hypertension (e.g., as seen in diastolic dysfunction) as an important cause of pulmonary hypertension. Direct measurement may be required in the presence of severe pulmonary hypertension when an adequate estimate of LVEDP cannot be obtained using a wedged pulmonary artery catheter. Right heart catheterization, using a balloon-tipped flow-directed pulmonary artery catheter, is performed to confirm the presence of pulmonary hypertension. While advancing the catheter, serial measurements of blood oxygen saturation should be performed for evidence of a â&#x20AC;&#x153;step upâ&#x20AC;? in oxyhemoglobin saturation that suggests the presence of left-to-right shunting of blood as an etiology for the pulmonary arterial hypertension. Attention also should be paid to the level of right atrial pressure since significant increase worsens the prognosis. As noted, pulmonary hypertension is defined as a mean pulmonary resting artery pressure greater than 25 mmHg. When pulmonary arterial pressure is normal at rest, measurement during exercise may be performed using serial leg lifts, arm raising with weights,

or a stationary bicycle. A mean pulmonary artery pressure greater than 30 mmHg with exercise is also diagnostic of pulmonary hypertension (Fig. 81-15). Pulmonary arterial hypertension is present when there is pulmonary hypertension and an adequately measured pulmonary capillary wedge pressure or, if necessary, a directly recorded LVEDP, is less than 15 mmHg. The cardiac output is obtained either by thermodilution or measuring arterial and venous hemoglobin oxygen contents and applying the Fick principle. The latter is apt to be more accurate if either significant tricuspid or pulmonary regurgitation is present or the cardiac output is very low. In patients with pulmonary arterial hypertension, vasodilator testing is performed at the time of right heart

Figure 81-15 Hemodynamic observations in five patients with interstitial lung disease. Two of the five had pulmonary hypertension at rest; the other three became pulmonary hypertensive during exercise, although only in one did the mean pulmonary artery pressure rise above 30 mmHg = at rest; â&#x2020;&#x2019;= exercise. The shaded background indicates the normal pulmonary arterial pressureflow relationship.

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catheterization to identify those in whom treatment with oral calcium channel antagonists is appropriate. This testing is described in the section below in which therapy of PAH is addressed.

GENERAL ASPECTS OF DISEASE MANAGEMENT This section describes general measures to be considered in the care of all patients with pulmonary hypertension and cor pulmonale. Treatment is also directed by the underlying disorder and the identification of any reversible causes.

Exercise and the Avoidance of Deconditioning Regardless of the cause, patients with pulmonary hypertension and cor pulmonale should be encouraged to maintain as active a lifestyle as possible. Recommendations that the patient minimize exertion for fear of further raising pulmonary pressures generally result only in deconditioning of the muscles and an increase in fatigue and breathlessness when activity is attempted. Regular, steady aerobic exercise should be encouraged, and is often best initiated under guidance of a pulmonary or cardiac rehabilitation program. The benefits include a decrease in the fear many patients with dyspnea experience when initiating exercise programs. Many rehabilitation programs teach techniques to cope with dyspnea when it occurs, thereby enabling exercise to continue. The result is an increase in compliance with regular fitness regimens, overall improvement in exercise tolerance and in the sense of well-being and in reducing or avoiding obesity. Activities that tend to cause lightheadedness or syncope are to be avoided. Among these are hot showers or baths and bending over to lift heavy objects.

Oxygen Therapy Of cardinal importance in the management of patients with pulmonary hypertension is the avoidance of acute hypoxia, as hypoxic pulmonary vasoconstriction adds to the burden on the right ventricle. Measurements of arterial oxyhemoglobin saturation should be performed at rest, during exertion, as well as during sleep. Levels of arterial oxygen saturation below 90 percent require supplemental oxygen. Maintenance of adequate oxygen saturation may be difficult in those patients with severe pulmonary hypertension in whom a patent foramen ovale allows right-to-left shunting. Supplemental oxygen has been demonstrated to benefit patients with COPD.113 Two separate trials, that of the Medical Research Council and of the National Heart, Lung, and Blood Institute (Nocturnal Oxygen Therapy Trial), have shown that intellectual function and survival of patients with COPD are improved in chronically hypoxemic patients (arterial PO2 under 55 mmHg) who are polycythemic (hematocrit greater than 55 percent), edematous, and show P pul-

monale on the electrocardiogram. However, in order to be effective, oxygen must be administered for at least 18 h per dayâ&#x20AC;&#x201D;including at night, when arterial hypoxemia and respiratory acidosis intensify. Oxygen relieves hypoxic pulmonary vasoconstriction, thereby decreasing vascular resistance and improving the cardiac output, lessens renal vasoconstriction improving the urinary excretion of sodium, and alleviates tissue hypoxia by improving oxygen delivery. Air travel is of particular concern because of the threat of hypoxic pulmonary vasoconstriction. As a rule, commercial airlines maintain cabin pressures equivalent to an altitude of about 8000 feet above sea level. Supplemental oxygen should be administered as necessary to avoid arterial oxygen saturation below 90 percent. Supplemental oxygen is usually required for those with borderline levels of arterial oxygen saturation at sea level; increased oxygen flow rates are apt to be needed for those who use oxygen therapy for the activities of daily life. Many pulmonary function laboratories can simulate conditions of high altitude by using an inspired oxygen concentration of 15 percent to determine whether the patient requires supplemental oxygen in order to maintain adequate oxyhemoglobin saturation. Patients must contact airlines in advance of travel to arrange for supplemental oxygen therapy while in flight.

Infection Acute respiratory infection may precipitate right heart failure in patients with cor pulmonale. Acute exacerbations are a particular and often recurrent problem for patients with pulmonary hypertension due to COPD. Worsened hypoxia and/or respiratory acidosis may worsen pulmonary hypertension, increase the work of an already strained right heart, and precipitate cardiac arrhythmias. Treatment for pulmonary infection must be instituted promptly and include oxygen and antibiotic therapies. Airways obstruction may increase intrathoracic pressures and interfere with venous return causing hepatic congestion and peripheral edema. Bronchodilators should be given as needed to relieve airways obstruction and relieve hypoxia. In patients receiving vasodilators (e.g., calcium channel antagonists or intravenous prostanoid therapies for pulmonary arterial hypertension) hypoxic vasoconstriction normally occurring at pneumonic infiltrates may be inhibited due to the drugâ&#x20AC;&#x2122;s nonspecific action resulting in the shunting of blood and worsened hypoxemia. Immunizations against influenza and pneumococcal pneumonia are important preventive measures in all patients with pulmonary hypertension and cor pulmonale.

Fluid Management and Diuretics Careful attention to avoid fluid overload is central to the management of cor pulmonale of any cause. Patients must be educated regarding appropriate dietary habits and must restrict sodium intake in order to minimize fluid retention and the development of right heart failure. Patients should weigh

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themselves daily so any trend toward fluid retention can be reversed. In addition to the harmful effects of excessive intravascular volume on cardiac function, the lungs share in the accumulation of excess water in the body; the excess fluid in the lungs further compromises pulmonary gas exchange and may heighten pulmonary vascular resistance. It has now been amply demonstrated that diuretics can improve alveolar ventilation and arterial oxygenation in cor pulmonale. Management of right heart failure relies heavily on diuretic therapy. Spironolactone is often used to manage mild fluid retention. It may also have beneficial effects in heart failure by modulating neurohormones. Loop diuretics are often required to prevent more significant fluid retention and right heart failure. Indeed, high doses and combinations of diuretics may be required to maintain appropriate fluid balance, but must be used cautiously to avoid electrolyte imbalances and volume depletion. Diuretic-induced hypokalemic metabolic alkalosis is of particular concern as it may diminish the effectiveness of the CO2 stimulus on the respiratory centers, thereby decreasing the ventilatory drive. Also, renal excretion of bicarbonate is compromised when diuretics decrease blood levels of potassium and chloride. For these reasons, careful monitoring of serum electrolytes—particularly bicarbonate, chloride, and potassium ions—is mandatory once a program of salt depletion, including salt restriction and diuretics, is begun. Carbonic anhydrase inhibitors (e.g., acetazolamide) were once first-line therapy for treating patients with cor pulmonale with chronic hypercapnia secondary to COPD. The rationale was to promote diuresis and loss of bicarbonate by the kidney. However, untoward effects, presumably the result of adding metabolic acidosis to the preexisting respiratory acidosis, have led many physicians to abandon the use of acetazolamide as a primary diuretic agent. At present, it is used only circumspectly to correct the alkalemia induced by excessive diuresis, contraction of the plasma volume and hypochloremia.

Digitalis and Theophylline Whether cardiac glycosides should play a role in treating right heart failure is unsettled. Nonetheless, digoxin is commonly used empirically, particularly when pulmonary hypertension is accompanied by atrial fibrillation. It is used by some clinicians to support the failing right ventricle; others shy away from this agent even when right-sided heart failure is evident. They do so on two accounts: (a) the inotropic effect of digitalis on right ventricular performance is modest; and (b) patients with cor pulmonale and right ventricular failure are often hypoxemic and somewhat acidotic, thereby predisposed to dysrhythmia. Even small doses of digitalis may trigger a dysrhythmia. Digitalis seems most apt to benefit patients with demonstrable left ventricular failure. Heart rate is a poor guide to digitalis dosage because hypoxemia, as well as heart failure, evokes tachycardia. In essence, the safest use of digitalis for its cardiotonic effect is when right ventricular failure is unaccompanied by arterial hypoxemia, acid-base upsets, or the need for administration of bronchodilators (i.e., in disor-

Pulmonary Hypertension and Cor Pulmonale

ders other than obstructive airway disease). Also predisposing to dysrhythmias are hypokalemia induced by diuretics and medications including theophylline, which are administered to relieve bronchospasm. The effect of theophylline in patients with COPD has been inconsistent, although some patients may experience a reduction in symptoms without demonstrable relief of airflow obstruction. Such benefit may be due to the drug’s ability to increase myocardial contractility and diaphragmatic strength as well as to promote mild pulmonary vasodilation. Theophylline’s use in patients with pulmonary hypertension is not of established benefit and must be used cautiously. Careful attention to the level of the drug in blood is required to avoid the development of toxicity that might provoke cardiac dysrhythmias. This requirement may limit theophylline use.

Dysrhythmias Dysrhythmias occur occasionally with cor pulmonale. Common precipitating mechanisms are anxiety and excessive use of bronchodilators. Occasionally, a bout of respiratory failure triggers an episode of atrial tachycardia, nodal rhythm, a wandering pacemaker, atrial flutter, or fibrillation. Stimuli that provoke intense adrenergic discharge increase the possibility of adverse effects from therapeutic agents, such as digitalis. As a rule, arrhythmias in cor pulmonale are transient and resolve with discontinuation of the precipitant (e.g., an acute respiratory infection.). However, arrhythmias may be life threatening if they occur in the presence of disturbances in acid-base balance, arterial hypoxemia, and heightened sympathetic activity. The occurrence of such a life-threatening arrhythmia, usually ventricular fibrillation, is most likely during a bout of acute respiratory failure, with its accompanying disturbances in gas exchange and electrolyte imbalances. Respiratory alkalosis, induced by mechanical hyperventilation and accompanied by hypokalemia, can also be a precipitating mechanism.

Pulmonary Vasodilators in non-PAH Forms of Pulmonary Hypertension Many vasodilator drugs have been used in the attempt to reduce pulmonary vascular resistance and improve right heart function in cor pulmonale. However, except for an occasional patient with pulmonary arterial hypertension, the use of vasodilators has not been of benefit in cor pulmonale. Although overall success rates have been modest, occasional instances of dramatic improvement have been reported. Results in patients with cor pulmonale due to COPD, for example, have been mixed and, at best, successful only in the short term (see subsequent section on Pulmonary Hypertension Associated with Hypoxemic Lung Disease). For example, the use of calcium channel antagonists in patients with COPD may worsen ventilation-perfusion mismatch and hypoxemia. In addition, the depressant effects of these agents on cardiac inotropy may significantly worsen right heart function.

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The use of pulmonary vasodilators is discussed in detail below in treatment specifically for pulmonary arterial hypertension.

Phlebotomy When the hematocrit increased to more than 50 to 60 percent, phlebotomy was once standard treatment for the polycythemia of chronic hypoxia. However, even though repeated small phlebotomies often did result in symptomatic improvement and increase exercise tolerance, it proved difficult to show objective improvement in gas exchange, pulmonary mechanics, or pulmonary arterial pressure after “safe” phlebotomies (i.e., of 250 mL or so); larger phlebotomies were avoided because they occasionally resulted in minor strokes and episodes of hypotension. However, gradual restoration of hematocrits toward normal (i.e., by repeated 250-mL phlebotomies at intervals of several days or weekly) did decrease pulmonary arterial pressure as hematocrits approached normal levels (i.e., about 50 percent); lower hematocrits offer no further advantage. Therefore, small phlebotomies still have a role when secondary polycythemia becomes severe. Supplemental oxygen therapy in hypoxemic patients with COPD should reduce the severity of secondary polycythemia and in most cases obviate the need for phlebotomy.

EPIDEMIOLOGY AND TREATMENT OF INDIVIDUAL PULMONARY HYPERTENSIVE DISEASES Pulmonary Arterial Hypertension Table 81-5 presents the known and suspected risk factors for the development of PAH, as assessed at the 1998 World Symposium on Pulmonary Hypertension.26 Risks are ranked as “definite” if established by controlled studies or clear-cut epidemics (anorexigenic-associated PAH caused by fenfluramine)114,115 and “possible” when based on fewer definitive data (e.g., case series). Intermediate levels of evidence are ranked accordingly. Idiopathic Pulmonary Arterial Hypertension Idiopathic pulmonary arterial hypertension (IPAH) is a rare disease with an estimated incidence in industrialized countries of one to two cases per million.114,116,117 The paucity in the number of patients with IPAH and the likelihood that diverse causes and pathogenetic mechanisms can produce the same clinical syndrome have complicated descriptions of the natural history of the disease. For a while, certain stereotypes were regarded as prototypical, e.g., young women with Raynaud’s syndrome, with the acute onset of dyspnea and fatigue and progression to death within 2 years. It is appreciated that even though there is such a subset, longevity in response to medical therapy is no longer unusual and that the disease may affect all ages, both sexes, and different ethnic groups.118

Table 81-5 Risk Factors for the Development of Pulmonary Arterial Hypertension Drugs and toxins Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Very likely Amphetamines L-Tryptophan Possible Meta-amphetamines Cocaine Chemotherapeutic agents Unlikely Antidepressants Oral contraceptives Estrogen therapy Cigarette smoking Demographic and medical conditions Definite Gender Possible Pregnancy Systemic hypertension Unlikely Obe´sity Diseases Definite HIV infection Very likely Portal hypertension/liver disease Collagen vascular diseases Congenital systemic-pulmonary-cardiac shunts Possible Thyroid disorders Risk factors and conditions associated with the development of pulmonary arterial hypertension, as were assessed at the 1998 World Symposium on Pulmonary Hypertension in Evian, France. Source: Adapted From: Simonneau G, et al: J Am Coll Cardiol 43:5S–12S, 2004.

In order to overcome the limitations of sporadic reports, the National Institutes of Health (NIH) established a nationwide registry in 1981 to collect and analyze data on IPAH (then called PPH). Criteria for entry of a patient into the national registry included normal pulmonary function tests (except for a moderate reduction in diffusing capacity), a right heart catheterization to exclude congenital or left heart disease, perfusion scans, and angiography if the scans were

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inconclusive for pulmonary emboli, and serologic testing to rule out collagen vascular disease. Included in the registry were certain associated diseases, such as hepatic cirrhosis, because the reason for the association between pulmonary hypertension and the liver disease was unclear and because of the suspicion that the association might provide a clue to etiology. By the close of the registry in 1987, data were available on 187 patients.119 The mean age was 36.4 years and similar for women and men, although the female-to-male ratio was 1.7:1. Few patients were older than 60 years, although race and ethnicity of the cohort were similar to that of the general population. Similar demographic trends have been reported in series from France, Israel, Japan, and Mexico.117,120,121 Dyspnea was the most common initial symptom and the mean time to diagnosis among patients in the NIH Registry was 2 years.

Prognosis of IPAH

Without effective therapy the prognosis of IPAH is very poor. The median survival of patients in the NIH Registry was 2.8 years; estimated survival at 1, 3, and 5 years was 68, 48 and 34 percent, respectively.119 Similar or even worse data have been reported in other series from various countries.25,122 Most patients in these series died of right heart failure. The outlook was worse with more advanced symptoms. NIH registry patients who had symptoms corresponding to those of World Health Organization (WHO) functional classes III and IV symptoms had a median survival of only 31.5 months as compared with a median survival of 58.6 months in patients with milder impairment (class I or II) (Table 81-6). Although the data have improved, functional status remains a significant indicator of prognosis even with effective therapy.117,123−126 For example, functional assessment using the 6-minute walk test is a useful means of following the response to therapy and independently predicts prognosis.125,127−129 Maximal oxygen consumption has also been used to assess response to therapy and also correlates with survival.128 On the echocardiogram, either enlargement of the right atrium and/or the presence of a large pericardial effusion is associated with an increased risk of death.109−112 A relative increase in the isovolumetric contraction and relaxation times of the RV as compared to its ejection time indicates RV dysfunction and a poorer prognosis.108 Levels of endothelin, catecholamines, and atrial natriuretic peptide in serum have been correlated with disease severity, and increases in serum uric acid, von Willebrand factor, D-dimer, troponin-T, and brain natriuretic peptide have been individually associated with poorer survival in patients with IPAH.130−137 Recently, a low serum albumin has been associated with an increased risk of death, independent of other measurements that reflect passive hepatic congestion or right heart dysfunction.112 None of these putative prognostic markers is currently incorporated into clinical decision making.

Pulmonary Hypertension and Cor Pulmonale

Table 81-6 World Health Organization Functional Classification of Patients with Pulmonary Hypertension Class I: Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. Class II: Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class III: Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. Class IV: Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Source: Adapted from: Rich S. Primary Pulmonary hypertension: Excutive summary. Evian, France. World Health Organization, 1998.

Hemodynamic variables that reflect the development of right heart failure (e.g., an increased right atrial pressure and a decreased cardiac index) worsen the prognosis.117,121,138,139 Decreased survival has been seen in association with both increasing and decreasing mean pulmonary artery pressures (mPAP). These observations are not necessarily contradictory. Instead, they reflect the natural history of right heart failure in PAH: mPAP increases initially as the vascular derangements grow worse only to fall later as the right heart fails and is no longer able to generate an increased pressure (Figs. 81-16 and 81-17). A regression equation based on hemodynamic data from the NIH Registry has been used to predict survival.121,140 Because of the dismal prognosis of the disease, the use of long term “control” groups without treatment in clinical trials is unethical and assessments of survival with new therapies has been compared with the outcomes predicted by the NIH equation. Such comparisons have demonstrated improved survival with the use of epoprostenol, calcium channel blockers, or endothelin receptor antagonists. These improvements are addressed in the discussion of individual therapies below. As the number of effective drugs grows and is routinely employed, the relevance of survival estimates based on data from an era that lacked effective treatment is questionable. In essence, the NIH Registry equation may no longer be sufficient at predicting survival as standards of care and therapies have since improved dramatically. Indeed, when applied to a

1380 Part IX

Disorders of the Pulmonary Circulation PROGRESSION OF PAH Presymptomatic/ compensated

Declining/ decompensated

PAP

Right heart dysfunction

PVR Time

Figure 81-16 Hemodynamic changes during the progression of pulmonary arterial hypertension. With progressive increase in the pulmonary vascular resistance (PVR), the pulmonary artery pressure (PAP) initially increases until a failing right heart can no longer generate the required pressures to maintain cardiac output (CO). At this late stage both the cardiac output and pulmonary pressures may fall. (Reproduced from Friedman EB, et al: Classification and prognosis of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

more recent cohort of patients treated with current agents, the NIH equation underestimated survival.112 It is not surprising that the prognosis of patients with IPAH who have suffered cardiac arrest is dismal even when resuscitative efforts are initiated promptly. In a retrospective review of the records of over 3000 patients, 132 episodes of attempted cardiopulmonary resuscitation (CPR) following

Figure 81-17 Schematic representation of evolution of chronic cor pulmonale. Hemodynamic studies at rest and during exercise in a normal subject (A). The stage of pulmonary arterial hypertension (B) is succeeded by cor pulmonale (C) in which the right ventricle performs normally despite pulmonary arterial hypertension but is known to be enlarged because of radiographic and echocardiographic findings. Once right ventricular failure supervenes (D) cardiac output fails to increase normally during exercise despite an increase of right ventricular filling pressure (enddiastolic) to abnormally high levels.

cardiac arrest were identified. Survival at 90 days following CPR was only 6 percent.141 Familial Pulmonary Arterial Hypertension A family of patients with IPAH, then termed primary pulmonary hypertension was first described by Dresdale in 1951.3 Thereafter, additional families were reported. Subsequently, Loyd and Newman identified an autosomal dominant pattern of inheritance, an increased tendency for female carriers to manifest clinical disease, and an earlier onset in successive generations (genetic anticipation).142,143 Linkage analysis led to a marker at chromosome 2q31-32, and mutations in the gene for a member of the TGF-β family of receptors, the bone morphogenetic protein receptor II (BMPRII), was identified as the cause of familial PAH.70,71,144,145 Moreover, mutations in another member of the TGFβ family, activin receptor-like kinase-1 (ALK 1) predispose patients with hereditary hemorrhagic telangiectasia to develop PAH.78,79,146,147 TGFβ receptors control an array of cell growth and differentiation systems. BMP signaling is involved in the control of normal vascular development as well as in the homeostasis of the adult pulmonary vasculature, probably by regulating the growth and apoptosis of endothelial and smooth muscle cells.69 In an assessment of mutations from the coding sequence of BMP-RII in 210 patients, more than 140 distinct mutations were identified, the majority predicting premature truncation of the gene transcript. Disease is believed to be due to haploinsufficiency, which results in inadequate quantities of BMP-RII protein being produced for normal function.148 In addition, the low penetrance observed in familial PAH suggests that environmental factors probably contribute to disease development in genetically susceptible individuals.149 Up to 60 percent of patients with familial PAH have germline mutations in a BMP-RII. So do some patients with idiopathic and other associated forms of PAH.70−77 Clinically asymptomatic carriers may have evidence of mild pulmonary hypertension on the echocardiogram.150 Common ancestries, identified in some individuals with IPAH, have linked some patients with PAH previously assumed to be sporadic. Failure to recognize familial cases of PAH may sometimes be due to incomplete family history taking or reporting and low disease penetrance, particularly in smaller families.73,151 There are no established differences between the approach to treating patients with familial PAH and those with IPAH. At present, the clinical evaluation of patients remains the same. Genetic testing of family members is to be considered in order to assess the risk that relatives will develop PAH. As a rough guide, there is a one-in-five chance of PAH developing in a first order relative who carries a disease-causing BMP-RII mutation. If genetic testing has not been performed, the risk of disease developing in the first-order relative of a patient with known familial PAH is approximately one in ten. In the absence of a disease causing BMP-RII mutation, the risk of disease is the same as in the general population (estimated at one in a million).149 Because of the potential interpersonal, psychological, and economic implications of identifying an

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at-risk genotype, genetic testing should only be performed in conjunction with professional genetic counseling.

1.0

Pulmonary Arterial Hypertension Associated with Specific Conditions

0.6

0.8

Human Immunodeficiency Virus

Individuals infected with the human immunodeficiency virus (HIV) are at increased risk of developing pulmonary arterial

IPAH

Survival 0.4 SScPH

Collagen Vascular Diseases

The lungs, as well the pleura, are commonly affected in patients with collagen vascular disease. Although the frequency of pulmonary hypertension differs among the various collagen vascular diseases, fibrotic, interstitial changes are more common etiologies for pulmonary hypertension than is isolated involvement of the pulmonary vasculature. When present, however, pulmonary arterial hypertension is frequently a deadly development. It is important in this population to differentiate between pulmonary hypertension that is associated with hypoxia that stems from interstitial lung disease and hypoxia that occurs without significant interstitial changes. Pulmonary hypertension may also be due to left heart ischemic or diastolic dysfunction, or to thromboembolic complications of collagen vascular disease. Unfortunately, both interstitial disease and pulmonary arterial hypertension appear to coexist in many patients with collagen vascular diseases. Most clinical studies of therapy for pulmonary arterial hypertension have excluded patients with collagen vascular disease who have evidence of significant restrictive lung disease (usually defined as an FVC of less than 70 percent predicted) or evidence of interstitial changes in the lungs on chest radiographs. Extrapolation of efficacy data from such trials to justify the use of particular medications in patients with significant ILD may be problematic. PAH occurs most often in systemic sclerosis among patients with limited disease or the CREST syndrome. Estimates have ranged significantly, but when confirmed by right heart catheterization, PAH has been found in between 7 and 29 percent of patients.152 The prognosis of patients with scleroderma is worse when the disease is complicated by PAH than by severe pulmonary fibrosis. Nearly half of patients with PAH die within 1 year as compared with 3 years when the lung is affected by fibrosis alone.153,154 Even with the use of equivalent therapies, the outcome of patients with PAH associated with systemic sclerosis is less favorable than for IPAH56,124,153 (Fig. 81-18). When estimated by echocardiogram, pulmonary hypertension has been identified in approximately 10 percent of patients with systemic lupus erythematosus, and as many as 43 percent when patients are followed prospectively.155−159 In patients with mixed connective tissue disease, estimates are broad and without confirmation by catheterization. However, regardless of frequency, when pulmonary hypertension is present it appears to be a significant cause of death is these patients. PAH occurs in numerous other rheumatologic disorders, including Sj¨ogren’s disease and rheumatoid arthritis although firm data on incidence or survival are lacking.

Pulmonary Hypertension and Cor Pulmonale

Log-rank test χ2 = 4.88, p value = 0.03

0.2 0.0

Time (years) SScPH N= 22 PPH

N= 23

7 24

−

Figure 81-18 Survival of patients with systemic sclerosis associated pulmonary arterial hypertension is worse than that of patients with idiopathic pulmonary arterial hypertension despite equivalent therapies. (Reproduced from Kawut et al: Chest 123:344–350 2003.)

hypertension. The mechanism by which HIV predisposes to the development of PAH is not known, but does not appear to be due to direct viral infection of pulmonary vascular endothelial cells.160 Infection may elicit increases in the growth factors of mediators, such as endothelin and thereby result indirectly in the development of PAH.161−163 The estimated incidence of PAH among HIV-infected patients is 0.5 percent, significantly higher than the estimated annual incidence of 1.7 per million in the general population.114,164 Symptoms, hemodynamic findings, and survival of PAH associated with HIV appear to be similar to those of IPAH.165 As in the case of IPAH, prognosis is worse with more advanced symptoms (e.g., WHO functional class III or IV as compared with either I or II). A CD4 lymphocyte count below 212 cells/mm3 is also associated with a poorer prognosis.166 Mortality is more often directly attributable to PAH and right heart failure than to infectious complications.165,166 The annual incidence of pulmonary hypertension at a large Swiss cohort of HIV-positive patients appears to be declining, having peaked at 0.24 percent in 1993 as compared with 0.02 percent in 2001; this decline may relate to the introduction of highly effective antiretroviral therapies.167 It is possible, therefore, that better control of HIV infection decreases the risk of developing PAH. Whether this is true, or if therapy for HIV infection in individual patients with established PAH will alter the course of the pulmonary vascular disease remains unknown. Portal Hypertension

The lungs may be affected by chronic liver disease in several ways, including vascular dilatations with resultant hypoxemia (the hepatopulmonary syndrome), the development of pleural effusions (hepatothorax), and pulmonary hypertension. Liver disease is frequently associated with a low systemic vascular resistance and a high cardiac output; the accompanying increase in blood flow and blood volume can cause pulmonary hypertension. Vascular changes that increase pulmonary vascular resistance occur when pulmonary arterial hypertension is associated with portal hypertension, i.e., the

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Disorders of the Pulmonary Circulation

so-called portopulmonary hypertension (POPH). The pathogenesis of pulmonary hypertension in these patients may be difficult to unravel since the high cardiac output state that accompanies the liver disease may precede or accompany the development of POPH. Thus, as compared with patients with IPAH, patients with similar degrees of clinical impairment and POPH may manifest numerically smaller increments in pulmonary vascular resistance (PVR) or decrements in cardiac output. The histopathological changes seen in POPH are the same as described in other forms of PAH: vasoconstrictive, proliferative, and obliterative changes that include both plexiform and thrombotic lesions.168,169 The pathogenesis is not well understood. Although it has been suggested to involve abnormal proliferative (or other) vascular responses, the inducing trigger(s) have not been identified. As in other forms of PAH, altered levels of vasodilators and constrictors have been seen in patients with POPH.170,171 In addition, portal hypertension might alter the vasoactive mediators to which the pulmonary circulation is exposed.172 The severity of the portal hypertension does not appear to influence the risk of POPH.173 Predisposing, probably genetic, factors are also believed to determine why only some patients with liver disease develop POPH. For example, whether mutations in BMPRII are involved in the development of POPH remains unknown. The frequency of PAH in patients with liver disease has not been established. Estimates of up to 16 percent have been reported. But, these estimates are based on patients with more advanced liver disease.170,174 In one series of patients evaluated for liver transplantation the prevalence of POPH was 8.5 percent.168 Without effective treatment the prognosis of POPH is poor, a mean survival of only 15 months has been reported in one retrospective series of 78 patients.175 Survival with current therapies is worse for patients with POPH than with IPAH. In a retrospective cohort of 13 patients with POPH, survival at 1 and 3 years was 85 and 38 percent as compared to 82 and 72 percent in 33 patients with IPAH.176 The symptoms and findings on physical examination of POPH are those of both PAH and of chronic liver disease. While shortness of breath may be overshadowed by abdominal complaints and fatigue, dyspnea becomes prominent as POPH advances. Differentiating between the contributions of PAH-related cor pulmonale and liver cirrhosis to the fatigue, edema, and abdominal complaints, including satiety, bloating, and ascites, can be difficult. Compared with IPAH, relatively little is known regarding effective treatments for POPH. The small number of patients with POPH and the exclusion of these patients from clinical trials of therapy for PAH has resulted in less being known regarding the safety and efficacy of many agents. Mild disease usually does not require specific treatment; whether early therapy will prevent progression is unknown. Treatment for more severe disease differs from that of other patients with PAH in that some experts have advised against the use of calcium channel antagonists even if acute vasoreactivity to these agents has been demonstrated during cardiac catheterization. This concern is based upon the poten-

tial worsening of intrahepatic venous gradients by calcium channel antagonists.177â&#x2C6;&#x2019;180 Diuretics are particularly important in POPH due to the concomitant presence of cor pulmonale and cirrhosis, both of which cause fluid retention, edema, and ascites. Anticoagulation is less frequently used because of either underlying hepatic synthetic deficiencies and abnormal coagulation, or the presence of splenomegaly and the resulting significant thrombocytopenia. Individual patients have been treated with either intravenous or inhaled prostanoids.181â&#x2C6;&#x2019;188 The significant incidence of liver function abnormalities associated with endothelin antagonists has raised concern about their use in patients with POPH. Bosentan (Tracleer) was successfully used in a nonrandomized study of 11 patients with POPH and child class A resulting in improvements in hemodynamic values, exercise capacity, and no significant liver toxicity.189 Randomized trials have not been done. The possibility exists of using relatively specific endothelin-A receptor antagonists with lower toxic profiles. Such agents might allow the treatment of additional patients with POPH. However, such studies have not been reported. Although individual instances of improved hemodynamics following the use of sildenafil in patients with POPH have been reported, no data are available from a randomized study.190,191 Many patients with advanced hepatic dysfunction require liver transplantation. However, the perioperative mortality is significantly increased by the presence of PAH and a mean PA pressure above 50 mmHg is a contraindication to transplantation.192,193 Effective treatment has lowered pressure in some patients who subsequently underwent successful orthotopic liver transplantation.181â&#x2C6;&#x2019;184,190,194 Therefore, it is essential that POPH be recognized in patients being considered for liver transplantation prior to surgery. All potential liver transplant patients should be assessed by echocardiography followed by cardiac catheterization if the estimated right ventricular systolic pressure exceeds 50 mmHg. Serial monitoring should be performed to detect the development of pulmonary hypertension in patients listed for liver transplantation.195 Unlike the hepatopulmonary syndrome in which liver transplantation results in resolution of the pulmonary vascular abnormality, liver transplantation is not consistently curative of POPH. While some instances of reversal have been reported, in other patients POPH has progressed after transplantation.177 Drugs and Toxins

The term dietary pulmonary hypertension refers to the fact that substances taken by mouth can damage the pulmonary circulation. In animals, ingestion of crotalaria spectabilis, an annual shrub, causes multiorgan injury, including damage to the lungs. In humans, certain appetite suppressant drugs exert similar effects. Between 1966 and 1968, an epidemic of PAH erupted in Switzerland, Austria, and Germany in which the incidence of PAH

ANORECTIC AGENTS: AMINOREX AND FENFLURAMINE DERIVATIVES

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increased 20-fold.196 The epidemic followed the introduction in these countries of an appetite-depressant agent, aminorex (2-amino-5-phenyl-2-oxazoline), in November 1965. Although only 2 percent of those exposed to the drug developed PAH, the relative risk compared to unexposed individuals was 52:1.197 Aminorex resembles epinephrine and amphetamine in chemical structure; both of these agents release endogenous stores of catecholamines. Aminorex was banned in 1968, and the epidemic subsided. In some patients, the level of pulmonary hypertension decreased or stabilized at a tolerable level; in others, it seemed to reverse completely. Nonetheless, in many patients, after the drug was no longer obtainable, the disease continued inexorably from pulmonary hypertension to cor pulmonale and death. The pathology produced by aminorex in humans was identical with that of IPAH, including plexiform lesions and intimal fibrosis. Attempts to produce pulmonary hypertension by administering aminorex to experimental animals were consistently unsuccessful. This outbreak had several important epidemiological implications: (a) a medication taken by mouth could damage pulmonary arteries and arterioles; (b) since only few of the many individuals who used the agent developed pulmonary hypertension, the possibility was raised of genetic susceptibility to injury by aminorex; (c) another possibility was that other anorectic medications that resemble the catecholamines and amphetamines in structure might have similar effects in predisposed individuals (this possibility was reinforced by subsequent experience with phenformin, an anorectic agent that resembles the amphetamines in structure); and (d) pulmonary hypertension can be reversible, particularly when detected early in its course and before pressures reach systemic levels. After the aminorex epidemic, a variety of appetitesuppressant medications were used with little heed to the possibility that these agents might cause PAH. Then, in the early 1990s, Brenot et al. called attention to the coincidence in Europe of pulmonary arterial hypertension and the use of fenfluramine derivatives for weight reduction,32 prompting the establishment of an international registry in Europe to assess the incidence and risks of IPAH. Among the 95 patients enrolled in the registry, the use of anorectic agents was clearly associated with an increased risk of PAH, especially when taken longer than 3 months (odds ratio 23.8). In 1996, Abenheim et al. sounded the alarm that an epidemic might be in the making: The Food and Drug Administration in the United States had approved the use of dexfenfluramine, a major fenfluramine derivative, for the long-term treatment of obesity, even though experience with its long-term use was extremely sparse.114 Approval of dexfenfluramine by the FDA was followed by a tremendous increase in sales of dexfenfluramines and other anorectic agents. A registry of idiopathic and anorectic agent-associated PAH in the United States revealed that use of fenfluramine was strongly associated with the development of PAH (odds ratio 7.5 with more than 6 months of use). A high frequency of the use of anorectic agents in patients with other forms of PAH was also seen, suggesting these agents

Pulmonary Hypertension and Cor Pulmonale

might precipitate disease in the presence of other risks such as a collagen vascular disease.115 A few lessons were learned: (a) although aminorex and the fenfluramines differ in their pharmacologic characteristics, the pulmonary vascular lesions in the patients who die of pulmonary hypertension after taking either drug are identical; (b) the longer the anorectic agent is used, the more likely is pulmonary hypertension to occur; (c) early pulmonary hypertension is difficult to diagnose and mortality is high after the disease is established; and (d) the occurrence of pulmonary hypertension in users of anorectic agents is apt to be related to other determinants of susceptibility, perhaps genetic factors. Aminorex and fenfluramine derivatives may cause PAH by altering blood levels of serotonin (5-HT). These agents cause the release of serotonin from storage in platelets and inhibit its reuptake.40 Since 5-HT is a potent vasoconstrictor and induces aggregation of platelets, this may be a mechanism by which anorectic agents induce PAH (see Pathobiologic Mechanisms). Additional mechanisms by which aminorex and fenfluramine derivatives might contribute to pulmonary vasoconstriction is via the inhibition of potassium channels that mediate vasodilation.65 As indicated, it has also been proposed that anorexigens play an inductive role in promoting the development of PAH in genetically susceptible individuals. Genotyping for the presence of mutations in BMPRII (with familial PAH) has not revealed a significant number of abnormalities among patients with anorexigen-associated PAH.75,198 In a series of 62 patients with fenfluramine-associated PAH evaluated over a 10-year period at a single center in France, the interval between drug exposure and the development of dyspnea was approximately 4 years. Hemodynamic values at the time of diagnosis were similar to those of a control group of patients with IPAH, although patients exposed to anorectic-agents were less likely to demonstrate acute vasoreactivity and, therefore, less likely to be treated with calcium channel antagonists.199 The approach to therapy for PAH associated with the use of anorectic agenesis is the same as for IPAH. Relatively little is known regarding the prognosis of anorectic agent-associated PAH. Compared with IPAH, the data concerning prognosis are conflicting. In a retrospective study of 104 patients with aminorex-associated PAH and 69 with IPAH, survival was better in both groups when treated with warfarin and better overall for the patients with anorectic-agent associated disease.200 However, in one study, with the use of additional therapies, such as oral vasodilators and epoprostenol, survival in fenfluramine-exposed patients with PAH appears to be similar to that of IPAH patients. Another study of IPAH and fenfluramine-exposed patients, in which treatments and severity of the disease were matched, found poorer survival in the anorexigen group.201 Another episode in the story of dietary pulmonary hypertension unfolded with the occurrence of the toxic oil syndrome. In May and June 1981, adulterated

TOXIC OIL SYNDROME

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Disorders of the Pulmonary Circulation

rapeseed oil, a bootleg pseudo-olive oil sold door-to-door in Spain, caused an outbreak of noncardiogenic pulmonary edema.202 Twenty thousand persons were affected, and about 375 died. About 2000 experienced sequelae. As a consequence of close surveillance, the features of three stages of the disease were categorized: early (first 6 months), intermediate (6 months to 2 years), and chronic (persisting 5 years). From the outset, it was clear that the damage was widespread (affecting lungs, liver, skin, nervous system, immune system, muscle, and fat) and endothelial injury everywhere featured prominently in the pathogenesis of the clinical syndromes. The early stage of the toxic oil syndrome was characterized by noncardiogenic pulmonary edema, eosinophilia, and in some individuals, pulmonary hypertension; these resolved within 6 months. The intermediate stage was marked by thromboembolic events, weight loss, and neuromuscular dystrophies; PAH developed in some but often resolved. The chronic stage (particularly 4 and 5 years after the oil was ingested) involved progressive PAH and cor pulmonale. Increasingly evident were the vascular lesions of intimal fibrosis and proliferation in association with organized pulmonary thromboemboli. Plexiform lesions were also seen. Unfortunately, the chemical ingredients in the toxic oil responsible for the syndrome remain enigmatic and are unlikely to be identified, since the bootleggers provided no recipe for the adulterated cooking oil as they went out of business. Nonetheless, the outbreak did show that material taken by mouth—often in small quantities—could cause widespread endothelial injury in the lungs. It also underscored the spontaneous reversibility of the pulmonary hypertension (as well as the ineffectiveness of vasodilators tried at different stages in the disease). Hemoglobinopathies

Patients with sickle cell anemia and β–thalassemia are at increased risk for the development of pulmonary arterial hypertension. Multiple factors might contribute to the pathogenesis of PAH in patients with hemolytic states, including recurrent thromboembolism, recurrent infectious or hemolytic crises causing lung damage and hypoxia, asplenia, and the hematologic effects of the intravascular hemolysis. Hemolysis contributes to the development of PAH by decreasing the bioavailability of NO. Hemoglobin is released into the plasma from destroyed red blood, where it can destroy NO. The substrate for NO production, l-arginine, is also destroyed by increased levels the enzyme arginase, which is released into the plasma by hemolysis. Further effects of hemolysis include an increase in the expression of vascular adhesion molecules, platelet activation, the production of free radicals, and increased levels of endothelin; all of which might contribute to the vasculopathy.203−205 The reported prevalence of pulmonary hypertension in patients with sickle cell anemia has ranged from zero to 40 percent depending upon whether the population was symptomatic, whether testing involved echocardiograms or catheterization, and the age of the patients. In a prospective study of 195 adult patients with sickle cell anemia, 32

percent of patients had echocardiographic evidence of pulmonary hypertension; more than 90 percent of the patients had the SS phenotype.206 In thalassemia, the prevalence of pulmonary hypertension may vary.207−210 Pulmonary hypertension has also been noted in patients with other chronic hemolytic disorders, including hereditary spherocytosis and paroxysmal nocturnal hemoglobinuria.211,212 Pulmonary hypertension worsens the prognosis in patients with sickle cell anemia.203,206 The hemodynamic findings of PAH associated with sickle cell anemia differ from those seen in patients with idiopathic or other forms of associated PAH. In particular, the mean PAP tends to be lower and cardiac output higher in patients with sickle cell anemia and PAH than in patients with IPAH. In addition, many of the pulmonary hypertensive patients with hemoglobinopathy demonstrate a combination of intrinsic pulmonary vascular disease suggested by an increase in pulmonary vascular resistance in association with left heart diastolic dysfunction and an increase in pulmonary wedge pressure. For example, in 20 patients with PAH associated with sickle cell anemia the mean PAP was 36 mmHg, the cardiac output 8.6 L/min and the PCWP 16 mmHg; half of the patients had PCWP values greater than 15.213 The optimal treatment of patients with PAH associated with a hemoglobinopathy has not been established. Since markers of ongoing hemolysis correlate with the severity of the pulmonary hypertension as well as survival in patients with sickle cell disease, optimizing treatment of the hemolytic anemia is likely an important component in the control of PAH itself.203,206 Treatment includes the use of hydroxyurea or transfusions in order to minimize anemia and ongoing hemolysis. Prostacyclin administered intravenously can acutely decrease the mean PAP and pulmonary vascular resistance in patients with PAH associated with sickle cell anemia, but its long-term benefits have not been established.213 In an uncontrolled series of adult patients with PAH associated with sickle cell anemia, oral sildenafil acutely improved the mPAP, PVR, and cardiac index; when given chronically to 12 patients the 6-minute walk distance was improved.214 Improvements with sildenafil have also been reported in a small, uncontrolled series that included patients with thalassemia, but further evaluations of efficacy and safety issues, such as the occurrence of headache and priapism are required.215 Supplemental oxygen should be used as in other forms of PAH to prevent hypoxia. Anticoagulation to prevent thromboembolic complications of sickle cell anemia also warrants consideration. Pulmonary Veno-occlusive Disease Pulmonary veno-occlusive disease (PVOD) is a rare form of PAH in which the understanding of mechanisms and experience with treatment are even less than in other forms of PAH.18,216 Pathological changes at both the arterial and venous sides of the pulmonary circulation are found in all forms of PAH, but arterial changes tend to be the preponderate in most. In contrast, alterations at the veins described

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by the pathological term pulmonary occlusive vasculopathy are the predominant histological finding seen in PVOD17,26 (described above under Anatomic Changes in Pulmonary Arterial Hypertension). In PVOD,5 the pulmonary veins are occluded by fibrous tissue, intimal thickening, and large numbers of hemosiderin-laden macrophages. Lymphatic dilation in the lung and pleura are additional features. The incidence and prevalence of PVOD are unknown, owing at least in part to its misdiagnosis as IPAH. Thirteen percent of cases in the National Institutes of Health Registry had histological changes of PVOD. In a series of IPAH patients in which patients who met the criteria for the diagnosis of PVOD, Mandel estimated the incidence to be 0.1 to 0.2 patients per million persons in the general population.18 Prospective studies have not been performed, and the true incidence of PVOD may be higher, since patients are apt to be misclassified because of similarities in the radiographic appearance, as either interstitial lung disease or heart failure.216 There is no apparent predilection for women (as occurs in IPAH) and the diagnosis has been made in patients ranging in age from infancy to the seventh decade of life. The risk factors for PVOD are not well known. Since sibling cases of this apparently rare disease have been reported, a genetic predisposition has been postulated. Indeed, a mutation in BMPRII has been identified in a patient with PVOD whose mother had died of pulmonary hypertension (although the possible occurrence of PVOD in the parent could not be confirmed).77 Case reports of PVOD complicating treatment of cancer with various chemotherapeutic agents (notably mitomycin, bleomycin, carmustine, and gemcitabine) or following bone marrow transplantation suggest that toxic exposures might elicit pathological vascular responses.217−230 Other case reports have noted the development of PVOD in association with various thrombophilic states, autoimmune disorders, or following bacterial or viral infection, including HIV.231−238 Patients with PVOD usually present with dyspnea and fatigue; symptoms that are less typical in other forms of PAH such as cough, orthopnea, and hemoptysis have also been observed.105,239−243 The presence of basilar inspiratory crackles on physical examination, although nonspecific, might favor a diagnosis of PVOD over other forms of PAH. Decreased breath sounds might suggest the presence of a pleural effusion, which tends to occur more commonly in PVOD.244,245 The diagnosis of PVOD is suggested by the triad of pulmonary hypertension, radiographic evidence of pulmonary edema and a normal pulmonary artery occlusion (wedge) pressure. Unfortunately, all three are not universally present in cases of PVOD and the diagnosis is often delayed by confusion with other findings. For example, “high probability” findings on ventilation-perfusion scanning may lead to an erroneous diagnosis of chronic thromboembolic pulmonary hypertension.246 Findings on plain radiographs and CTs in PVOD might suggest left heart failure under other circumstances. These findings include enlargement of the central pulmonary arteries, peribronchial cuffing, Kerley B lines, interstitial infiltrates, and pleural effusions105,247 (Fig. 81-19).

Pulmonary Hypertension and Cor Pulmonale

Figure 81-19 Pulmonary veno-occlusive disease. Posteroanterior chest radiograph demonstrates pulmonary venous engorgement and edema. Diagnosis established by cardiac catheterization angiography and lung biopsy.

However, unlike left heart failure, the pulmonary artery wedge pressure is normal in patients with PVOD.248,249 Obtaining an adequate tracing, however, can be difficult. Of note has been the observation of a marked increase in pressure followed by a slow decrease to normal when saline is flushed through the wedged catheter; this sequence is presumably due to impaired run-off of fluid through the restricted pulmonary venous vessels. The diagnosis of PVOD often requires surgical biopsy, which may be too risky in the setting of severe pulmonary hypertension and not likely to lead to therapy that will alter outcome. However, the information may be helpful in avoiding needless and possibly harmful therapies and in providing the patient with information about the prognosis. Features that are atypical for other forms of PAH (e.g., radiographic abnormalities that are consistent with left heart failure) should heighten caution when considering acute vasodilator testing.105,247 Acute pulmonary edema has been precipitated by the administration of vasodilators to patients with PVOD, and deaths have been reported. There are no established therapies for PVOD. Controlled studies have not been performed and only anecdotal reports are available; these indicate both positive and negative responses to various agents. Some patients have experienced benefit, while others have died following the use of either calcium channel antagonists or intravenous epoprostenol administered intravenously.105,250−254 A single patient is reported to have experienced an improvement in exercise tolerance with the use of inhaled iloprost.255 Glucocorticoids and other immunosuppressive agents have been attempted but here too the experience has been anecdotal, with mixed results, and their use not generally recommended except in patients in whom a concomitant inflammatory condition exists.216,256,257 As in other forms of PAH, diuretics,

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supplemental oxygen, and digoxin should be employed as indicated. Newer agents for the treatment of PAH have not yet been assessed (e.g., endothelin receptor antagonists and phosphodiesterase inhibitors); for some patients, lung transplantation may be the only therapeutic option. The prognosis of patients with PVOD is poor, with most dying within 2 years of diagnosis. Pulmonary Capillary Hemangiomatosis Pulmonary capillary hemangiomatosis is another rare form of PAH with predominant involvement of the pulmonary veins. Pathologically, the findings are those of pulmonary microvasculopathy marked by angioproliferative capillary lesions that appear to invade the pulmonary vessels, interstitium, and in some instances, the airways.19,258 The etiology is unknown. The presence of vascular growth factors as well as markers of altered endothelial cell proliferation has been reported; altered expression of NO synthase has also been noted.259−261 A familial form has been identified in three siblings, but specific genetic linkage has not been reported.262 Since only scattered case reports are available for evaluation, the epidemiologic features of the disease are unknown. Pulmonary capillary hemangiomatosis may present with dyspnea and/or hemoptysis, and instances with and without associated pulmonary hypertension have been reported. The radiographic findings consist of diffuse bilateral reticulonodular infiltrates, often associated with enlargement of the central pulmonary arteries.263,264 The prognosis is terrible with most cases reported as fatal, often rapidly. Attempts at treatment with epoprostenol administered intravenously have evoked pulmonary edema.265−267 Successful treatment of a few patients with α-interferon has been reported; one patient with superimposed endotheliomatosis was stabilized with doxycycline.22,268 Lung transplantation remains an option. Therapy for Pulmonary Arterial Hypertension Treatment for pulmonary arterial hypertension aims to reduce pulmonary vascular resistance, thereby improving cardiac output. Acute improvements occur in some patients with certain vasodilators. Used chronically, some agents also appear to have cellular effects that may ameliorate some of the vascular derangements seen in untreated disease. Whereas a diagnosis of IPAH was only recently associated with a dismal prognosis, recent remarkable progress has resulted in the availability of multiple therapies and a significantly improved outlook with many long-term survivors. No currently available medical treatment, however, is curative. Lung transplantation remains an option for some who fail medical therapy. Most patients in controlled clinical trials of treatment with calcium channel antagonists, prostanoids, endothelin receptor antagonists, or phosphodiesterase inhibitors have had IPAH. Fewer patients have been studied with familial PAH or various forms of associated PAH. It is important to bear in mind the paucity of data available on the efficacy

of certain agents when used in some forms of PAH. It is also important to recognize the limits of our knowledge regarding the relative efficacy of available agents. Data from head-tohead comparisons are lacking. Most often, patients treated with epoprostenol have been sicker than those treated with oral therapies. In general, the choice of initial therapy depends upon the functional class and hemodynamic status of the patient. Most clinical trials have enrolled patients and assessed response, at least in part, on the basis of a WHO modification of the New York Heart Association functional assessment of patients with heart failure (Table 81-6). Such a scheme is often used as a rough gauge when deciding upon therapy. WHO functional class, however, should also be considered in the context of the patient’s hemodynamic status. For example, a WHO functional class III patient who has not recently experienced acute clinical change and who has a cardiac index of 2.5 L/min/m2 might be appropriately treated initially with oral therapy. In contrast, a WHO class III patient who is either experiencing a rapid clinical decline or has a severely depressed cardiac index (e.g., below 2 L/min/m2 ), might be more appropriately managed initially with intravenous prostanoid therapy. Social factors often influence the type of treatment acceptable to the patient. In addition, psychosocial issues, cognitive abilities, and other determinants of patient compliance may make certain therapies unsafe even if otherwise medically indicated.269

Acute Vasodilator Testing and Calcium Channel Antagonist Therapy

The calcium channel antagonists diminish vascular tone by preventing an increase in cytosolic calcium concentration by inhibiting both the influx of extracellular calcium and the release of calcium from intracellular stores. The longterm prognosis is good for some IPAH patients who respond acutely to the administration of short-acting pulmonary vasodilators and are treated subsequently with calcium channel antagonists. However, since other patients may be harmed by such treatment, acute vasodilator testing is performed at the time of right heart catheterization to determine suitability for such treatment. Agents commonly used include inhaled NO, infused adenosine, or epoprostenol administered by either route.270−276 Although the definition of a positive acute vasodilator response has varied, a decrease in the mPAP of at least 10 mmHg to less than 40 mmHg, and a cardiac output increased or unchanged is generally considered to be a positive response103,277 (Fig. 81-20). Acute vasodilator testing carries significant risk and deaths have been reported.278 It should not be performed when pulmonary veno-occlusive disease is suspected, as the inability of the venous system to accommodate an acute increase in flow may precipitate pulmonary edema.18 Acute vasodilator testing should be performed only at experienced centers and when the results will influence therapy. Some patients who manifest acute vasoreactivity respond to treatment with oral calcium channel antagonists

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Figure 81-20 Acute vasodilator testing. An intravenous infusion of epoprostenol (prostacyclin) was used in a patient with idiopathic pulmonary arterial hypertension illustrating vasodilation in a â&#x20AC;&#x2DC;â&#x20AC;&#x2DC;responder.â&#x20AC;? The infusion was started at 12:15. Within 15 min (12:30) the pulmonary arterial pressure (Ppa) had begun a dramatic decline despite an increase in cardiac output. The decrease in pulmonary vascular resistance lasted as long as the infusion was continued (until 13:35). After the infusion was stopped (13:35) the Ppa increased rapidly to preinfusion levels and the cardiac output dropped. The changes in systemic arterial pressure (Psa) were much less striking. (Courtesy of Dr. H Palevsky.)

and have a better prognosis. In one study, the survival rate of acutely responsive patients treated chronically with oral calcium antagonists was maintained at 94 percent when measured at 1, 3, and 5 years.279 Unfortunately, relatively few patients demonstrate acute vasoreactivity (little more than 10 percent by recent estimates) and of these only about half experience a sustained clinical response.280 Oral calcium antagonists should not be used as vasodilator therapy in the absence of acute vasoreactivity. Nonresponders not only fail to benefit but are also prone to adverse side effects, including systemic hypotension, a decrease in cardiac output because of a negative inotropic effect on the heart, arrhythmias, and retention of salt and water. Patients who do manifest a significant acute pulmonary vasodilator response to short-acting agents should undergo monitored trials of oral calcium channel antagonists. Increasing doses of nifedipine or diltiazem are usually administered until pulmonary hemodynamics are improved (i.e., there is a significant decrease in pulmonary vascular resistance, pulmonary arterial pressure, and a possible increase in cardiac output). Agents such as verapamil, which exert negative inotropic effects, should be avoided. Testing is stopped if sys-

temic hypotension develops or hemodynamic values tend to worsen. Relatively high doses of calcium channel antagonists are required to promote sufficient pulmonary vasodilation. In some instances, the required daily doses of nifedipine and diltiazem have exceeded 200 and 700 mg, respectively.281 The total daily dose should be divided and administered in two or three doses of long-acting formulations to minimize peak and trough effects during the day. Patients treated with oral calcium antagonists must be monitored for the development of side effects including systemic hypotension or peripheral edema.

Endothelin Receptor Antagonists

Recognition of the role played by endothelin in the pathogenesis of pulmonary arterial hypertension has led to the rapid development of agents which inhibit interaction with its receptors (ET A and ET B ). Both dual ET A /ET B and relatively ET A -selective antagonists have been developed for oral use. Bosentan is a dual ET A /ET B antagonist that improves hemodynamics, exercise capacity, WHO functional class and

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the time to clinical worsening (defined as death, PAHrelated hospitalization, need for altered therapy or lung transplantation).56,282 At 16 weeks, in a double-blind, randomized, placebo-controlled trial of patients with IPAH and PAH associated with collagen vascular disease (predominantly systemic sclerosis), bosentan improved the 6-minute walk distance by 44 meters as compared with placebo. Exercise capacity was improved in IPAH patients, while stabilized or the rate of deterioration slowed in patients with systemic sclerosis.56 Bosentan’s beneficial effects on exercise capacity and functional class persist at 1 year with open-label use.283 Survival of IPAH patients treated with bosentan in these trials and their open-label extensions was 96 percent at 1 year and 89 percent at 2 years as compared with expected survival of 69 and 57 percent, respectively, as predicted by the NIH registry equation.58 In nonrandomized studies or case series, bosentan appears to be effective in patients with PAH associated with HIV infection,284 adults with congenital heart disease285 and those with chronic thromboembolic pulmonary hypertension.286,287 Although data are limited, its use also appears to be effective in pediatric patients.288−290 Bosentan therapy is initiated at a dose of 62.5 mg twice daily by mouth. If liver function remains normal, the dose is increased after 1 month to 125 mg twice daily. Liver function must be monitored monthly as significant disturbances may occur; severe increases in transaminase levels (greater than eight times normal) require discontinuation of therapy. Notable side effects include peripheral edema (usually readily responsive to diuretics), anemia, and nasal congestion. Bosentan is contraindicated for use with either cyclosporine or glyburide. Ambrisentan and sitaxsentan are relatively specific ETA -receptor antagonists that, like bosentan, improve hemodynamics, exercise capacity and WHO functional class. In randomized controlled trials, each has demonstrated improvement in 6 minute walk distance (corrected for placebo effect).291−293 Patients in these studies had IPAH, or associated PAH (e.g., in patients with scleroderma). One small study showed that most patients maintain this improvement after one year of open label sitaxsentan therapy. Both drugs appear to have a lower incidence of increase in liver enzymes than bosentan, but as of the time of this writing definitive evaluation and approval for use are pending.

Phosphodiesterase Inhibition

The relative deficiency of NO-mediated vasodilation and modulation of cell growth in patients with PAH has led to attempts to enhance its therapeutic effects. NO acts through the second messenger cGMP, which is metabolized in the lung predominantly by phosphodiesterase-5. Specific inhibitors of phosphodiesterase 5 (e.g., sildenafil, vardenafil, and tadalafil) can promote acute pulmonary vasodilation.294 At present, published clinical experience is predominantly with the use of sildenafil citrate (Revatio). In a double-blind, randomized placebo controlled trial of 267 patients predominantly with IPAH and fewer with ei-

ther congenital heart or collagen vascular disease, sildenafil administered orally at 20, 40, or 80 mg three times daily improved hemodynamics, exercise capacity, and functional class.295 Although the time to clinical worsening was not affected in this single trial, the improvement in exercise capacity (51 meters as compared with baseline) was maintained over 1 year with continued open-label use of sildenafil at 80 mg three times daily. No statistically significant dose-response was seen in this trial; the FDA-approved dosage for treatment of PAH is 20 mg by mouth three times daily. In a small noninferiority study of 26 patients with either IPAH or connective tissue–associated disease, no difference in the improvement of echocardiographic measurements or 6-minute walk distance was found after 16 weeks of treatment with either sildenafil, 50 mg three times daily, or bosentan (used as described above).296 The most common side effects of sildenafil when used for treatment of PAH are headache, flushing, diarrhea, and epistaxis; systemic hypotension also has occurred, particularly when sildenafil is used in combination with nitrates. Prostanoid Therapies

Prostacyclin analogs have played a key role in the management of idiopathic and other forms of PAH. Prostacyclin is a powerful vasodilator (both pulmonary and systemic) as well as an inhibitor of smooth muscle proliferation and platelet aggregation. It is a product of arachidonic acid metabolism and acts, at least in part, by stimulating the intracellular production of cAMP. Its major source is the vascular endothelial cell and deficiencies are noted in patients with PAH. Several synthetic prostacyclin analogs are currently available for the long-term treatment of PAH, including formulations that are administered by continuous intravenous infusion (epoprostenol, treprostinil, and iloprost), or subcutaneous infusion (treprostinil) or via inhalation (iloprost). An oral prostanoid formulation (beraprost) is rarely used, except where more effective treatments are unavailable. Additional formulations are in development (e.g., treprostinil for inhalation or for oral use). Epoprostenol (Prostacyclin) (Flolan)

Epoprostenol (Prostacyclin) was the first prostanoid therapy shown in randomized clinical trials to be beneficial in the treatment of PAH. Because of its short half-life (on the order of only minutes) it requires continuous intravenous infusion. Eighty-one patients with IPAH were randomized to receive epoprostenol infusion or treatment that was standard at the time (i.e., oral vasodilators, diuretics, cardiac glycosides, and anticoagulants).297 After 12 weeks of treatment, hemodynamic values were improved in the epoprostenol group (e.g., a 21 percent decrease in pulmonary vascular resistance compared with an increase in the control patients) as was the 6-minute walk distance (increased by 31 meters compared with a decrease of 29 meters in the control patients). None of the patients treated with epoprostenol died during the

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Percent Survival

study, in contrast to a 20 percent mortality by 12 weeks with conventional therapy. Intravenous epoprostenol therapy for IPAH was approved by the FDA in 1995. Additional reports have confirmed and extended these observations. Indeed, originally conceived as a bridge to lung transplantation in patients with severe PAH, the long-term use of epoprostenol and other treatments has resulted in a decrease in the demand for lung transplantation for this indication.298 In 1998, Robbins et al. reported that more than two-thirds of their patients treated with epoprostenol were so much improved that their names could be removed from the waiting list for lung transplantation.299 In a cohort of 162 IPAH patients, McLaughlin et al. observed 1- and 3-year survival rates of 88 and 62 percent, compared to rates of 59 and 35 percent predicted by the NIH Registry equation.126 Remarkably similar results were observed by Sitbon et al. in a cohort of 178 epoprostenol-treated patients with IPAH at 1 and 3 years; somewhat lower results were obtained by Kuhn et al. In each report, survival was improved over that predicted by the NIH Registry equation.124,125 Unfortunately, however, one-third of patients with idiopathic PAH died within 3 years and nearly half by 5 years (Fig. 81-21). Epoprostenol infusion therapy has also been used in other forms of PAH. A randomized multicenter trial in patients with systemic sclerosis associated PAH (without significant interstitial lung disease) showed improvements in both hemodynamics and exercise capacity.300 Favorable results of epoprostenol treatment have also been reported for patients with PAH due to systemic lupus erythematosus,301 congenital left-to-right shunts,302 the use of anorectic agents,199 patients with HIV, portopulmonary hypertension,181 and inoperable chronic thromboembolic pulmonary hypertension.303 Epoprostenol has been used successfully in isolated instances of patients with pulmonary veno-occlusive disease. However, the use of epoprostenol in patients with PVOD must be approached with extreme caution, since its use in patients with impeded pulmonary venous blood flow might precipitate pulmonary edema.18 Isolated attempts at epoprostenol infusion therapy in patients with pulmonary capillary hemangiomatosis (also characterized by predominant involvement of the pulmonary veins) have resulted in death.22 In a single randomized trial of patients with left ventricular dysfunction,

1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

the use of epoprostenol was associated with a trend toward increased mortality. Epoprostenol therapy is initiated at 1 to 4 ng/kg/min and progressively increased in 0.5 to 1 ng/kg/min increments, at intervals dictated by patient response and side effects. Continuous increases in dosage are required in order to maintain relief of symptoms. Often, daily or alternate-day increases in dosage are needed to relieve severe symptoms (e.g., dyspnea, lightheadedness). Such titration must be closely monitored for prostanoid side effects (e.g., nausea, tachycardia, diarrhea, masticatory jaw pain).304 Patients typically reach a steady dosage between 20 and 40 ng/kg/min after several months. Thereafter, the dosage may be held stable or increased every few weeks. Even patients who do not manifest an acute vasodilator response (e.g., to infused epoprostenol) have shown improved hemodynamics and exercise capacity after sustained treatment, suggesting that epoprostenolâ&#x20AC;&#x2122;s beneficial effects are not mediated merely through acute vasodilation, but also by effects on cell growth, platelet function and cardiac output. Treatment with epoprostenol requires a tunneled intravenous catheter. Therefore, treatment is associated with a significant risk of bacterial infection. Infusion requires the use of a battery-powered portable infusion pump that must be carried at all times; the drugâ&#x20AC;&#x2122;s short half-life demands the constant availability of a back-up medication cassette and pump since an interruption in the infusion of only a few minutes can result in hemodynamic compromise. In addition, the drug is unstable at room temperature and must be mixed daily and kept cool with ice packs. For these reasons, the patient must be relatively highly functional and compliant for the safe administration of epoprostenol intravenously, preferably in conjunction with a strong social support system at home. Intensive patient and family education is required for safe initiation of therapy and is often performed in the hospital until appropriate understanding has been demonstrated.304 Despite the significant risks and inconveniences, as well as the development of longer-acting formulations, experience and duration of benefit are greatest with epoprostenol infusion, which remains an important treatment for severe PAH. It is also a benchmark against which other therapies are often compared.

Epoprostenol Treated No Epoprostenol

3 Years

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Figure 81-21 The effect of chronically infused epoprostenol therapy on survival in patients (n = 431) from multiple series with idiopathic pulmonary hypertension. Survival in the absence of epoprostenol was estimated using a predication equation derived from observations in the NIH registry of primary pulmonary hypertension at which time effective therapy was not available. (Reproduced from McLaughlin VV, et al: Chest 126:78Sâ&#x20AC;&#x201C;92S, 2004.)

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Treprostinil

A longer half-life (3 hours) and stability at room temperature has prompted the development of treprostinil (Remodulin) as an alternative prostanoid analog for intravenous therapy. While fewer data are available regarding efficacy and duration of benefit as compared with intravenous epoprostenol, treprostinil appears to have acute hemodynamic effects similar to those of epoprostenol,305 and was approved by the FDA in 2004 for the intravenous therapy of PAH. Its advantages over epoprostenol include the availability of prefilled syringes, thus obviating the need for daily mixing. Also, its stability at room temperature eliminates the need to carry ice packs to cool the infusion. Finally, the longer half-life lessens the risk of hemodynamic collapse should interruption of the infusion occur. Currently, treprostinil may be administered with the same infusion pump as that used for epoprostenol therapy, although the availability of smaller equipment may make for less inconvenient therapy. A higher dosage of treprostinil is required than epoprostenol in order to maintain improvement in symptoms. Further observation is required to establish whether survival with treprostinil is similar to that observed with epoprostenol. Treprostinil is also available for subcutaneous administration. In a large randomized double-blind placebocontrolled trial of 470 patients with idiopathic or PAH associated with congenital heart or collagen vascular disease, subcutaneous treprostinil improved hemodynamic parameters and the distance walked in 6 minutes; the distance walked improved by 16 meters at 12 weeks.306 The major advantage of subcutaneous treprostinil is the avoidance of an intravenous catheter and the associated risk of life-threatening bacteremia. While infections can occur at the subcutaneous infusion site, these are usually mild and manageable with oral antibiotics. Side effects are the same as for other prostanoid therapy (nausea, diarrhea, flushing, and jaw discomfort). The major drawback with subcutaneous treprostinil has been a considerable incidence of troublesome infusion site pain (occurring in 85 percent of patients in clinical trial).306 There is no consistently effective treatment for discomfort at the infusion site. A significant number of patients require narcotic analgesics and/or discontinue the subcutaneous use. Another relative disadvantage is a slower possible rate of dosage titration as compared with intravenous therapy, making it less attractive for use in severely ill patients at the initiation of prostanoid therapy. In select patients, however, subcutaneous treprostinil has proved to be effective therapy with minimal side effects and has allowed for avoidance of the risks and inconveniences of intravenous therapy. Reports of the development of treprostinil for either inhaled or oral administration remain preliminary at this time and require further study and review. Iloprost

Iloprost (Ilomedin, Ventavis) is an inhaled prostacyclin analog that has been available in Europe for several years and was approved in the United States in 2004. Its major advantage over other currently available prostacyclins is the lack of need

for any invasive administration equipment and a relative ease in the initiation of therapy. Inhaled iloprost requires multiple repeated administrations daily (six to nine treatments lasting approximately 10 minutes each while awake), and despite such frequency the hemodynamic effects wane prior to each administration.307 Conflicting results of efficacy were seen in uncontrolled studies,308−310 but a 12-week randomized, placebo-controlled trial of 203 patients demonstrated a placebo-corrected improvement of 36 meters in a 6-minute walk distance.311 Most of the patients studied had IPAH; the remainder had either disease associated with an anorectic or collagen vascular agent, or had chronic thromboembolic pulmonary hypertension. The hemodynamic effects are not sustained between treatments; whether this affects the long-term benefits of inhaled iloprost therapy remains to be seen. Iloprost inhalational therapy is initiated with a dosage of 2.5 µg and, if tolerated, increased to 5 µg with the subsequent dose. It is administered with any of several available delivery devices including a recently available battery-powered portable device. The major side effects are coughing, flushing, and jaw discomfort. Systemic hypotension and syncope which also occur have not been associated with clinical deterioration in clinical trials.311 Iloprost for intravenous administration is available in some European countries, but not the United States. In uncontrolled trials it has been used in patients with idiopathic collagen vascular disease associated and chronic thromboembolic pulmonary hypertension.312−314 A major use has been in patients with systemic sclerosis for the treatment of digital ulcers. The acute hemodynamic effects are similar to those of epoprostenol, but no controlled trials of its efficacy are available. Beraprost

An orally active prostacyclin analog, beraprost, has been studied in two randomized placebo-controlled trials of patients with various forms of PAH. The drug appears to result in a nonsustained improvement in exercise capacity. An initial trial of 130 patients demonstrated an improvement in 6-minute walk distance after 12 weeks of therapy, but in a subsequent study of 116 patients the effect was not sustained beyond 6 months.315,316 Neither trial with beraprost demonstrated significant hemodynamic improvement as compared with placebo. Beraprost is rarely used currently except when other agents remain unavailable. Combination Therapy

Despite the significant improvements in function and survival that have accompanied the advent of several classes of clinically effective drugs, PAH remains a life-threatening disease and many patients suffer progressive decline. As clinical deterioration progresses, it is tempting to replace one agent with another. Alternatively, additional agents are added and used in combination. Few data are available regarding the best approach. In 33 patients with IPAH, bosentan was administered in a randomized, placebo-controlled trial 2 days after starting

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epoprostenol. Both control and test groups demonstrated improved exercise capacity and hemodynamics, but no statistically significant difference resulted from the combination therapy. However, the small sample size may have precluded identification of differences in efficacy or safety.317 Moreover, such evaluation does not inform whether there is benefit to the patient from adding either agent to the other in a patient who deteriorates despite treatment with the single agent. In an observational study of 20 patients who had already received an average of 16 months prostanoid therapy with either inhaled iloprost or oral beraprost, the addition of bosentan significantly increased the 6-minute walk distance and maximal oxygen consumption.318 The majority of patients received beraprost, and an analysis of patients treated only with iloprost is not available. Although combination therapy appeared to be safe in each of these trials as long as liver function was monitored as for bosentan alone, adverse events did occur and firm conclusions about safety cannot be drawn. The addition of inhaled iloprost to already established bosentan therapy has been evaluated in a randomized, double-blind, placebo controlled trial. Patients in this study had received at least 4 months of bosentan therapy prior to the initiation of iloprost. Sixty-seven patients with either idiopathic or associated PAH and WHO functional class 3 symptoms were enrolled. Following 12 weeks of inhaled iloprost there was a placebo-adjusted improvement in 6 minute walk distance of 26 meters. Hemodynamic values were also improved, as was the time to clinical worsening. It is not known whether the patient’s initial response to bosentan monotherapy influences subsequent change with the addition of iloprost.318a Experience with prostanoids used in combination with phosphodiesterase inhibitors is also limited. In a series of 14 patients who were deteriorating despite ongoing therapy with inhaled iloprost, the addition of sildenafil resulted in an improvement in exercise capacity that was sustained during 1 year of follow-up.319 Patients had either idiopathic PAH or PAH related to collagen vascular disease, and the dosage of sildenafil was either 25 or 50 mg three times daily. Sildenafil may potentiate and prolong the vasodilatory effects of iloprost alone.320−321 Further evaluation of the combination has not yet been performed. There is little published experience with the combination of oral therapies. In a series of nine IPAH patients whose exercise capacity had initially improved but subsequently declined during an average of 11 months of bosentan monotherapy, the addition of sildenafil at up to 50 mg three times daily resulted in a recovery of the prior gain in 6-minute walk distance.322 Although the improvement was sustained during a median of 9 months of combination therapy, randomized trials have not been reported. The combination of an endothelin receptor antagonist and a phosphodiesterase inhibitor may have beneficial pharmacologic effects, the clinical importance of which has not been fully studied. Anticoagulation

In the absence of contraindications, most practitioners recommend anticoagulation with warfarin for patients with sig-

Pulmonary Hypertension and Cor Pulmonale

nificant PAH. This is reasoned to be of benefit on the basis of autopsy studies, which have revealed in situ thrombosis of both venous and arterial vessels without evidence of an embolic source in a significant proportion of patients with PAH.23−25 Anticoagulation is also justified on the basis of the increased risk of venous thromboembolic disease in patients with severe heart failure and immobility, and the anticipated poor tolerance of such patients for embolic events. However, the efficacy of anticoagulant therapy in patients with PAH has not been studied in randomized controlled trials. Nonetheless, uncontrolled observational reports have demonstrated an association between warfarin use and increased survival. In a study of 64 IPAH patients treated with or without calcium channel antagonists, survival after 5 years was greater among those patients in either group who at their provider’s discretion had received warfarin.279 In a retrospective evaluation of 173 patients with either idiopathic or anorexigenassociated PAH, anticoagulation was associated with a statistically greater survival in the anorexigenic-agent patients and a trend toward improvement after 5 years of therapy in patients with idiopathic PAH.200 Extrapolating from such studies, warfarin is often prescribed to patients with other forms of PAH despite the absence of disease-specific data. The generally recommended target international normalized ratio (INR) for warfarin therapy in patients with PAH is 1.5 to 2.5.323 The severity of disease (e.g., threshold mean PAP or PVR) at which anticoagulation should be initiated has not been determined.

Surgical Treatments

Lung transplantation is addressed in detail elsewhere in this volume. Here, it suffices to note that lung transplantation remains an important option for some patients with IPAH whose disease fails to respond adequately to medical therapy. Single-lung, double-lung, and heart-lung transplants have been performed, but the outcomes favor a doublelung procedure.324 The reported outcome of patients undergoing lung transplant for IPAH have been poorer than for other indications, with 1-year survival of approximately 65 percent in patients with IPAH as compared with 74 percent overall.325 Fortunately, however, advances in medical therapies have markedly reduced the need for lung transplantation.326 Whereas 10 percent of all lung transplant recipients in 1990 had IPAH, more recently these patients account for only 4 percent of procedures.327 Recently, a new organ allocation system has been adopted for lung transplantation that aims to assign a priority score by assessing both acute need (expected survival in the absence of transplant) and likely benefit (survival with transplant) for individual patients. It remains unclear how this system will influence the availability and outcomes of transplantation for patients with IPAH. There is concern that the system may assign a lower priority to patients with IPAH by failing to account for factors indicating a poorer prognosis (and thus an increased acute need) in these patients. In addition, since likely benefit is assessed by survival rates 1 year following transplantation, this criterion may also lower the assigned priority of IPAH

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patients to receive available organs. Although survival at 5 years is similar to that of other populations, rates for IPAH at 1 year after transplantation have been inferior. Atrial septostomy has been performed as a palliative measure, as well as a “bridge” to lung transplantation in some patients with severe PAH and symptoms refractory to other therapies. The creation of a right-to-left shunt is aimed at decreasing the pressure overload of the right ventricle, and simultaneously increasing preload of the left ventricle, thereby improving systemic perfusion. Controlled studies have not been performed, and appropriate selection criteria are not known. Significant palliation of patients has been reported, but deaths have occurred as well. The procedure remains an option at institutions that are experienced in its use. Other Considerations

Pregnancy in women with IPAH is associated with a high mortality, i.e. of the order of 30 to 50 percent.328−330 Mechanical barriers to conception are recommended in females of child-bearing age. Most experts recommend early termination of pregnancy in this group.331 Should pregnancy be continued, early hospitalization is advisable for monitoring and supportive therapy.332 Case reports have appeared of the successful management of pregnant IPAH patients using intravenous epoprostenol and inhaled NO.333−335 Postmenopausal hormonal replacement therapy using estrogens should be undertaken with caution because of the associated risk of thromboembolism; concomitant anticoagulation should be considered. Patients should be queried about the concomitant use of medications and herbs. Warfarin is particularly apt to be associated with drug-drug interactions. The use of vasoconstrictor or serotoninergic medications for unrelated illnesses, such as migraine, should also be undertaken cautiously. Patients taking bosentan are at risk of interaction with such medications as cyclosporine and azole-type antimicrobial agents, and care must be taken to avoid glyburide-containing diabetic therapies. Surgical procedures may entail considerable operative and postoperative risk in patients with hemodynamic compromise from PAH. Vulnerability of patients with severe PAH to vasovagal events has to be kept in mind. A vasovagal attack can be precipitated by pain, nausea, vomiting, or straining at the stool (Fig. 81-22). The induction of anesthesia and intubation is a particularly troublesome time. The combination of bradycar-

Figure 81-22 Idiopathic pulmonary arterial hypertension. Bradycardia and prolongation of atrioventricular conduction progressed to atrioventricular dissociation while patient was on bedpan. Associated with syncope.

dia and systemic vasodilation can lead to a precipitous drop in systemic blood pressure. Atropine or a similar agent should be kept at hand during invasive procedures.

Pulmonary Hypertension Associated with Left Heart Disease or with Extrinsic Restriction of Pulmonary Venous Blood Flow Left heart disease, such as mitral stenosis and ventricular dysfunction, generally elicits pulmonary hypertension by increasing pulmonary venous pressure. Precapillary vasoconstriction, presumably a reflex phenomenon, contributes to the pulmonary hypertension. Elevated end-diastolic pressures in the left ventricle are additional contributing factors. This mechanism is operative in left ventricular systolic or diastolic dysfunction. The pulmonary hypertension is a consequence of parenchymal fibrosis secondary to interstitial edema, trapping of the resistance vessels in the perivascular fibrosis, and reflex arterial vasoconstriction elicited by pulmonary venous hypertension. In chronic pulmonary hypertension due to heart disease, the muscular pulmonary arteries undergo changes that depend on the severity and chronicity of the pulmonary hypertension. These changes may determine the response to medical treatment, the benefit and risk of surgery, and the ultimate outcome. Early in the evolution of the pulmonary hypertension, the changes reflect, in large measure, the initiating mechanism—e.g., predominantly intimal changes in a large left-to-right shunt in contrast to predominantly medial changes in lesions that expose the vessels to systemic arterial pressures (e.g., Eisenmenger’s disease). However, in unremitting chronic pulmonary hypertension such distinctions tend to blur and are often complicated by secondary effects, such as in situ thrombosis, perivascular fibrosis, and decrease in parenchymal elasticity. In general, chronic pulmonary hypertension may be sustained by two mechanisms: vasoconstrictive, attributable to intrapulmonary reflexes, and/or heightened sympathetic activity; and structural changes in the vessels or in their immediate vicinity, which may reverse if pulmonary arterial pressures can be lowered. The possibility of vasoconstriction has been the basis for trials of pulmonary vasodilators. A role for remodeling of the small muscular arteries and arterioles is indicated by instances of striking relief of pulmonary hypertension 1 to 2 years after surgical treatment of mitral stenosis. Unfortunately, such remodeling is not universal, and pulmonary vascular derangements with progressive pulmonary hypertension can occur well after correction of the mitral valvular or other left heart abnormality. In the management of pulmonary hypertension secondary to congestive heart failure, a cardiotonic regimen that features the use of diuretics and an inhibitor of the angiotensin-converting enzyme (ACE) plays a pivotal role. The role of digitalis is debatable. In general, pulmonary vasodilators (other than ACE inhibitors) have not been shown to be effective in maintenance therapy.336 Indeed, the beneficial effect of ACE inhibition is more apt to be due to the reduction in systemic vascular resistance and the resultant

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improvement in left ventricular function than to the modest direct effects of ACE inhibition on pulmonary vessels. Prostacyclin has increased morbidity and mortality, and in some patients, acetylcholine infusion has elicited pulmonary vasoconstriction instead of vasodilatation. Increased pulmonary venous pressures can also result from obstruction of the large pulmonary veins en route to the left atrium. The underlying cause may be fibrosing mediastinitis (e.g., due to histoplasmosis), neoplastic invasion of lymph nodes (e.g., metastatic carcinoma of the breast), lymphoma (e.g., Hodgkin’s disease), or lymphadenitis (e.g., due to sarcoidosis). Pulmonary vein stenosis can also occur as a complication of catheter ablation for treatment of atrial fibrillation. Isolated reports have described amelioration of patients with stenting of the affected pulmonary veins.337,338

Pulmonary Hypertension Associated with Hypoxemic Lung Disease Various disorders and diseases of the breathing apparatus, including derangements of the respiratory muscles, chest wall, airways, and alveoli, and the drive to breathe can be accompanied by pulmonary hypertension. These include prevalent problems, such as COPD and OSA. As a result, these abnormalities comprise relatively common causes of pulmonary hypertension. In turn, pulmonary hypertension and associated cor pulmonale can contribute significantly to the morbidity and mortality of these diseases. Hypoxia is commonly present when these disorders result in pulmonary hypertension and can contribute to the increase in pulmonary arterial pressures. Management of pulmonary hypertension in each is generally aimed at optimal treatment of the underlying disorder. Little is known about therapy directed at the pulmonary hypertension itself in these settings and such efforts have not been shown to be helpful. Chronic Obstructive Pulmonary Disease Chronic hypoxic vasoconstriction is thought to contribute to remodeling of the vasculature in COPD. The remodeling involves hypertrophy of the pulmonary vascular smooth muscle with extension into normally nonmuscularized branches of the pulmonary arteries, intimal thickening, and an accumulation of extracellular matrix components (intimal fibroelastosis).339 Such changes have also been reported in patients with milder COPD and in the absence of hypoxia.340 Furthermore, treatment of hypoxia with oxygen, although beneficial, does not always result in complete resolution of the pulmonary hypertension. These data suggest the involvement of additional mechanisms in the vascular remodeling. Possibilities include endothelial cell dysfunction with abnormal levels of vasoactive mediators, including increased endothelin and decreased NO synthase.341,342 Vascular injury might also be caused by smoking-induced oxidative stress or inflammatory infiltrates.340,343 Increased blood viscosity (due to polycythemia) and flow have also been suggested. Finally, destruction of the pulmonary vasculature by emphysema itself will contribute to a decrease in vascular compliance (Fig. 81-23).

Pulmonary Hypertension and Cor Pulmonale

The prevalence of pulmonary hypertension in patients with COPD has not been firmly established. Right ventricular hypertrophy has been seen at autopsy in up to 40 percent of patients with COPD. When measured by right catheterization, pulmonary hypertension has been found in 20 to 90 percent of patients.344−349 Although the severity of the pulmonary hypertension tends to correlate with the degree of airflow obstruction and the severity of hypoxemia,350,351 the degree of pulmonary hypertension tends to be mild to moderate. Mean PA pressure tend to be no higher than 35 to 40 mmHg even when the airways obstruction is severe346,349,350 and progression over time is slow.345,352 However, there does appear to be a small subset of patients with COPD who, despite only moderate degrees of airflow obstruction, develop severe hypoxemia (PaO2 of the order of 40 mmHg) and more severe pulmonary hypertension, with mean PAP greater than 45 mmHg.349,353 Why some patients with COPD develop more severe pulmonary hypertension than others is not known. Hypotheses include an increased vasoconstrictor response to hypoxia or the possible presence of intrinsic pulmonary vascular disease in a patient who (independently) also has COPD.354 Such patients must undergo a complete evaluation for additional causes of pulmonary hypertension (e.g., coexisting obesity hypoventilation, sleep apnea, or coronary artery disease). Other causes are common and may significantly influence therapy.353 In patients with COPD, whether mild or more severe, the presence of pulmonary hypertension is associated with an increase in hospitalization and a poorer prognosis.344,346,355−357 Indeed in some studies the degree of pulmonary hypertension is a more powerful indicator of prognosis than are measures of airflow obstruction.351 Abnormal right ventricular function is also associated with a poorer prognosis in patients with COPD.358 Hyperinflation of the lungs may obscure the physical examination, radiographic and electrocardiographic evaluation of pulmonary hypertension and cor pulmonale. Heart sounds are frequently less audible than normal in patients with severe COPD. Nonetheless, an accentuated second heart sound, ventricular gallops and a tricuspid regurgitant murmur can often be heard upon deep inspiration. Physical examination of the patient may also reveal tender hepatomegaly, as well as peripheral edema and cyanosis. On plain chest radiographs, prominence of the pulmonary arteries may be seen, together with peripheral vascular “pruning.” The presence of cardiac enlargement may become evident in serial studies obtained in the course of treating cor pulmonale that is due to an acute exacerbation of COPD (discussed below). Electrocardiographic evidence of right ventricular or atrial enlargement can also be obscured by cardiac rotation and interposition of an increase in air between the heart and the chest wall. As in other forms of pulmonary hypertension, the echocardiogram is often the first test performed when the presence of pulmonary hypertension is suspected. Frequently, these studies are limited technically due to hyperinflation of the chest that accompanies severe airways obstruction. As a result, a reliable estimate of pulmonary arterial pressure is frequently not possible.359 Right heart catheterization is

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Figure 81-23 Gough (sagittal) sections. Lung architecture in normal lung and in obstructive airway diseases. A. Normal lung. Between large airways and vessels the parenchyma is intact. B. Centrilobular emphysema. C. Cystic fibrosis. The large airways are dilated and bronchiectatic, whereas the gas-exchanging surface is well preserved. (Courtesy of Dr. S Moolten.)

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frequently needed to confirm the diagnosis when the presence of pulmonary hypertension will influence therapeutic decisions (e.g., in evaluation for lung transplantation or volume reduction surgery). The treatment of pulmonary hypertension in patients with COPD applies, in general, to the management of patients with cor pulmonale. Most important for the treatment of pulmonary hypertension in patients with COPD is the prevention of arterial hypoxemia. Supplemental oxygen therapy is used to prevent hypoxic pulmonary vasoconstriction and can increase survival and quality of life in patients with COPD.113 Oxygen therapy can also result in modest improvements in pulmonary hemodynamics, although pressures do not tend to normalize. Although longterm oxygen therapy has been shown to improve survival, this benefit may not be attributable to improvement in pulmonary hemodynamics.360−363 Oxygen should be prescribed and titrated to maintain oxyhemoglobin saturation above 90 percent, not only at rest but also during exertion. Treatment of airways obstruction with bronchodilators and antibiotics to clear acute respiratory infection is also important. Diuretics are often needed for management of cor pulmonale but must be used cautiously. Chloride-losing agents run the risk of promoting hypercapnia, which predisposes to respiratory depression and the aggravation of ventilatory insufficiency. The use of digitalis must also be undertaken with caution because of the threat of digitalis-associated cardiac dysrhythmias during hypoxia. Vasodilators (other than oxygen) have no proven use in the management of pulmonary hypertension due to COPD. No pulmonary vasodilator has proved to be as effective as oxygen in chronic obstructive (hypoxemic) pulmonary disease with respect to either survival or exercise tolerance. Overall, the sporadic trials of vasodilators in COPD have shown little benefit: As a rule, pulmonary hemodynamics have shown little improvement, while gas exchange has been further compromised. Also, undesirable systemic side effects have been common. While some studies have demonstrated acute improvements in hemodynamic parameters following the administration of calcium channel antagonists, long-term benefit has not been proved. Moreover, these agents may worsen oxygenation by interfering with ventilation-perfusion matching and may precipitate ventricular dysfunction, systemic hypotension and dysrhythmias.364−370 Prostacyclin has had only limited trials in COPD and has not become popular for both practical and theoretical reasons. Although it increases the cardiac output by dilating pulmonary vessels that are vasoconstricted due to hypoxia, prostacyclin runs the countervailing risk of aggravating ventilation-perfusion abnormalities. In the few studies to date, the increase in cardiac output resulting from pulmonary vasodilation has left pulmonary arterial pressure virtually unchanged without decrease in the work of the right ventricle.371,372 Similarly, there is no proven benefit to the endothelin receptor antagonists or phosphodiesterase inhibitors in patients with COPD. In contrast, NO can improve pulmonary vascular resistance in patients with COPD and pulmonary hypertension, and long-term use with

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a “pulsed” inhalational delivery system may improve hemodynamics. Confirmation of a benefit from NO awaits further study.373−375 Alveolar Hypoventilation In patients with normal lungs who develop alveolar hypoventilation, the common pathogenetic denominators are alveolar hypoxia and arterial hypoxemia, often reinforced by respiratory acidosis. In contrast to the alveolar hypoventilation of obstructive airway disease, which is a consequence of ventilation-perfusion imbalances, alveolar hypoventilation in patients with normal lungs is global, affecting the lung everywhere, although not necessarily to the same extent. Global alveolar hypoventilation generally stems from an inadequate ventilatory drive or an ineffective chest bellows (Fig. 81-24). In particular, a variety of disorders, ranging from the sleep apnea syndromes, a “dead” respiratory center, paralysis of respiratory muscles in the Guillain-Barr´e syndrome, kyphoscoliosis, and morbid obesity, can each be responsible.376 The diverse causes share hypoxia and often respiratory acidosis as the common pathogenetic mechanism for pulmonary hypertension. In the chronic hypoventilation that follows damage to the respiratory center (as by encephalitis), the normal lungs and chest wall do not receive adequate ventilatory drive. Postpoliomyelitis damage to the respiratory center is often associated not only with paralyzed respiratory muscles but also with damaged nerves to the intercostal muscles. Extreme obesity imposes a mechanical burden on the respiratory apparatus, chiefly by way of the abdomen, but often the mechanical load is accompanied by another derangement (e.g., an inherently inadequate ventilatory drive) that contributes to the alveolar hypoventilation. In kyphoscoliosis, not only is the lung compressed and distorted but the mechanical operation of the chest bellows is compromised and the elastic properties of the lungs and chest wall are abnormal, albeit to different degrees. Although the routes to hypoxia are different, once the arterial PO2 falls below 40 to 50 mmHg, the pulmonary arterial walls of the patients undergo the same changes as those that occur spontaneously in native dwellers at high altitude: pulmonary arteries and arterioles undergo muscular hypertrophy, and a self-perpetuating mechanism appears to have been established (Fig. 81-32). Obstructive Sleep Apnea OSA is a common disorder characterized by repetitive episodes of hypoventilation and associated oxyhemoglobin desaturation. It is associated with alterations in sympathetic nervous system activity that results in systemic hypertension and an increase in the risk of stroke, myocardial infarction, and left heart dysfunction. In some patients, OSA is associated with the development of pulmonary hypertension. Participating in the pathogenesis of the pulmonary hypertension are believed to be hypoxic pulmonary vasoconstriction that accompanies repetitive episodes of hypoventilation, endothelial cell dysfunction, and progressive vascular remodeling.

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Figure 81-24 Gough (sagittal) sections. A. Alveolar hypoventilation secondary to abnormalities in chest wall and pleura. Kyphoscoliosis. (Courtesy of Dr. J Gough Cardiff.) B. Asbestosis. Encasement of lung by thickened pleura. (Courtesy of Dr. S Moolten.)

Estimates of the prevalence of pulmonary hypertension in patients with OSA have ranged from 17 to approximately 50 percent.377 It must be noted that many studies have defined pulmonary hypertension at a value lower than that generally used (e.g., a pulmonary artery pressure greater than 20 mmHg) and that not all studies have excluded concomitant left heart or pulmonary disease. Consistent across several studies, however, has been a tendency for patients with OSA and pulmonary hypertension to be older and have more severe nocturnal hypoxemia and worse lung function (spirometric values) than the OSA patients without pulmonary hypertension. The apnea-hypopnea index, on the other hand, has not been consistently associated with the presence of pulmonary hypertension. Patients with OSA and chronic lung diseases have an increased propensity for developing pulmonary hypertension.378â&#x2C6;&#x2019;381 In one study, which defined pulmonary hypertension as a mean PAP greater than 20 mmHg, pulmonary hypertension was found in 17 of 27 patients (58 percent) with obesity hypoventilation as compared to 19 of 181 (9 percent) with only OSA; 11 or 26 (36 percent) of patients with OSA and COPD (the overlap syndrome) had pulmonary hypertension. The severity of OSA was similar in the three groups.382 Pulmonary hypertension in most patients with OSA is usually mild. Typically, mean PA pressures range between 20 to 35 mmHg.381,383 Usually, patients with more severe

pulmonary hypertension and right heart failure also have COPD, obesity hypoventilation, or other causes of daytime hypoxemia.380,384 However, patients with OSA may have obesity that is severe enough not only to evoke more severe nocturnal hypoxemia, but also to result in restrictive ventilatory defects and daytime hypoxia.381,383,385 Treatment of the OSA itself using continuous, or bilevel, positive airway pressure usually suffices for the management of pulmonary hypertension. Oxygen should also be administered as required to prevent oxyhemoglobin desaturation during sleep and while awake. No specific therapy (e.g., pulmonary vasodilators) is usually required or indicated for treatment of mild pulmonary hypertension. Treatment of OSA for at least 3 months with continuous positive airway pressure in patients without concomitant lung or heart disease can decrease pulmonary artery pressures in patients with mild baseline increases in pulmonary arterial pressures.386,387 The role of other therapies for more severe pulmonary hypertension in patients with OSA has not been specifically evaluated, nor when OSA is accompanied by significant left heart or lung disease. Interstitial Lung Disease A wide variety of pathological processes can evoke pulmonary interstitial fibrosis (see Figs. 81-25 and 81-26). These include sarcoidosis, asbestosis, idiopathic pulmonary fibrosis (IPF),

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Figure 81-25 Sarcoidosis. Consecutive stages in evolution of diffuse pulmonary fibrosis that in time became associated with ventilation-perfusion abnormalities and cor pulmonale. (Courtesy of Dr. GG Pietra)

and radiation pneumonitis. Connective tissue diseases such as scleroderma, systemic lupus erythematosus (SLE), rheumatoid arthritis, SjÂ¨ogrenâ&#x20AC;&#x2122;s syndrome, and mixed connective tissue disease, also are commonly complicated by interstitial lung disease (ILD). Lymphangitic spread of carcinoma within the lungs can produce the same effect (see Fig. 81-26). In these disorders, progressive fibrosis and infiltration not only thicken and distort the pulmonary interstitium, replacing the normal extracellular matrix with cells and scar tissue, but also

entrap the pulmonary blood vessels and obliterate segments of the pulmonary vascular bed (see Fig. 81-7). As a result, some segments of the pulmonary vascular bed are amputated, others are encased in scar, and the overall distensibility of the pulmonary parenchyma is diminished. In some disorders, such as silicosis, distortion of the lung due to the pulling of scar tissue on normal and less-affected lung intensifies the derangements in the pulmonary parenchyma. Disorders such as sarcoidosis affect not only the parenchyma of the lung but

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Figure 81-26 Diffuse interstitial disease. A and B. Lymphangitic spread of carcinoma of the breast in a 50-year-old woman. In the 2 years between the chest radiographs, dyspnea and tachypnea had progressed. The pulmonary function tests showed severe impairment of diffusion; the electrocardiogram indicated right ventricular enlargement (cor pulmonale). C and D. Sarcoidosis in a 50-year-old man. In the 2 years between the chest radiographs, pulmonary fibrosis had progressed strikingly. At autopsy pulmonary fibrosis was marked; bronchi were widely dilated and emphysematous areas were juxtaposed to areas of dense fibrosis. Cor pulmonale was confirmed.

also the walls of the airways. In each, hypoxic pulmonary vasoconstriction may contribute to the development of pulmonary hypertension. The resulting loss of vascular surface area and vasoconstriction increase pulmonary vascular resistance. The common denominator in pulmonary interstitial disease is a pattern of restrictive lung disease. The original descriptions of this disease focused disproportionately on impairment of the diffusing capacity of the lungs by thickened alveolar-capillary membranes; hence, the designation

â&#x20AC;&#x153;alveolar-capillary block.â&#x20AC;? But since then, disturbances in ventilation-perfusion relationships have been appreciated as dominant features, particularly in the later stages of the disease. The lungs are stiff (poorly compliant) because of the diffuse interstitial disease, which limits distensibility and increases pulmonary vascular resistance by obliterating small pulmonary arteries and arterioles. Elastic recoil is correspondingly elevated. In some diseases, such as asbestosis, thickening of the pleura can be another factor in reducing

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pulmonary compliance. Oxygen consumption becomes abnormally high, largely because of an increase in the work of breathing. As the disease progresses, lung volumes undergo gradual, concentric reduction. As an adaptation that minimizes the elastic work of breathing, the minute and alveolar ventilation are high and breathing is rapid and shallow. These adaptations help to maintain the arterial PO2 at near-normal levels. However, exercise often elicits a precipitous drop in arterial PO2 . When the interstitial process has advanced sufficiently to be seen on the chest radiograph, the arterial PCO2 either remains slightly low or begins to return toward normal levels, largely as the result of ventilation-perfusion abnormalities (see below). The diffusing capacity decreases progressively as the interstitial fibrosis progresses; even though the value for the diffusion capacity may fall within normal limits at rest, it generally fails to increase normally during graded exercise. Derangements in alveolar ventilation and blood flow are present early in interstitial disease but arterial blood oxygenation may remain at near-normal levels. But, in time, progressive disease exaggerates the imbalances sufficiently to cause arterial hypoxemia at rest. As long as the arterial hypoxemia remains mild, pulmonary hypertension is generally modest at rest, increasing during exercise. But as the disease progresses and arterial hypoxemia intensifies, the level of pulmonary hypertension also increases, and cor pulmonale begins to evolve. Arterial eucapnia or hypocapnia is gradually succeeded by hypercapnia. Right ventricular failure occurs late in the course of the disease, often in association with severe hypoxemia and respiratory acidosis. The pulmonary hypertension associated with interstitial lung disease progresses over time, often with an accelerated course later in the disease. At this point further worsening of the interstitial process often cannot be detected by changes in lung function or in the appearance of chest radiographs. At this point, attention usually turns to the pulmonary hypertension as the “cause” of worsening dyspnea. However, distinction between the pulmonary vascular and interstitial contributions to the dyspnea is rarely clinically possible. Even though the pulmonary vascular derangements are doubtlessly contributing symptoms, therapy at this point frequently fails to bring about substantial relief. Dyspnea may become manifest at rest, and is often exacerbated by coexistent musculoskeletal complaints or anemia.388 Unlike that usually seen in most patients with COPD or OSA, the pulmonary hypertension associated with ILD can be severe. Estimation of pulmonary artery pressure by Doppler echocardiography in patients with advanced ILD can be difficult and at times inaccurate.389 Cardiac catheterization is often required to confirm the diagnosis of pulmonary hypertension and exclude left heart disease as a contributing factor. In addition to ILD, other causes of pulmonary hypertension must be considered in patients with collagen vascular disease. Categorizing the disease is frequently problematic. In particular, SLE, systemic sclerosis (scleroderma), and its variant forms, can each cause pulmonary hypertension in the absence of apparently significant interstitial lung disease.

Pulmonary Hypertension and Cor Pulmonale

Characterization of these patients as having either pulmonary arterial hypertension associated with collagen vascular disease or alternatively pulmonary hypertension associated with interstitial lung disease may be difficult, as the two may frequently coexist. In the scleroderma spectrum of diseases, isolated pulmonary arterial hypertension is more likely to be seen in patients with the CREST variant (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, and telangiectasias), while patients with systemic sclerosis more often have prominent pulmonary fibrosis and restrictive lung disease. In addition to ILD, sarcoidosis can cause pulmonary hypertension by direct granulomatous involvement of the pulmonary vasculature, by hypoxia from direct involvement of the airways or by extrinsic compression of the pulmonary veins by enlarged hilar lymph nodes.390 However, these distinctions are clinically important since, as a rule, no therapies have been established as useful for the specific treatment of pulmonary hypertension that complicates interstitial lung disease. On the other hand, drugs used for treatment of pulmonary arterial hypertension are known to be efficacious in the treatment of disease associated with collagen vascular disease (discussed above under Pulmonary Arterial Hypertension Associated with Specific Conditions).300,391 As a rule, clinical trials that have demonstrated benefit have excluded patients with either significant restrictive ventilatory defects (typically a total lung capacity less than 70 percent predicted) or the subjective assessment of “significant” interstitial disease on chest radiographs. Only isolated instances have been reported of hemodynamic improvement following with the administration of various vasodilators in patients with IPF and sarcoidosis. Convincing larger studies that demonstrate benefit are lacking.392,394 In patients with ILD, the possibility of worsening ventilation-perfusion relationships and aggravating hypoxia by the administration of vasodilators has been a concern as in the use of vasodilators in patients with COPD. Inhalational therapy with vasodilators (e.g., iloprost or other prostacyclin analogs) has the theoretical advantage of avoiding ventilation-perfusion mismatch. A small series has demonstrated acute hemodynamic improvements with either inhaled prostacyclin or NO in patients with pulmonary hypertension and ILD, and long-term administration of inhaled iloprost was beneficial in a single patient.395 It has been hypothesized that the antifibrotic activities of endothelin receptor antagonists will be of benefit in patients with ILD (with or without pulmonary hypertension), but this has not been proved. Since the presence of pulmonary hypertension is a poor prognostic sign in patients with ILD, early referral for evaluation of lung transplantation should be considered. Patients with hypoxemia at rest or with exertion should be treated with supplemental oxygen, titrated to prevent oxyhemoglobin desaturation. When cor pulmonale is present, diuretics may be beneficial, but must be used cautiously so as to prevent dehydration, systemic hypotension, or electrolyte derangements (as discussed above under General Aspects of Disease Management).

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Chronic Thromboembolic Pulmonary Hypertension Chronic thromboembolic pulmonary hypertension (CTEPH) is a more common complication of pulmonary embolism (PE) than has been previously appreciated.396,397 At a large referral center that followed 223 patients for up to 5 years after an initial pulmonary embolus (PE), symptomatic CTEPH developed in 3.1 percent. CTEPH was found in 13.3 percent of 82 patients with a prior history of either deep venous thrombosis or PE. Symptoms and the diagnosis of CTEPH occurred in all cases within 2 years of pulmonary embolus. Risks identified in this population for developing CTEPH were idiopathic PE, younger age at presentation, multiple embolic events, and larger perfusion defects.398 Prior cohorts have identified a significant risk of CTEPH following anatomically massive PE (defined as obstructing at least 50 percent of the pulmonary vasculature). In one study, 20 percent of 227 patients with massive PE developed CTEPH following initial thrombolytic treatment.399 Perfusion defects do not consistently resolve following acute PE, and residual defects despite anticoagulation have been assumed to confer a greater risk of CTEPH, although this has not been definitively established.400−403 The genetic, hematologic, or other determinants of clot resolution are also not completely understood. Various causes of thrombophilia have been studied with mixed results and none firmly established as increasing the risk of CTEPH. It is not clear to what degree the eventual development of CTEPH is determined by each recurrent thromboembolic event, in situ thrombosis or by other changes in the vasculature distal to the vessels initially obstructed by clot (Fig. 81-27). In addition to recanalized clot, histological changes similar to those seen in other forms of pulmonary hypertension have been identified in patients with CTEPH404 (Fig. 81-28).

Figure 81-27 Acute and chronic clot within the pulmonary vasculature of a patient with chronic thromboembolic pulmonary hypertension. Recanalization of chronic clot has occurred. (Courtesy of Dr. GG Pietra.)

Figure 81-28 Contrast between plexiform and thromboembolic occlusions. A. Plexiform lesions in a muscular pulmonary artery in a 56-year-old woman with idiopathic pulmonary arterial hypertension. There is an active proliferation of intimal cells with capillary-like channels in between. The branch is dilated. To the left is focal destruction of the arterial wall, which contains some lymphocytes and polymorphs (H&E ×140). B. Muscular pulmonary artery in a 63-year-old man with chronic thromboembolic pulmonary hypertension. Many vessels were obstructed by intravascular fibrous septa as remnants of recanalized emboli. (Elastic-van Gieson stain ×140.) (Courtesy of Dr. CA Wagenvoort.)

Patients with CTEPH have symptoms of progressive dyspnea, fatigue, and presyncope or loss of consciousness similar to the symptoms of patients with other forms of pulmonary hypertension. Many are unaware of prior venous thromboembolic events and the diagnosis is appreciably delayed while other causes of dyspnea are pursued and possibly treated. Physical examination findings of cor pulmonale may predominate and are similar to those seen in other causes. Findings that might narrow consideration to CTEPH are chronic postphlebitic changes of the lower extremity and the presence of pulmonary flow murmurs, described as high pitched and best heard over the lung fields during an inspiratory breath-hold.405 Recognition of the diagnosis usually follows identification of pulmonary hypertension on the echocardiogram and evidence of chronic thromboembolic disease by ventilation-perfusion scanning or pulmonary angiography (Fig. 81-29).

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Figure 81-29 Chronic thromboembolic pulmonary hypertension before and after surgery in a 35-year-old woman suspected of having had episodes of pulmonary emboli between 1977 and 1979. Progressive pulmonary hypertension cor pulmonale and right ventricular failure. A. Preoperative chest radiograph. (Pulmonary arterial pressure = 96/78 mmHg; pulmonary wedge pressure = 4 mmHg; cardiac output = 31 L/min.) The chest radiograph reveals hyperlucency and diminished vasculature in the right upper and left lower lobes. Also cardiomegaly with prominent central pulmonary arteries. B. Preoperative perfusion scan. Confirms chest radiograph above. C. Preoperative angiogram of right upper lobe showing absence of blood flow. D. Organized clot removed by Dr. LH Edmunds from the right upper and left lower pulmonary arteries at surgery. E. Postoperative (1 year later) chest radiograph. The chest radiograph is virtually normal. (Pulmonary arterial pressure = 42/20 mmHg; cardiac output = 50 L/min.) F. Postoperative perfusion scan. Blood is now perfusing the right upper and left lower lobes G. Postoperative angiogram of right upper lobe. Larger vessels that were previously unfilled (see C) now extend to right upper lobe. (Courtesy of Dr. H Palevsky.)

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Ventilation-perfusion radionuclide scanning is the best screening test for CTEPH. Multiple segmental or even larger perfusion defects are usually identified. These contrast with the “mottled” appearance and subsegmental defects often seen in cases of IPAH. In one study, 24 of 25 patients with CTEPH had a high probability scan.406 A notable but significantly less common cause of mismatched perfusion defects of particular importance in evaluation of patients with pulmonary hypertension is pulmonary veno-occlusive disease.246 It should also be noted that ventilation-perfusion scans may underestimate the severity of disease and do not predict the hemodynamic status. CT has also been reported to be sensitive and specific in the evaluation of CTEPH. However, CT is less sensitive at detecting chronic thrombus than acute intraluminal clot and instances of CTEPH have been missed.324,397,408,409 As in other forms of pulmonary hypertension, right heart catheterization is performed to establish the diagnosis. In addition, pulmonary arteriography is important to determining the location of the clot and its amenability to pulmonary thromboendarterectomy (Fig. 81-29C ). Such angiography is best performed at a center where experienced operators can appropriately monitor the patient and assess the suitability of surgical intervention. In cases in which the results are not definitive, pulmonary angioscopy may be performed by those experienced with the procedure in order to better define the amenability of clot to surgical removal and predict the hemodynamic effect of removal. Pulmonary thromboendarterectomy is distinct from embolectomy. In an embolectomy fresh clot is removed from the intraluminal space. A thromboendarterectomy, by contrast, involves meticulous dissection of chronic, fibrotic clot that has become incorporated within the vessel intima410,411 (Fig. 81-29D). The procedure is performed through a sternotomy with cardiopulmonary bypass and complete hypothermic circulatory arrest to provide adequate visualization of the dissection plane within the vessel. Selection of patients involves not only careful assessment of the clot burden and its location, but also the prediction of the expected hemodynamic consequences of surgery and the patient’s comorbid conditions.324,412 The procedure should only be performed at experienced centers. At a single center where the majority of pulmonary thromboendarterectomies have been performed (UCSD Medical Center), mortality has declined progressively from 17 percent in the program’s initial series to under 5 percent as experience has grown.413,414 Pulmonary thromboendarterectomy can markedly reduce and even normalize pulmonary hemodynamics. The majority of patients experience improvements in exercise capacity, gas exchange, WHO functional class and quality of life.411,415−420 In a retrospective follow up of more than 500 patients who underwent pulmonary thromboendarterectomy at UCSD between 1970 and 1994, the probability of survival beyond 6 years was 75 percent.420 Although direct comparison between populations and centers has not been performed, survival of patients at 5 years who were treated with anticoagulation alone in separate series was less than 30 percent.421,422

All patients, regardless of surgery, should be treated with lifelong anticoagulation provided contraindications do not arise. Experience with medical therapies beyond anticoagulation for CTEPH is limited. Small case series have reported improved hemodynamics or exercise capacity in patients treated with intravenous epoprostenol, or with oral bosentan, sildenafil, or beraprost.286,287,303,313,423−425 A randomized, placebo-controlled study of inhaled iloprost in 203 patients with various forms of pulmonary hypertension, included 57 patients with inoperable CTEPH. Although subset analysis of the CTEPH patients alone was not shown, iloprost therapy was reported to improve hemodynamics, quality of life and WHO functional class in these patients.311 Medical therapies have also been used in patients with residual pulmonary hypertension and symptoms following thromboendartectomy and in attempts to stabilize high-risk patients prior to surgery.426,427 Once again, controlled studies are lacking.

Cor Pulmonale The term cor pulmonale denotes hypertrophy and/or dilatation of the right ventricle secondary to a disturbance in the breathing apparatus, i.e. abnormal lungs, chest bellows, or the control of breathing (see Fig. 81-1). Cor pulmonale may be acute or chronic. The most common cause of acute cor pulmonale is a massive embolus to the lungs. Acute cor pulmonale may also occur during a bout of acute respiratory failure in the course of chronic obstructive lung disease. Chronic cor pulmonale is a consequence of the increased work of the right ventricle, almost invariably due to pulmonary hypertension. In chronic cor pulmonale, hypertrophy of the right ventricle generally predominates over dilation; in acute cor pulmonale, dilatation is the preponderant. The major physiological consequence of high pulmonary arterial pressure is that it increases the work of the right ventricle. Abrupt modest increments in mean pulmonary arterial pressure of up to 50 mmHg (e.g., after a large pulmonary embolus), can usually be accommodated by a normal right ventricle without a clinically significant decrease in cardiac output. However, larger acute surges in pressure usually cause either the right ventricle to fail or evoke a life-threatening dysrhythmia. If the higher afterloads are applied gradually, the right ventricle can sustain its output by a combination of dilation and hypertrophy. The common denominator for cor pulmonale shared by diverse causes is pulmonary hypertension that stems from a primary disorder of the lungs or respiratory apparatus. Although the anatomic lesions underlying pulmonary hypertension may not be reversible, the functional component due to hypoxia can generally be alleviated or relieved, thereby decreasing a major vasoconstrictive component responsible for the pulmonary hypertension. Observations in the 1950s suggested that once the right ventricle fails and systemic venous congestion ensues, life expectancy is less than 4 years. But the ability to tide these patients over episodes of acute respiratory failure associated with infections and heart failure has improved enormously. In our own experience, 5- to 10-year

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survival after the first appearance of peripheral edema is not unusual. Incidence and Prevalence The incidence of cor pulmonale varies from country to country, between urban and rural areas, and with exposure to air pollutants. In the United States, cor pulmonale averages about 6 to 7 percent of all types of adult heart disease, and COPD is the most common cause. In Delhi, India, where a large segment of the population lives under conditions of severe air pollution, the incidence has been estimated to be about 16 percent. In Sheffield, England, where air pollution is rife, cor pulmonale affects 30 to 40 percent of patients with clinical heart failure. In general, in areas in which smoking is widespread, air pollution severe, and chronic bronchitis and emphysema prevalent, the incidence of cor pulmonale is high. Historically, men have been more often affected than women because of their greater exposure to air pollutants. Not all patients with COPD develop cor pulmonale. Many manage (e.g., by pursed-lip breathing, the “pink puffers”) to maintain arterial oxygenation at near-normal levels, and thereby avoiding pulmonary hypertension. In general, the more deranged the ventilation-perfusion balance, the more likely abnormal blood gases, pulmonary hypertension, and cor pulmonale are to develop. Diffuse interstitial lung disease is a less common cause of cor pulmonale and right ventricular failure. Most pulmonary disorders affect too little of the lungs, or are too circumscribed in their effects on alveolar-capillary gas exchange, to elicit pulmonary hypertension and cor pulmonale. Tuberculosis, although extensive, is rarely the cause of cor pulmonale, unless both lungs are extensively affected by destruction and conglomerate fibrosis or if surgical intervention has deranged the functioning of the chest bellows. Not uncommonly, alveolar hypoventilation, secondary to sleep apnea syndromes, is accompanied by pulmonary hypertension and chronic cor pulmonale (as discussed above). Cor pulmonale is uncommon in uncomplicated silicosis, anthrasilicosis, or tuberculosis. On the other hand, it is not uncommon when silicosis, anthrasilicosis, or long-standing fibrotic tuberculosis is complicated by extensive, conglomerate, massive fibrosis, distorted adjacent parenchyma, shrunken lobes, and bronchitis (Fig. 81-30). The likelihood of cor pulmonale is increased further by chronic pleurisy, fibrothorax, or excisional surgery. In such patients, a combination of anatomic restriction of the vascular bed and disturbances in gas exchange are implicated in the pathogenesis of the pulmonary hypertension. Disturbances in gas exchange brought about by an acute respiratory infection are usually the most reversible element of this disorder. Cystic fibrosis is another common cause of obstructive airways disease that results in pulmonary hypertension (see Fig. 81-23C ). Here, too, the root cause is persistent alveolar and arterial hypoxia resulting from ventilation-perfusion abnormalities. Hemodynamic Features of Cor Pulmonale The normal right ventricle is a thin-walled, distensible muscular pump that accommodates considerable variations in

Pulmonary Hypertension and Cor Pulmonale

systemic venous return without large changes in filling pressures. In response to chronic pressure overload imposed by pulmonary hypertension, the right ventricle enlarges, primarily by hypertrophy, which predominantly affects the free wall of the right ventricle. In time, if the pressure load continues, the right ventricle fails. The advent of heart failure is indicated hemodynamically by failure of the cardiac output to increase normally during exercise despite increases in the filling pressures of the right ventricle to abnormally high levels (see Fig. 81-17). Salt and water retention, expansion of the plasma volume, and systemic venous congestion are hallmarks of right ventricular failure; the interstitial water content of the lungs also increases. The mechanisms responsible for the salt and water retention in right ventricular failure are still indefinite. Recovery from right heart failure reverses the water and electrolyte disturbances. As relief of pulmonary hypertension diminishes the load on the right ventricle, its filling pressures return to normal, and the cardiac output once again responds appropriately to the level of exercise. Support of the heart by cardiotonic agents is much less effective than relief of the afterload (i.e., pulmonary hypertension) in restoring adequate cardiac performance. The left atrial pressure remains normal in cor pulmonale except when circulating blood volume is increased or if right ventricular enlargement becomes severe enough to affect left ventricular filling. Proper function of one ventricle is dependent upon the performance of the other (so-called interventricular dependence). Severe enlargement of the right heart can displace the interventricular septum and impede the left ventricular performance. Further, both ventricles are bound by their common pericardial sac. As intrapericardial pressures increase with progressive enlargement of the right heart, further right ventricular dilatation becomes limited along with limited left ventricular distensibility.428 Perhaps the more usual cause of left ventricular failure in cor pulmonale is independent disease of the left ventricle (Fig. 81-31). In elderly people, it is usually reasonable to implicate the coincidence of independent arteriosclerotic disease of the coronary arteries. In the young patient with cor pulmonale and myocardial impairment, the inclination is to attribute the left ventricular dysfunction to underlying disease, such as granulomatous involvement of the myocardium in sarcoidosis. On the other hand, a damaged or overloaded left ventricle from any cause is not apt to perform well in a patient with persistent hypoxemia and acidosis, particularly if these derangements are severe. Cor Pulmonale in COPD The designation chronic obstructive airway disease includes not only COPD but also other obstructive diseases of the airways, such as cystic fibrosis (Fig. 81-23). Although chronic bronchitis and emphysema usually coexist, it is the chronic bronchitis, because of the ventilation-perfusion abnormalities that it produces, that is primarily responsible for the abnormal blood gases that lead to pulmonary hypertension. In dealing with COPD, one time-honored clinical approach has been the distinction between the “pink puffer”

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Figure 81-30 Gough (sagittal) sections. A. Coal minersâ&#x20AC;&#x2122; pneumoconiosis. Except for the coal macules (black starts upper right), the architecture is virtually normal. B. Anthracosilicotic nodules predominantly in vicinity of fissure. Background lung shows centrilobular emphysema. C. Progressive massive fibrosis. Cor pulmonale is uncommon in (A) unless parenchymal changes are associated with chronic bronchitis (which cannot be seen on these sections). However, cor pulmonale is not uncommon in (B and C), which often derange blood-gas composition severely. (Courtesy of JC Wagner, Cardiff.)

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(predominantly emphysema) and the â&#x20AC;&#x153;blue bloaterâ&#x20AC;? (predominantly chronic bronchitis) (Fig. 81-33). The pink puffer spends a lifetime breathing through pursed lipsâ&#x20AC;&#x201D;an automatic mechanism for achieving positive-pressure ventilation, which in turn maintains arterial PCO2 at near-normal levels. In this group, pulmonary arterial pressures remain at nearnormal levels unless some complication, such as a spontaneous pneumothorax or pneumonia, precipitates a bout of severe arterial hypoxemia. In contrast, the blue bloater is continuously on a downhill course of progressive arterial hypoxemia and hypercapnia, which lead to increasing pulmonary hypertension. It is difficult to explain the onset of cor pulmonale in the blue bloater because work of the right ventricle is not greatly increased even when arterial hypoxemia is quite marked (e.g., PaO2 of about 35 mmHg) and accompanied by respiratory

Pulmonary Hypertension and Cor Pulmonale

Figure 81-31 Cor pulmonale right ventricular failure and coexistent pulmonary edema due to left heart disease. A. In 1956 enlarged heart cause unknown. The lungs appear normal. B. In 1976 increased cardiomegaly is associated with idiopathic interstitial fibrosis (lung biopsy in 1970) and pulmonary edema. C. Four days later. Edema has cleared leaving evidence of interstitial fibrosis.

acidosis (e.g., PaCO2 of about 50 mmHg). At these levels, mean pulmonary arterial pressure is generally only about 30 mmHg, and the cardiac output is only moderately increased. Undoubtedly, the blood gas abnormalities increase during sleep and the activities of daily life. Nonetheless, the levels of pulmonary arterial pressure that have been recorded are generally tolerated without difficulty in native residents at high altitude, raising the question of what factors other than pulmonary hemodynamic abnormalities are at work on the road to right ventricular failure and peripheral edema.429 Clinical Evaluation In chronic bronchitis and emphysema, cor pulmonale and right ventricular failure are encountered in three different settings: in the pink puffer during an acute respiratory infection, in the blue bloater who is chronically refractory to all

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Figure 81-32 Evolution of pulmonary hypertension and cor pulmonale in chronic hypoventilation such as with kyphoscoliosis.

Figure 81-33 The pink puffer and the blue bloater. Natural histories. The pink puffer leads a breathless existence that is interrupted by bouts of acute respiratory insufficiency (center) from which he or she may recover completely (upper right) or go on to a stage of persistent cyanosis and respiratory acidosis (lower right). In contrast the blue bloater generally leads a briefer existence with more frequent bouts of acute respiratory insufficiency from which he or she is less apt to recover completely. During the stage of acute respiratory insufficiency the pink puffer and blue bloater are usually indistinguishable.

cardiotonic and pulmonary measures, and in the blue bloater during an acute respiratory infection. During a bout of respiratory failure, the clinical pictures of the pink puffer and the blue bloater are often indistinguishable. As the infection subsides, however, it usually becomes clear whether a patient is predominantly emphysematous or bronchitic (Fig. 81-33). Hyperinflation of the lungs in patients with cor pulmonale secondary to COPD often obscures enlargement of the right ventricle. Although heart sounds at auscultation are often reduced with chest hyperinflation, S3 and S4 gallops of right ventricular failure are generally present, and the murmur of tricuspid insufficiency can often be elicited upon a deep inspiration. Additional characteristic features of right ventricular enlargement can be uncovered if looked for carefully: a rhythmic lift of the sternum with each heartbeat, a remote but accentuated pulmonary component of the second heart sound, cardiac pulsations in the epigastrium. Right ventricular failure is often accompanied by striking cyanosis, unexplained drowsiness or inappropriate behavior, distended neck veins, warm hands, suffused conjunctivae, hepatomegaly, and edema of the extremities. Not only is the liver generally displaced downward by the low diaphragm, it is also enlarged and tender to gentle pressure over the right upper part of the abdomen. Once suspicion is raised that ventilation-perfusion abnormalities are the cause of the clinical picture, an arterial blood sample may confirm that the PaO2 is low (less than 40 to 50 mmHg), the PaCO2 is high (more than 50 mmHg), and respiratory acidosis is present. These blood gas values are rare in left ventricular disorders unless the patient is in frank pulmonary edema. Plain chest radiographs may suggest enlargement of the right ventricle in a patient with COPD. The chest radiograph depends on the state of the underlying pulmonary disorder and the degree of pulmonary hypertension and right ventricular failure. Most characteristic is the combination of â&#x20AC;&#x153;dirty lungs,â&#x20AC;? prominent pulmonary arterial trunks at the hili, and a pruned peripheral arterial tree. Serial radiographs are generally more useful in detecting changes in the cardiac silhouette as a result of acute exacerbations of cor pulmonale than is a single examination (Fig. 81-34). An initially enlarged cardiac silhouette is often more obvious in retrospect when compared with a repeat study performed after treatment and clinical improvement. Electrocardiographic evidence of right ventricular enlargement is often blurred in patients with COPD by rotation and displacement of the heart, increased distance between the electrodes on the skin and cardiac surface, and the predominance of dilatation over hypertrophy in the cardiac enlargement. If a distinctive pattern of right ventricular enlargement does occur, the degree of cardiomegaly is invariably severe. Because of these limitations, it is not surprising that the standard criteria for right ventricular enlargement have been satisfied in only one-third of patients with chronic obstructive lung disease who have been shown to have right ventricular hypertrophy at autopsy.

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Figure 81-34 Chronic bronchitis and emphysema. A and B. Posteroanterior and lateral views during episode of right ventricular failure. Enlargement of the cardiac silhouette is evident. C and D. Posteroanterior and lateral views 3 weeks later after recovery.

Treatment of Acute Cor Pulmonale in COPD In the patient with COPD, as in the patient with general alveolar hypoventilation (despite normal lungs), the center of attention is the blood gases: Relief of arterial hypoxemia and hypercapnia (acidosis) may alleviate the pulmonary hypertension. The pulmonary hypertension itself usually requires no special treatment: Pulmonary arterial pressures generally decrease as a result of management of the obstructive airway disease: antibiotics to clear an acute upper respira-

tory infection, bronchodilators, and supplemental oxygen as needed. The first episodes of right ventricular failure generally respond to a cardiotonic regimen that includes longterm oxygen therapy, diuretics, and digitalis. Each component of this regimen entails some uncertainty. Thus, although long-term oxygen therapy has been shown to improve survival, this benefit may not be attributable to improvement in pulmonary hemodynamics.113,360 As far as diuretics are

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concerned, chloride-losing agents run the risk of promoting hypercapnia, predisposing to respiratory depression, and aggravating ventilatory insufficiency. The use of digitalis must also be undertaken with caution because of the threat of digitalis-associated cardiac arrhythmias during hypoxia. Right ventricular failure generally responds to clearance of the precipitating mechanism (e.g., an upper respiratory infection). As ventilatory failure increases, however, the margin for recovery from heart failure narrows. Nonetheless, many patients who experience one or more bouts of heart failure per year have survived for 5 to 10 years after the first episode. Acute Cor Pulmonale or Respiratory Failure in Pulmonary Arterial Hypertension Patients with PAH may become acutely unstable in a number of settings, including infection, volume overload with dietary indiscretion, or complications of medicines (Table 81-7). In many, an acute stress will convert a chronic state of clinically stable cor pulmonale into rapidly progressive hemodynamic failure. Acutely worsened hypoxemia, if not the precipitating cause of the hemodynamic instability will usually develop quickly as well.428 Although the precipitating events may differ, each tends to lead to a vicious cycle that will result in worsening right ventricular function and hypotension (Fig. 81-35). Increased work of the right heart, whether due to acute hypoxia and pulmonary vasoconstriction, or fever and infection, will increase ventricular wall stress, further impeding ventricular performance. A decreased cardiac output will

Table 81-7 Clinical Presentations of Patients with Pulmonary Arterial Hypertension with Acute Hemodynamic Instability Acute recognition/late presentation Syncope, shock, renal failure, ascites, hypoxemia Acute medication failure Medical noncompliance, interrupted infusions Intolerance (calcium channel antagonist) Dietary indiscretion/fluid retention Infection (sepsis with infused therapy) Fever (environmental causes, infection) Venous thromboembolism Medical/surgical procedures/anesthesia Pregnancy Source: Reproduced from: Jeffery ME, Taichman DB: Management of the acutely ill patient with pulmonary arterial hypertension in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.

↓O2

Fever Heat Infection HR

↑ PVR

↑ RV O2 demand Acidosis

RV failure RV ischemia RV dilate ↓ Coronary perfusion

↓ SBP

LV diastolic dysfunction

Figure 81-35 Interacting mechanisms in the acute development of worsened right heart function in patients with pulmonary arterial hypertension. A vicious cycle frequently results in both respiratory failure and hemodynamic instability. (Reproduced from Jeffery ME, Taichman DB: Management of the acutely ill patient with pulmonary arterial hypertension in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006.)

impede myocardial perfusion, as will the increase in intraventricular pressure. Worsening the situation may be resultant hypoxemia and left ventricular ischemia, acidemia from either respiratory insufficiency or poor systemic perfusion. The goals of management are the same as for any patient who is hemodynamically unstable or in respiratory distress: to decrease the demand for oxygen while improving its delivery. Supportive care therefore aims to reverse the hypotension and hypoxemia. Few data are available to guide the management of acute hemodynamic instability in patients with PAH. Studies of various agents have frequently been reported on in patients with acute right heart dysfunction following cardiac surgery, who generally do not suffer from severe underlying disease of the pulmonary vasculature. It is similarly important to recognize the limitations in extrapolating data from acute vasodilator trials performed on an elective basis in patients with PAH to the care of a hemodynamically unstable PAH patient. Although useful, data from published acute vasodilator studies have been performed in hemodynamically stable patients and may not necessarily reflect response in the setting of acute instability. As in any patient, administration of fluids intravenously is an appropriate initial measure for hypotension, especially when infection or other factors exist that might predispose to hypovolemia. However, in many patients with PAH and chronic cor pulmonale acute hypotension is caused by, or complicated by, worsened right heart dilation that further impairs function. In such patients, fluid removal is required to restore right ventricular function. Vasopressors may be

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needed for hemodynamic support while fluid removal is accomplished with diuretics. There are few data to firmly guide the choice of vasopressors. Norepinephrine or dopamine are often employed for their inotropic properties, while agents which may constrict pulmonary vessels such as neosynephrine are usually avoided if possible.430−432 Attempts to promote pulmonary vasodilatation by intravenous or oral agents are frequently complicated by hypotension from the drugs’ systemic effects; the use of inhaled agents (iloprost, NO, or aerosolized epoprostenol) is preferable.395,433 Oxygen is a potent pulmonary vasodilator and should be administered at concentrations adequate to prevent hypoxemia. When mechanical ventilation is required, the same principles apply as in other patients with respiratory failure, although certain points are worth noting in the management specifically of patients with PAH. While intra-alveolar vessels are stretched and their resistance increased by overdistention of alveoli, compression of extra-alveolar vessels by atelectasis at low lung volumes might increase their vascular resistance. Thus, at either extreme, pulmonary vascular resistance might increase. The application of positive end-expiratory pressure must also be done with attention to possible overdistention of alveolar vessels and a resultant increase in their resistance. Since hypercarbia tends to promote pulmonary vasoconstriction, lung-protective strategies that permit hypoventilation (and hypercapnia) must be carefully monitored to be certain of overall benefit.434 Hyperventilation to induce mild alkalemia and pulmonary vasodilation has been used empirically, but with attention to avoid dynamic hyperinflation. Finally, care must be taken to avoid agitation by noxious procedures (e.g., endotracheal suctioning), which may promote further surges in vascular resistance; sedation and analgesia during such procedures should be employed judiciously.435

SUGGESTED READING 1. Braunwald E: Cor pulmonale, in Braunwald E, Hauser SL, Fauci AS, et al (eds), Harrison’s Principles of Internal Medicine, 15th ed. New York, McGraw-Hill, 2001, pp 1355–1359. 2. Romberg E von: Uber sklerose der lungen arterie. Dtsch Arch Klin Med 48:197–206, 1891. 3. Dresdale DT, Schultz M, Michtom RJ: Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 11:686–705, 1951. 4. Pietra GG: Histopathology of primary pulmonary hypertension. Chest 105:2S–6S, 1994. 5. Pietra GG: The histopathology of primary pulmonary hypertension, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal. Mechanisms, Management, and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 459–472. 6. Loyd JE, et al: Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 138:952–957, 1988.

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7. Wissler RW, Vesselinovitch D: Atherogenesis in the pulmonary artery, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal. Mechanisms, Management, and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 245–255. 8. Edwards WD: The pathology of secondary pulmonary hypertension, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal. Mechanisms, Management, and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 329–342. 9. Wagenvoort CA: Primary pulmonary hypertension: A pathologic study of the lung vessels in 156 classically diagnosed cases. Circulation 42:1163–1168, 1970. 10. Wagenvoort CA, Wagenvoort N: Pulmonary vascular bed: Normal anatomy and responses to disease, in Morse KM (ed), Pulmonary Vascular Diseases: Lung Biology in Health and Disease. New York, Marcel Dekker, 1979, pp 1–109. 11. Heath D, et al: The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J 58:204– 213, 1987. 12. Wagenvoort CA, Wagenvoort N: Pathology of Pulmonary Hypertension. New York, Wiley, 1977. 13. Voelkel NF, Tuder RM, Weir EK: Pathophysiology of primary pulmonary hypertension: From physiology to molecular mechanisms, in Rubin LJ, Rich S (eds), Primary Pulmonary Hypertension. New York, Marcel Dekker, New York, 1997, pp 83–129. 14. Cool CD, et al: Three-dimensional reconstruction of pulmonary arteries in plexiform pulmonary hypertension using cell-specific markers. Evidence for a dynamic and heterogeneous process of pulmonary endothelial cell growth. Am J Pathol 155:411–419, 1999. 15. Yeager ME, et al: Microsatellite instability of endothelial cell growth and apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res 88:E2–E11, 2001. 16. Jamison BM, Michel RP: Distribution of plexiform lesions in primary and secondary pulmonary hypertension Hum Pathol 26:987–993, 1995. 17. Pietra GG, et al: Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 43:25S–32S, 2004. 18. Mandel J, Mark EJ, Hales CA: Pulmonary venoocclusive disease Am J Respir Crit Care Med 162:1964– 1973, 2000. 19. Wagenvoort CA, Beetstra A, Spijker J: Capillary hemangiomatosis of the lungs. Histopathology 2:401–406, 1978. 20. Havlik DM, et al: Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases. Am J Clin Pathol 113:655–662, 2000. 21. Erbersdobler A, Niendorf A: Multifocal distribution of pulmonary capillary haemangiomatosis. Histopathology 40: 88–91, 2002. 22. Almagro P, et al: Pulmonary capillary hemangiomatosis associated with primary pulmonary hypertension:

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Report of 2 new cases and review of 35 cases from the literature. Medicine (Baltimore) 81:417–424, 2002. 23. Cohen M, Fuster V, Edwards WD: Anticoagulation in the treatment of pulmonary hypertension, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal Mechanisms, Management, and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 501–510. 24. Bjornsson J, Edwards WD: Primary pulmonary hypertension: A histopathological study of 80 cases. Mayo Clin Proc 60:16–25, 1985. 25. Fuster V, et al: Primary pulmonary hypertension: Natural history and the importance of thrombosis. Circulation 70:580–587, 1984. 26. Simonneau G, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S–12S, 2004. 27. Mecham RP, et al: Smooth muscle-mediated connective tissue remodeling in pulmonary hypertension. Science 237:423–426, 1987. 28. Kinsella JP, Abman SH: Recent developments in the pathophysiology and treatment of persistent pulmonary hypertension of the newborn. J Pediatr 126:853–864, 1995. 29. Fishman AP: Pulmonary circulation, in Fishman AP, Fisher A (eds), Handbook of Physiology, Sec 3: The Respiratory System: Circulation and Nonrespiratory Functions. Bethesda, MD, American Physiological Society, 1985, pp 93–166. 30. Fishman AP: The Pulmonary Circulation: Normal and Abnormal. Philadelphia, University of Pennsylvania Press, 1990. 31. de Meer K, Heymans HS, Zijlstra WG: Physical adaptation of children to life at high altitude. Eur J Pediatr 154:263–272, 1995. 32. Brenot F, et al: Primary pulmonary hypertension and fenfluramine use. Br Heart J 70:537–541, 1993. 33. Kilbourne EM, et al: Clinical epidemiology of toxic-oil syndrome. Manifestations of a new illness. N Engl J Med 309:1408–1414, 1983. 34. Steudel W, et al: Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res 81:34–41, 1997. 35. Ozaki M, et al: Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension 37:322–327, 2001. 36. Fagan KA, et al: The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest 103:291–299, 1999. 37. Zhao YD, et al: Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrowderived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res 96:442–450, 2005. 38. Petkov V, et al: Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest 111:1339–1346, 2003.

39. Christman BW, et al: An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med 327:70–75, 1992. 40. Rothman RB, et al: Aminorex fenfluramine and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation 100:869–875, 1999. 41. Herve P, et al: Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99:249–254, 1995. 42. MacLean MR, et al: Overexpression of the 5-hydroxytryptamine transporter gene: Effect on pulmonary hemodynamics and hypoxia-induced pulmonary hypertension. Circulation 109:2150–2155, 2004. 43. Eddahibi S, et al: Attenuated hypoxic pulmonary hypertension in mice lacking the 5-hydroxytryptamine transporter gene. J Clin Invest 105:1555–1562, 2000. 44. Guignabert C, et al: Serotonin transporter inhibition prevents and reverses monocrotaline-induced pulmonary hypertension in rats. Circulation 111:2812– 2819, 2005. 45. Eddahibi S, et al: Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest 108:1141–1150, 2001. 46. Machado RD, et al: Genetic association of the serotonin transporter in pulmonary arterial hypertension. Am J Respir Crit Care Med 173:793–797, 2006. 47. Giaid A, et al: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739, 1993. 48. Rubens C, et al: Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 120:1562–1569, 2001. 49. Yamakami T, et al: Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise. Eur Respir J 10:2055–2060, 1997. 50. Cambrey AD, et al: Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. Am J Respir Cell Mol Biol 11:439–445, 1994. 51. Yang Z, Krasnici N, Luscher TF: Endothelin-1 potentiates human smooth muscle cell growth to PDGF: Effects of ETA and ETB receptor blockade. Circulation 100:5–8, 1999. 52. Hocher B, et al: Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 23:19–26, 2000. 53. Helset E, et al: Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats. Am J Physiol 271:L538–546, 1996. 54. Davie N, et al: ET(A) and ET(B) receptors modulate the proliferation of human pulmonary artery smooth

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muscle cells. Am J Respir Crit Care Med 165:398–405, 2002. 55. Kuc RE, Davenport AP: Endothelin-A-receptors in human aorta and pulmonary arteries are downregulated in patients with cardiovascular disease: an adaptive response to increased levels of endothelin-1? J Cardiovasc Pharmacol 36:S377–379, 2000. 56. Rubin LJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 346:896–903, 2002. 57. Barst RJ, et al: Clinical efficacy of sitaxsentan an endothelin-A receptor antagonist in patients with pulmonary arterial hypertension: Open-label pilot study. Chest 121:1860–1868, 2002. 58. McLaughlin V, Sitbon O, Rubin LJ, et al: The effect of first-line Bosentan on survival of patients with primary pulmonary hypertension. Am J Respir Crit Care Med 167:A442, 2003. 59. Michelakis ED, et al: Dichloroacetate a metabolic modulator prevents and reverses chronic hypoxic pulmonary hypertension in rats: Role of increased expression and activity of voltage-gated potassium channels. Circulation 105:244–250, 2002. 60. Platoshyn O, et al: Chronic hypoxia decreases K(V) channel expression and function in pulmonary artery myocytes. Am J Physiol Lung Cell Mol Physiol 280:L801– 812, 2001. 61. Pozeg ZI, et al: In vivo gene transfer of the O2 -sensitive potassium channel Kv15 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 107:2037–2044, 2003. 62. Geraci MW, et al: Gene expression patterns in the lungs of patients with primary pulmonary hypertension: A gene microarray analysis. Circ Res 88:555–562, 2001. 63. Yuan JX, et al: Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 98:1400–1406, 1998. 64. Yuan XJ, et al: Attenuated K+ channel gene transcription in primary pulmonary hypertension. Lancet 351:726–727, 1998. 65. Weir EK, et al: Anorexic agents aminorex fenfluramine and dexfenfluramine inhibit potassium current in rat pulmonary vascular smooth muscle and cause pulmonary vasoconstriction. Circulation 94:2216–2220, 1996. 66. Remillard CV, Yuan JX: Activation of K+ channels: An essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol 286:L49–67, 2004. 67. Krick S, et al: Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol Cell Physiol 280:C970–979, 2001. 68. Yu Y, et al: Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension. Proc Natl Acad Sci USA 101:13861–13866, 2004.

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69. Stewart DJ: Bone morphogenetic protein receptor-2 and pulmonary arterial hypertension: Unraveling a riddle inside an enigma? Circ Res 96:1033–1035, 2005. 70. Deng Z, et al: Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 67:737–744, 2000. 71. Lane KB, et al: Heterozygous germline mutations in BMPR2 encoding a TGF-beta receptor cause familial primary pulmonary hypertension. The International PPH Consortium. Nat Genet 26:81–84, 2000. 72. Thomson JR, et al: Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II: A receptor member of the TGF-beta family. J Med Genet 37:741–745, 2000. 73. Newman JH, et al: Mutation in the gene for bone morphogenetic protein receptor II as a cause of primary pulmonary hypertension in a large kindred. N Engl J Med 345:319–324, 2001. 74. Newman JH, et al: Genetic basis of pulmonary arterial hypertension: Current understanding and future directions. J Am Coll Cardiol 43:33S–39S, 2004. 75. Humbert M, et al: BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Respir J 20:518–523, 2002. 76. Roberts KE, et al: BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 24:371–374, 2004. 77. Runo JR, et al: Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med 167:889–894, 2003. 78. Trembath RC, et al: Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 345:325–334, 2001. 79. Chaouat A, et al: Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 59:446–448, 2004. 80. Atkinson C, et al: Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor. Circulation 105:1672–1678, 2002. 81. Morrell NW, et al: Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation 104:790–795, 2001. 82. Zhang S, et al: Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 285:L740– 754, 2003. 83. Yang X, et al: Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 96:1053– 1063, 2005.

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84. Du L, et al: Signaling molecules in nonfamilial pulmonary hypertension. N Engl J Med 348:500–509, 2003. 85. Zhao YD, et al: Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res 92:984– 991, 2003. 86. Hirose S, et al: Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. Pathol Int 50:472–479, 2000. 87. Tuder RM, et al: Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: Evidence for a process of disordered angiogenesis. J Pathol 195:367–374, 2001. 88. Christou H, et al: Increased vascular endothelial growth factor production in the lungs of rats with hypoxiainduced pulmonary hypertension. Am J Respir Cell Mol Biol 18:768–776, 1998. 89. Campbell AI, et al: Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotalineinduced pulmonary hypertension. Circulation 104:2242–2248, 2001. 90. Herve P, et al: Pathobiology of pulmonary hypertension. The role of platelets and thrombosis. Clin Chest Med 22:451–458, 2001. 91. Geggel RL, et al: von Willebrand factor abnormalities in primary pulmonary hypertension. Am Rev Respir Dis 135:294–299, 1987. 92. Eisenberg PR, et al: Fibrinopeptide A levels indicative of pulmonary vascular thrombosis in patients with primary pulmonary hypertension. Circulation 82:841– 847, 1990. 93. Welsh CH, et al: Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 110:710–717, 1996. 94. Humbert M, et al: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 43:13S–24S, 2004. 95. Jeffery TK, Morrell NW: Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis 45:173–202, 2002. 96. Jones PL, Rabinovitch M: Tenascin-C is induced with progressive pulmonary vascular disease in rats and is functionally related to increased smooth muscle cell proliferation. Circ Res 79:1131–1142, 1996. 97. Ivy DD, et al: Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: A new model of severe pulmonary arterial hypertension. Circulation 111:2988– 2996, 2005. 98. Jones PL, et al: Altered hemodynamics controls matrix metalloproteinase activity and tenascin-C expression in neonatal pig lung. Am J Physiol Lung Cell Mol Physiol 282:L26–35, 2002. 99. Cowan KN, Jones PL, Rabinovitch M: Elastase and matrix metalloproteinase inhibitors induce regression and tenascin-C antisense prevents progression of vascular disease. J Clin Invest 105:21–34, 2000.

100. Jones PL, Cowan KN, Rabinovitch M: Tenascin-C proliferation and subendothelial fibronectin in progressive pulmonary vascular disease. Am J Pathol 150:1349– 1360, 1997. 101. Ihida-Stansbury K, et al: Paired-related homeobox gene Prx1 is required for pulmonary vascular development. Circ Res 94:1507–1514, 2004. 102. Jones PL, Crack J, Rabinovitch M: Regulation of tenascin-C a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol 139:279–293, 1997. 103. McGoon M, et al: Screening early detection and diagnosis of pulmonary arterial hypertension: ACCP evidencebased clinical practice guidelines. Chest 126:14S–34S, 2004. 104. Kawut SM, et al: Extrinsic compression of the left main coronary artery by the pulmonary artery in patients with long-standing pulmonary hypertension. Am J Cardiol 83:984–986 A10, 1999. 105. Holcomb BW Jr, et al: Pulmonary veno-occlusive disease: A case series and new observations. Chest 118:1671–1679, 2000. 106. Barst RJ, et al: Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43:40S–47S, 2004. 107. Borgeson DD, et al: Frequency of Doppler measurable pulmonary artery pressures. J Am Soc Echocardiogr 9:832–837, 1996. 108. Yeo TC, et al: Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol 81:1157–1161, 1998. 109. Eysmann SB, et al: Two–dimensional and Dopplerechocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation 80:353–360, 1989. 110. Hinderliter AL, et al: Frequency and prognostic significance of pericardial effusion in primary pulmonary hypertension. PPH Study Group Primary pulmonary hypertension. Am J Cardiol 84:481–484 A10, 1999. 111. Raymond RJ, et al: Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol 39:1214–1219, 2002. 112. Kawut SM, et al: New predictors of outcome in idiopathic pulmonary arterial hypertension. Am J Cardiol 95:199–203, 2005. 113. Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: A clinical trial. Ann Intern Med 93(3):391–398, 1980. 114. Abenhaim L, et al: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 335:609–616, 1996. 115. Rich S, et al: Anorexigens and pulmonary hypertension in the United States: Results from the surveillance

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of North American pulmonary hypertension. Chest 117:870–874, 2000. 116. Group IPPHS: The International Primary Pulmonary Hypertension Study. Chest 105:37S–41S, 1994. 117. Appelbaum L, et al: Primary pulmonary hypertension in Israel: A national survey. Chest 119:1801–1806, 2001. 118. Braman SS, et al: Primary pulmonary hypertension in the elderly. Arch Intern Med 151:2433–2438, 1991. 119. Rich S, et al: Primary pulmonary hypertension. A national prospective study. Ann Intern Med 107:216–223, 1987. 120. Brenot F: Primary pulmonary hypertension: Case series from France. Chest 105:33S–36S, 1994. 121. Sandoval J, et al: Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation 89:1733–1744, 1994. 122. McLaughlin VV, et al: Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:78S–92S, 2004. 123. Bossone E, et al: The prognostic role of the ECG in primary pulmonary hypertension. Chest 121:513–518, 2002. 124. Kuhn KP, et al: Outcome in 91 consecutive patients with pulmonary arterial hypertension receiving epoprostenol. Am J Respir Crit Care Med 167:580–586, 2003. 125. Sitbon O, et al: Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol 40:780–788, 2002. 126. McLaughlin VV, Shillington A, Rich S: Survival in primary pulmonary hypertension: The impact of epoprostenol therapy. Circulation 106:1477–1482, 2002. 127. Miyamoto S, et al: Clinical correlates and prognostic significance of six–minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 161:487–492, 2000. 128. Wensel R, et al: Assessment of survival in patients with primary pulmonary hypertension: Importance of cardiopulmonary exercise testing. Circulation 106:319– 324, 2002. 129. Barst RJ, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 334: 296–302, 1996. 130. Nagaya N, et al: Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension. Am J Respir Crit Care Med 160:487–492, 1999. 131. Voelkel MA, et al: Hyperuricemia in severe pulmonary hypertension. Chest 117:19–24, 2000. 132. Lopes AA, et al: Endothelial cell dysfunction correlates differentially with survival in primary and sec-

Pulmonary Hypertension and Cor Pulmonale

ondary pulmonary hypertension. Am Heart J 139:618– 623, 2000. 133. Shitrit D, et al: Significance of a plasma D-dimer test in patients with primary pulmonary hypertension. Chest 122:1674–1678, 2002. 134. Torbicki A, et al: Detectable serum cardiac troponin T as a marker of poor prognosis among patients with chronic precapillary pulmonary hypertension. Circulation 108: 844–848, 2003. 135. Nagaya N, et al: Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension. Circulation 102:865–870, 2000. 136. Nootens M, et al: Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: Relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol 26:1581–1585, 1995. 137. Nagaya N, et al: [Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.] J Cardiol 37:110–111, 2001. 138. Okada O, et al: Prediction of life expectancy in patients with primary pulmonary hypertension. A retrospective nationwide survey from 1980–1990. Intern Med 38:12– 16, 1999. 139. Rajasekhar D, et al: Primary pulmonary hypertension: Natural history and prognostic factors. Indian Heart J 46:165–170, 1994. 140. D’Alonzo GE, et al: Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115:343– 349, 1991. 141. Hoeper MM, et al: Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 165:341–344, 2002. 142. Loyd JE, Primm RK, Newman JH: Familial primary pulmonary hypertension: Clinical patterns. Am Rev Respir Dis 129:194–197, 1984. 143. Loyd JE, et al: Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary hypertension. Am J Respir Crit Care Med 152:93–97, 1995. 144. Nichols WC, et al: Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet 15:277–280, 1997. 145. Morse JH, et al: Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation 95:2603–2606, 1997. 146. Harrison RE, et al: Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 40:865–871, 2003. 147. Abdalla SA, et al: Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J 23:373–377, 2004. 148. Machado RD, et al: Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 27:121–132, 2006. 149. Elliott CG: Genetics of pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary

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Disorders of the Pulmonary Circulation

Vascular Disease. Philadelphia, Elsevier Science, 2006, pp 50–65. 150. Grunig E, et al: Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene. Circulation 102:1145–1150, 2000. 151. Elliott G, et al: Coancestry in apparently sporadic primary pulmonary hypertension. Chest 108:973–977, 1995. 152. Mukerjee D, et al: Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: Application of a registry approach. Ann Rheum Dis 62:1088–1093, 2003. 153. Kawut SM, et al: Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 123:344–350, 2003. 154. Steen VD, Medsger TA Jr: Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 43:2437–2444, 2000. 155. Shen JY, et al: Pulmonary hypertension in systemic lupus erythematosus. Rheumatol Int 18:147–151, 1999. 156. Badui E, et al: Cardiovascular manifestations in systemic lupus erythematosus. Prospective study of 100 patients. Angiology 36:431–441, 1985. 157. Li EK, Tam LS: Pulmonary hypertension in systemic lupus erythematosus: Clinical association and survival in 18 patients. J Rheumatol 26:1923–1929, 1999. 158. Simonson JS, et al: Pulmonary hypertension in systemic lupus erythematosus. J Rheumatol 16:918–925, 1989. 159. Winslow TM, et al: Five-year follow-up study of the prevalence and progression of pulmonary hypertension in systemic lupus erythematosus. Am Heart J 129:510– 515, 1995. 160. Mette SA, et al: Primary pulmonary hypertension in association with human immunodeficiency virus infection. A possible viral etiology for some forms of hypertensive pulmonary arteriopathy. Am Rev Respir Dis 145:1196–1200, 1992. 161. Ehrenreich H, et al: Potent stimulation of monocytic endothelin-1 production by HIV-1 glycoprotein 120. J Immunol 150:4601–4609, 1993. 162. Humbert M, et al: Platelet-derived growth factor expression in primary pulmonary hypertension: Comparison of HIV seropositive and HIV seronegative patients. Eur Respir J 11:554–559, 1998. 163. Voelkel NF, Tuder RM: Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 8:2129–2138, 1995. 164. Speich R, et al: Primary pulmonary hypertension in HIV infection. Chest 100:1268–1271, 1991. 165. Petitpretz P, et al: Pulmonary hypertension in patients with human immunodeficiency virus infection. Comparison with primary pulmonary hypertension. Circulation 89:2722–2727, 1994. 166. Nunes H, et al: Prognostic factors for survival in human immunodeficiency virus-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 167:1433– 1439, 2003.

167. Zuber JP, et al: Pulmonary arterial hypertension related to HIV infection: Improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 38:1178–1185, 2004. 168. Ramsay MA, et al: Severe pulmonary hypertension in liver transplant candidates. Liver Transplant Surg 3:494– 500, 1997. 169. Edwards B, et al: Coexistent pulmonary and portal hypertension: Morphologic and clinical features. J Am Coll Cardiol 10:1233–1238, 1987. 170. Benjaminov FS, et al: Portopulmonary hypertension in decompensated cirrhosis with refractory ascites. Gut 52:1355–1362, 2003. 171. Tuder RM, et al: Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 159:1925– 1932, 1999. 172. Hoeper MM, Krowka MJ, Strassburg CP: Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 363:1461–1468, 2004. 173. Hadengue A, et al: Pulmonary hypertension complicating portal hypertension: Prevalence and relation to splanchnic hemodynamics. Gastroenterology 100:520– 528, 1991. 174. McDonnell PJ, Toye PA, Hutchins GM: Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 127:437–441, 1983. 175. Robalino BD, Moodie DS: Association between primary pulmonary hypertension and portal hypertension: Analysis of its pathophysiology and clinical laboratory and hemodynamic manifestations. J Am Coll Cardiol 17:492–498, 1991. 176. Kawut SM, et al: Hemodynamics and survival of patients with portopulmonary hypertension. Liver Transpl 11:1107–1111, 2005. 177. Rodriguez-Roisin R, et al: Pulmonary-Hepatic Vascular Disorders Scientific Committee ERS Task Force. Eur Respir J 24:861–880, 2004. 178. Ota K, et al: Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis. J Gastroenterol Hepatol 10:198–204, 1995. 179. Navasa M, et al: Effects of verapamil on hepatic and systemic hemodynamics and liver function in patients with cirrhosis and portal hypertension. Hepatology 8:850– 854, 1988. 180. Swanson KKM: Portopulmonary hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia Elsevier Science, 2006, pp 132–142. 181. Kuo PC, et al: Continuous intravenous infusion of epoprostenol for the treatment of portopulmonary hypertension. Transplantation 63:604–616, 1997. 182. Findlay JY, et al: Progressive splenomegaly after epoprostenol therapy in portopulmonary hypertension. Liver Transplant Surg 5:381–387, 1999. 183. Krowka MJ, et al: Improvement in pulmonary hemodynamics during intravenous epoprostenol (prostacyclin): A study of 15 patients with moderate to severe

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portopulmonary hypertension. Hepatology 30:641– 648, 1999. 184. Kahler CM, et al: Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension. Wiener Klinische Wochenschrift 112:637–640, 2000. 185. Halank M, et al: Combination therapy for portopulmonary hypertension with intravenous iloprost and oral bosentan. Wien Med Wochenschr 155:376–380, 2005. 186. Kett DH, et al: Recurrent portopulmonary hypertension after liver transplantation: Management with epoprostenol and resolution after retransplantation. Liver Transpl 7:645–648, 2001. 187. Schroeder RA, et al: Use of aerosolized inhaled epoprostenol in the treatment of portopulmonary hypertension. Transplantation 70:548–550, 2000. 188. Rafanan AL, et al: Progressive portopulmonary hypertension after liver transplant treated with epoprostenol. Chest 118:1497–500, 2000. 189. Hoeper MM, et al: Bosentan therapy for portopulmonary hypertension. Eur Respir J 25:502–508, 2005. 190. Makisalo H, et al: Sildenafil for portopulmonary hypertension in a patient undergoing liver transplantation. Liver Transplant 10:945–950, 2004. 191. Chua R, Keogh A, Miyashita M: Novel use of sildenafil in the treatment of portopulmonary hypertension. J Heart Lung Transplant 24:498–500, 2005. 192. Krowka MJ, et al: Hepatopulmonary syndrome and portopulmonary hypertension: A report of the multicenter liver transplant database. Liver Transplant 10:174–182, 2004. 193. Krowka MJ, et al: Pulmonary hemodynamics and perioperative cardiopulmonary-related mortality in patients with portopulmonary hypertension undergoing liver transplantation. Liver Transplant 6:443–450, 2000. 194. Minder S, et al: Intravenous iloprost bridging to orthotopic liver transplantation in portopulmonary hypertension. Eur Respir J 24:703–707, 2004. 195. Kim WR, et al: Accuracy of Doppler echocardiography in the assessment of pulmonary hypertension in liver transplant candidates. Liver Transplant 6:453–458, 2000. 196. Gurtner HP: Aminorex pulmonary hypertension, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal Mechanisms Management and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 397–411. 197. Brenot F: Risk factors for primary pulmonary hypertension, in Rubin LJ, Rich S (eds), Primary Pulmonary Hypertension. New York, Marcel Dekker, 1996, pp 131– 149. 198. Scholand MB, Singh NA, Leppert M, et al: BMPR2 mutations are uncommon in North American patients with appetite suppressant associated pulmonary arterial hypertension. Am J Resp Crit Care Med 167:A167, 2003.

Pulmonary Hypertension and Cor Pulmonale

199. Simonneau G, et al: Primary pulmonary hypertension associated with the use of fenfluramine derivatives. Chest 114:195S–199S, 1998. 200. Frank H, et al: The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 112:714–21, 1997. 201. Rich S, Shillington A, McLaughlin V: Comparison of survival in patients with pulmonary hypertension associated with fenfluramine to patients with primary pulmonary hypertension. Am J Cardiol 92:1366–1368, 2003. 202. Lopez-Sendon J, Gomez-Sanchez MA, Mestre de Juan MJ, et al: Pulmonary hypertension in the toxic oil syndrome, in Fishman AP (ed), The Pulmonary Circulation: Normal and Abnormal Mechanisms Management and the National Registry. Philadelphia, University of Pennsylvania Press, 1990, pp 385–395. 203. Morris CR, et al: Dysregulated arginine metabolism hemolysis-associated pulmonary hypertension and mortality in sickle cell disease. JAMA 294:81–90, 2005. 204. Castro O: Pulmonary hypertension in sickle cell disease and thalassemia, in Peacock L (ed), Pulmonary Circulation: Diseases and Their Treatment. London, Arnold Publishers, 2004, pp 237–243. 205. Machado MT: Hemolytic anemia associated pulmonary hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier, 2006, pp 170–187. 206. Gladwin MT, et al: Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med 350:886–895, 2004. 207. Jootar P, Fucharoen S: Cardiac involvement in betathalassemia/hemoglobin E disease: Clinical and hemodynamic findings. Southeast Asian J Trop Med Public Health 21:269–273, 1990. 208. Du Z, Roguin N, Milgram E, et al: Pulmonary hypertension in patients with thalassemia major. Am Heart J 134:532–537, 1997. 209. Aessopos A, et al: Thalassemia heart disease: A comparative evaluation of thalassemia major and thalassemia intermedia. Chest 127:1523–1530, 2005. 210. Aessopos A, Farmakis D: Pulmonary hypertension in β-thalassemia. Ann NY Acad Sci 1054:342–349, 2005. 211. Verresen D, et al: Spherocytosis and pulmonary hypertension coincidental occurrence or causal relationship? Eur Respir J 4:629–631, 1991. 212. Heller PG, et al: Pulmonary hypertension in paroxysmal nocturnal hemoglobinuria. Chest 102:642–643, 1992. 213. Castro O, Hoque M, Brown BD: Pulmonary hypertension in sickle cell disease: Cardiac catheterization results and survival. Blood 101:1257–1261, 2003. 214. Machado RF, et al: Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension. Br J Haematol 130:445–453, 2005. 215. Derchi G, et al: Efficacy and safety of sildenafil in the treatment of severe pulmonary hypertension in patients

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Disorders of the Pulmonary Circulation

with hemoglobinopathies. Haematologica 90:452–458, 2005. 216. Mandel J: Pulmonary veno-occlusive disease, in Taichman DB, Mandel J (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 157–169, 2006. 217. Doll DC, Yarbro JW: Vascular toxicity associated with chemotherapy and hormonotherapy. Curr Opin Oncol 6:345–350, 1994. 218. Joselson R, Warnock M: Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol 14:88–91, 1983. 219. Knight BK, Rose AG: Pulmonary veno-occlusive disease after chemotherapy. Thorax 40:874–875, 1985. 220. Swift GL, et al: Pulmonary veno-occlusive disease and Hodgkin’s lymphoma. Eur Respir J 6:596–598, 1993. 221. Waldhorn RE, et al: Pulmonary veno-occlusive disease associated with microangiopathic hemolytic anemia and chemotherapy of gastric adenocarcinoma. Med Pediatr Oncol 12:394–396, 1984. 222. Gagnadoux F, Capron F, Lebeau B: Pulmonary veno-occlusive disease after neoadjuvant mitomycin chemotherapy and surgery for lung carcinoma. Lung Cancer 36:213–215, 2002. 223. Vansteenkiste JF, et al: Fatal pulmonary veno-occlusive disease possibly related to gemcitabine. Lung Cancer 31:83–85, 2001. 224. Williams LM, et al: Pulmonary veno-occlusive disease in an adult following bone marrow transplantation. Case report and review of the literature. Chest 109:1388– 1391, 1996. 225. Hackman RC, et al: Pulmonary venoocclusive disease following bone marrow transplantation. Transplantation 47:989–992, 1989. 226. Kuga T, et al: Pulmonary veno-occlusive disease accompanied by microangiopathic hemolytic anemia 1 year after a second bone marrow transplantation for acute lymphoblastic leukemia. Int J Hematol 64:143– 150, 1996. 227. Salzman D, et al: Malignancy-associated pulmonary veno-occlusive disease: Report of a case following autologous bone marrow transplantation and review. Bone Marrow Transplant 18:755–760, 1996. 228. Trobaugh-Lotrario AD, et al: Pulmonary venoocclusive disease after autologous bone marrow transplant in a child with stage IV neuroblastoma: Case report and literature review. J Pediatr Hematol Oncol 25:405–409, 2003. 229. Seguchi M, et al: Pulmonary hypertension associated with pulmonary occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 69:177– 179, 2000. 230. Mukai M, et al: Pulmonary veno-occlusive disease following allogeneic peripheral blood stem cell transplantation for chronic myeloid leukaemia. Br J Haematol 123:1, 2003. 231. Ruchelli ED, et al: Pulmonary veno-occlusive disease. Another vascular disorder associated with human im-

munodeficiency virus infection? Arch Pathol Lab Med 118:664–666, 1994. 232. Escamilla R, et al: Pulmonary veno-occlusive disease in a HIV-infected intravenous drug abuser. Eur Respir J 8:1982–1984, 1995. 233. Hourseau M, et al: [Pulmonary veno-occlusive disease in a patient with HIV infection A case report with autopsy findings.] Ann Pathol 22:472–475, 2002. 234. Tsou E, et al: Pulmonary venoocclusive disease in pregnancy. Obstet Gynecol 64:281–284, 1984. 235. Townend JN, et al: Fatal pulmonary venoocclusive disease after use of oral contraceptives. Am Heart J 124:1643–1644, 1992. 236. Scully R, Mark E, McNeely B: Case records of the Massachusetts General Hospital: Weekly clinicopathologic exercises. Case 14–1983: A 67-year-old woman with pulmonary hypertension. N Engl J Med 308:823, 1983. 237. Kishida Y, et al: Pulmonary venoocclusive disease in a patient with systemic lupus erythematosus. J Rheumatol 20:2161–2162, 1993. 238. Saito A, et al: A case of pulmonary veno-occlusive disease associated with systemic sclerosis. Respirology 8:383–385, 2003. 239. Thadani U, et al: Pulmonary veno-occlusive disease. Q J Med 44:133–159, 1975. 240. Heath D, Segel N, Bishop J: Pulmonary veno-occlusive disease. Circulation 34:242–248, 1966. 241. Calderon M, Burdine JA: Pulmonary veno-occlusive disease. J Nucl Med 15:455–457, 1974. 242. Glassroth J, et al: Pulmonary veno-occlusive disease in the middle-aged. Respiration 47:309–321, 1985. 243. Chawla SK, et al: Pulmonary venoocclusive disease. Ann Thorac Surg 22:249–253, 1976. 244. Swensen SJ, et al: Pulmonary venoocclusive disease: CT findings in eight patients. AJR Am J Roentgenol 167:937– 940, 1996. 245. Wiener-Kronish JP, et al: Lack of association of pleural effusion with chronic pulmonary arterial and right atrial hypertension. Chest 92:967–970, 1987. 246. Bailey CL, et al: “High probability” perfusion lung scans in pulmonary venoocclusive disease. Am J Respir Crit Care Med 162:1974–1978, 2000. 247. Dufour B, et al: High-resolution CT of the chest in four patients with pulmonary capillary hemangiomatosis or pulmonary venoocclusive disease. AJR Am J Roentgenol 171:1321–1324, 1998. 248. Weed HG: Pulmonary “capillary” wedge pressure not the pressure in the pulmonary capillaries. Chest 100:1138–1140, 1991. 249. Rambihar VS, Fallen EL, Cairns JA: Pulmonary veno-occlusive disease: Antemortem diagnosis from roentgenographic and hemodynamic findings. Can Med Assoc J 120:1519–1522, 1979. 250. Salzman GA, Rosa UW: Prolonged survival in pulmonary veno-occlusive disease treated with nifedipine. Chest 95:1154–1156, 1989.

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251. Palevsky HI, Pietra GG, Fishman AP: Pulmonary venoocclusive disease and its response to vasodilator agents. Am Rev Respir Dis 142:426–429, 1990. 252. Okumura H, et al: Effects of continuous IV prostacyclin in a patient with pulmonary veno-occlusive disease. Chest 122:1096–1098, 2002. 253. Davis LL, et al: Effect of prostacyclin on microvascular pressures in a patient with pulmonary veno-occlusive disease. Chest 108:1754–1756, 1995. 254. Palmer SM, et al: Massive pulmonary edema and death after prostacyclin infusion in a patient with pulmonary veno-occlusive disease. Chest 113:237–240, 1998. 255. Hoeper MM, et al: Effects of inhaled nitric oxide and aerosolized iloprost in pulmonary veno-occlusive disease. Respir Med 93:62–64, 1999. 256. Gilroy RJ Jr, Teague MW, Loyd JE: Pulmonary venoocclusive disease. Fatal progression of pulmonary hypertension despite steroid-induced remission of interstitial pneumonitis. Am Rev Respir Dis 143:1130–1133, 1991. 257. Sanderson JE, et al: A case of pulmonary veno-occlusive disease responding to treatment with azathioprine. Thorax 32:140–148, 1977. 258. Eltorky MA, et al: Pulmonary capillary hemangiomatosis: A clinicopathologic review Ann Thorac Surg 57:772– 776, 1994. 259. Kawut SM, et al: Pulmonary capillary hemangiomatosis: Results of gene expression analysis. Chest 128:575S– 5766S, 2005. 260. Sullivan A, et al: Pulmonary capillary hemangiomatosis: An immunohistochemical analysis of vascular remodeling in a fatal case. Chest 128:576S, 2005. 261. Kradin R, Matsubara O, Mark EJ: Endothelial nitric oxide synthase expression in pulmonary capillary hemangiomatosis. Exp Mol Pathol 79:194–197, 2005. 262. Langleben D, et al: Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension. Ann Intern Med 109:106–109, 1988. 263. Lippert JL, et al: Pulmonary capillary hemangiomatosis: Radiographic appearance. J Thorac Imaging 13:49–51, 1998. 264. Lawler LP, Askin FB: Pulmonary capillary hemangiomatosis: Multidetector row CT findings and clinicopathologic correlation. J Thorac Imaging 20:61–63, 2005. 265. Humbert M, et al: Pulmonary edema complicating continuous intravenous prostacyclin in pulmonary capillary hemangiomatosis. Am J Respir Crit Care Med 157:1681–1685, 1998. 266. Ito K, et al: Pulmonary capillary hemangiomatosis with severe pulmonary hypertension. Circ J 67:793–795, 2003. 267. Gugnani MK, et al: Pulmonary edema complicating prostacyclin therapy in pulmonary hypertension associated with scleroderma: A case of pulmonary capillary hemangiomatosis. Arthritis Rheum 43:699–703, 2000.

Pulmonary Hypertension and Cor Pulmonale

268. White CW, et al: Treatment of pulmonary hemangiomatosis with recombinant interferon alfa-2a. N Engl J Med 320:1197–1200, 1989. 269. Taichman DB, et al: Validation of a brief telephone battery for neurocognitive assessment of patients with pulmonary arterial hypertension. Respir Res 6:39, 2005. 270. Morgan JM, et al: Hypoxic pulmonary vasoconstriction in systemic sclerosis and primary pulmonary hypertension. Chest 99:551–556, 1991. 271. Krasuski RA, et al: Inhaled nitric oxide selectively dilates pulmonary vasculature in adult patients with pulmonary hypertension irrespective of etiology. J Am Coll Cardiol 36:2204–2211, 2000. 272. Rubin LJ, et al: Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation 66:334–338, 1982. 273. Sitbon O, et al: Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension. A dose-response study and comparison with prostacyclin. Am J Respir Crit Care Med 151:384–389, 1995. 274. Galie N, Ussia G, Passarelli P, et al: Role of pharmacologic tests in the treatment of primary pulmonary hypertension. Am J Cardiol 75:55A–62A, 1995. 275. Nootens M, et al: Comparative acute effects of adenosine and prostacyclin in primary pulmonary hypertension. Chest 107:54–57, 1995. 276. Palevsky HI, et al: Prostacyclin and acetylcholine as screening agents for acute pulmonary vasodilator responsiveness in primary pulmonary hypertension. Circulation 82:2018–2026, 1990. 277. Barst RJ, Maislin G, Fishman AP: Vasodilator therapy for primary pulmonary hypertension in children. Circulation 99:1197–208, 1999. 278. Partanen J, Nieminen MS, Luomanmaki K: Death in a patient with primary pulmonary hypertension after 20 mg of nifedipine. N Engl J Med 329:812; author reply 812–813, 1993. 279. Rich S, Kaufmann E, Levy PS: The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 327:76–81, 1992. 280. Sitbon O, et al: Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 111:3105–3111, 2005. 281. Rich S, Kaufmann E: High dose titration of calcium channel blocking agents for primary pulmonary hypertension: Guidelines for short-term drug testing. J Am Coll Cardiol 18:1323–1327, 1991. 282. Channick RN, et al: Effects of the dual endothelinreceptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebocontrolled study. Lancet 358:1119–1123, 2001. 283. Sitbon O, et al: Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: A 1-year follow-up study. Chest 124:247– 254, 2003. 284. Sitbon O, et al: Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial

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hypertension. Am J Respir Crit Care Med 170:1212– 1217, 2004. 285. Schulze-Neick I, et al: Adult patients with congenital heart disease and pulmonary arterial hypertension: First open prospective multicenter study of bosentan therapy. Am Heart J 150:716, 2005. 286. Bonderman D, et al: Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 128:2599–603, 2005. 287. Hoeper MM, et al: Bosentan therapy for inoperable chronic thromboembolic pulmonary hypertension. Chest 128:2363–2367, 2005. 288. Maiya S, et al: Response to bosentan in children with pulmonary hypertension. Heart 92:664–670, 2005. 289. Rosenzweig EB, et al: Effects of long-term bosentan in children with pulmonary arterial hypertension. J Am Coll Cardiol 46:697–704, 2005. 290. Gilbert N, et al: Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children. Z Kardiol 94:570–574, 2005. 291. Barst RJ, et al: Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 169:441– 447, 2004. 292. Langleben D, et al: Sustained symptomatic functional and hemodynamic benefit with the selective endothelin-A receptor antagonist sitaxsentan in patients with pulmonary arterial hypertension: A 1-year follow-up study. Chest 126:1377–1381, 2004. 293. Galie N, et al: Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 46:529–535, 2005. 294. Ghofrani HA, et al: Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study. J Am Coll Cardiol 44:1488–1496, 2004. 295. Galie N, et al: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353:2148–2157, 2005. 296. Wilkins MR, et al: Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Respir Crit Care Med 171:1292–1297, 2005. 297. Barst RJ, et al: Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 121:409–415, 1994. 298. Lang G, Klepetko W: Lung transplantation for endstage primary pulmonary hypertension. Ann Transplant 9:25–32, 2004. 299. Robbins IM, et al: A survey of diagnostic practices and the use of epoprostenol in patients with primary pulmonary hypertension. Chest 114:1269–1275, 1998. 300. Badesch DB, et al: Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized controlled trial. Ann Intern Med 132:425–434, 2000.

301. Robbins IM, et al: Epoprostenol for treatment of pulmonary hypertension in patients with systemic lupus erythematosus. Chest 117:14–18, 2000. 302. Rosenzweig EB, Kerstein D, Barst RJ: Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 99:1858–1865, 1999. 303. McLaughlin VV, et al: Compassionate use of continuous prostacyclin in the management of secondary pulmonary hypertension: A case series. Ann Intern Med 130:740–743, 1999. 304. Archer-Chicko C, Housten-Harris T, Palevsky HI: Practical nursing issues in the outpatient management of pulmonary vascular disease, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 2006. 305. McLaughlin VV, et al: Efficacy and safety of treprostinil: An epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol 41:293–299, 2003. 306. Simonneau G, et al: Continuous subcutaneous infusion of treprostinil a prostacyclin analogue in patients with pulmonary arterial hypertension: A double-blind randomized placebo-controlled trial. Am J Respir Crit Care Med 165:800–804, 2002. 307. Fruhwald FM, et al: Continuous hemodynamic monitoring in pulmonary hypertensive patients treated with inhaled iloprost. Chest 124:351–359, 2003. 308. Olschewski H, et al: Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 124:820–824, 1996. 309. Olschewski H, et al: Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial German PPH Study Group. Ann Intern Med 132:435–443, 2000. 310. Machherndl S, et al: Long-term treatment of pulmonary hypertension with aerosolized iloprost. Eur Respir J 17:8–13, 2001. 311. Olschewski H, et al: Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 347:322–329, 2002. 312. de la Mata J, et al: Long-term iloprost infusion therapy for severe pulmonary hypertension in patients with connective tissue diseases. Arthritis Rheum 37:1528– 1533, 1994. 313. Higenbottam T, et al: Long-term intravenous prostaglandin (epoprostenol or iloprost) for treatment of severe pulmonary hypertension. Heart 80:151–155, 1998. 314. Scott JP, Higenbottam T, Wallwork J: The acute effect of the synthetic prostacyclin analogue iloprost in primary pulmonary hypertension. Br J Clin Pract 44:231–234, 1990. 315. Barst RJ, et al: Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol 41:2119–2125, 2003. 316. Galie N, et al: Effects of beraprost sodium an oral prostacyclin analogue in patients with pulmonary arterial hypertension: A randomized double-blind placebocontrolled trial. J Am Coll Cardiol 39:1496–1502, 2002.

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317. Humbert M, et al: Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 24:353–359, 2004. 318. Hoeper MM, et al: Bosentan treatment in patients with primary pulmonary hypertension receiving nonparenteral prostanoids. Eur Respir J 22:330–334, 2003. 318a. McLaughlin VV, Odiz RJ, Frost A, et al.: Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Resp Crit Care Med 174:1257–1263, 2006. 319. Ghofrani HA, et al: Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 42:158–164, 2003. 320. Ghofrani HA, et al: Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 136:515–522, 2002. 321. Wilkens H, et al: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104:1218–1222, 2001. 322. Hoeper MM, et al: Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J 24:1007–1010, 2004. 323. Badesch DB, et al: Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:35S–62S, 2004. 324. Doyle RL, et al: Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidencebased clinical practice guidelines. Chest 126:63S–71S, 2004. 325. Trulock EP, et al: The Registry of the International Society for Heart and Lung Transplantation: Twenty-first official adult lung and heart-lung transplant report—2004. J Heart Lung Transplant 23:804–815, 2004. 326. Edelman J, Palevsky HI: Has prostacyclin replaced transplantation as the treatment for primary pulmonary hypertension. Clin Pulmon Med 7:90–96, 2000. 327. Ahya V, Sager JS: Lung transplantation for pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 2006. 328. McCaffrey RM, Dunn LJ: Primary pulmonary hypertension in pregnancy. Obstet Gynecol Surv 19:567–591, 1964. 329. Weiss JR, Pietra GG, Scharf SM: Primary pulmonary hypertension and the human immunodeficiency virus. Report of two cases and a review of the literature. Arch Intern Med 155:2350–2354, 1995. 330. Weiss BM, et al: Outcome of pulmonary vascular disease in pregnancy: A systematic overview from 1978 through 1996. J Am Coll Cardiol 31:1650–1657, 1998. 331. Mandel J: Pregnancy and pulmonary hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 2006. 332. Bonnin M, et al: Severe pulmonary hypertension during pregnancy: Mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 102:1133– 1137; discussion 5A–6A, 2005.

Pulmonary Hypertension and Cor Pulmonale

333. Badalian SS, et al: Twin pregnancy in a woman on longterm epoprostenol therapy for primary pulmonary hypertension. A case report. J Reprod Med 45:149–152, 2000. 334. Decoene C, et al: Use of inhaled nitric oxide for emergency Cesarean section in a woman with unexpected primary pulmonary hypertension. Can J Anaesth 48:584–587, 2001. 335. Stewart R, et al: Pregnancy and primary pulmonary hypertension: Successful outcome with epoprostenol therapy. Chest 119:973–975, 2001. 336. Porter TR, et al: Endothelium-dependent pulmonary artery responses in chronic heart failure: Influence of pulmonary hypertension. J Am Coll Cardiol 22:1418– 1424, 1993. 337. Doyle TP, Loyd JE, Robbins IM: Percutaneous pulmonary artery and vein stenting: A novel treatment for mediastinal fibrosis. Am J Respir Crit Care Med 164:657– 660, 2001. 338. Purerfellner H, Martinek M: Pulmonary vein stenosis following catheter ablation of atrial fibrillation. Curr Opin Cardiol 20:484–490, 2005. 339. Wright JL, Petty T, Thurlbeck WM: Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health nocturnal oxygen therapy trial. Lung 170:109–124, 1992. 340. Peinado VI, et al: Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159:1605–1611, 1999. 341. Dinh-Xuan AT, et al: Impairment of endotheliumdependent pulmonary-artery relaxation in chronic obstructive lung disease. N Engl J Med 324:1539–1547, 1991. 342. Yildiz P, et al: Gene polymorphisms of endothelial nitric oxide synthase enzyme associated with pulmonary hypertension in patients with COPD. Respir Med 97:1282– 1288, 2003. 343. Hale KA, Niewoehner DE, Cosio MG: Morphologic changes in the muscular pulmonary arteries: Relationship to cigarette smoking airway disease and emphysema. Am Rev Respir Dis 122:273–278, 1980. 344. Weitzenblum E, et al: Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 36:752–758, 1981. 345. Weitzenblum E, et al: Long-term course of pulmonary arterial pressure in chronic obstructive pulmonary disease. Am Rev Respir Dis 130:993–998, 1984. 346. Burrows B, et al: Patterns of cardiovascular dysfunction in chronic obstructive lung disease. N Engl J Med 286:912–918, 1972. 347. Fishman AP: State of the art: Chronic cor pulmonale. Am Rev Respir Dis 114:775–794, 1976. 348. Pietra G: Pathology of the pulmonary vasculature and heart, in Cherniack N (ed), Chronic Obstructive

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Disorders of the Pulmonary Circulation

Pulmonary Disease. Philadelphia, WB Saunders, 1996, pp 21–26. 349. Thabut G, et al: Pulmonary hemodynamics in advanced COPD candidates for lung volume reduction surgery or lung transplantation. Chest 127:1531–1536, 2005. 350. Scharf SM, et al: Hemodynamic characterization of patients with severe emphysema. Am J Respir Crit Care Med 166:314–322, 2002. 351. Doi M, et al: Significance of pulmonary artery pressure in emphysema patients with mild-to-moderate hypoxemia. Respir Med 97:915–920, 2003. 352. Kessler R, et al: “Natural history” of pulmonary hypertension in a series of 131 patients with chronic obstructive lung disease. Am J Respir Crit Care Med 164:219– 224, 2001. 353. Chaouat A, et al: Severe pulmonary hypertension and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 172:189–194, 2005. 354. Weitzenblum E, Chaouat A: Severe pulmonary hypertension in COPD: Is it a distinct disease? Chest 127:1480–1482, 2005. 355. Oswald-Mammosser M, et al: Prognostic factors in COPD patients receiving long-term oxygen therapy Importance of pulmonary artery pressure. Chest 107:1193–1198, 1995. 356. Kessler R, et al: Predictive factors of hospitalization for acute exacerbation in a series of 64 patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 159:158–164, 1999. 357. Traver GA, Cline MG, Burrows B: Predictors of mortality in chronic obstructive pulmonary disease. A 15-year follow-up study. Am Rev Respir Dis 119:895–902, 1979. 358. Burgess MI, et al: Comparison of echocardiographic markers of right ventricular function in determining prognosis in chronic pulmonary disease. J Am Soc Echocardiogr 15:633–639, 2002. 359. Arcasoy SM, et al: Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 167:735–740, 2003. 360. Timms RM, Khaja FU, Williams GW: Hemodynamic response to oxygen therapy in chronic obstructive pulmonary disease. Ann Intern Med 102:29–36, 1985. 361. Zielinski J, et al: Effects of long-term oxygen therapy on pulmonary hemodynamics in COPD patients: A 6-year prospective study. Chest 113:65–70, 1998. 362. Weitzenblum E, et al: Long-term oxygen therapy can reverse the progression of pulmonary hypertension in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 131:493–498, 1985. 363. Gorecka D, et al: Effect of long–term oxygen therapy on survival in patients with chronic obstructive pulmonary disease with moderate hypoxaemia. Thorax 52:674–679, 1997. 364. Gassner A, et al: Differential therapy with calcium antagonists in pulmonary hypertension secondary to COPD. Hemodynamic effects of nifedipine diltiazem and verapamil. Chest 98:829–834, 1990.

365. Muramoto A, et al: Nifedipine dilates the pulmonary vasculature without producing symptomatic systemic hypotension in upright resting and exercising patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease. Am Rev Respir Dis 132:963–966, 1985. 366. Sajkov D, et al: Felodipine improves pulmonary hemodynamics in chronic obstructive pulmonary disease. Chest 103:1354–1361, 1993. 367. Bratel T, et al: The use of a vasodilator felodipine as an adjuvant to long-term oxygen treatment in COLD patients. Eur Respir J 3:46–54, 1990. 368. Simonneau G, et al: Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. N Engl J Med 304:1582– 1585, 1981. 369. Barbera JA, Peinado VI, Santos S: Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J 21:892–905, 2003. 370. Melot C, et al: Deleterious effect of nifedipine on pulmonary gas exchange in chronic obstructive pulmonary disease. Am Rev Respir Dis 130:612–616, 1984. 371. Archer SL, et al: A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD. Chest 109:750–755, 1996. 372. Jones K, Higenbottam T, Wallwork J: Pulmonary vasodilation with prostacyclin in primary and secondary pulmonary hypertension. Chest 96:784–789, 1989. 373. Yoshida M, et al: Combined inhalation of nitric oxide and oxygen in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 155:526–529, 1997. 374. Ashutosh K, et al: Use of nitric oxide inhalation in chronic obstructive pulmonary disease. Thorax 55:109– 113, 2000. 375. Vonbank K, et al: Controlled prospective randomised trial on the effects on pulmonary haemodynamics of the ambulatory long term use of nitric oxide and oxygen in patients with severe COPD. Thorax 58:289–293, 2003. 376. Bergofsky EH, Turino GM, Fishman AP: Cardiorespiratory failure in kyphoscoliosis. Medicine (Baltimore) 38:263–317, 1959. 377. Atwood CW Jr, et al: Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical practice guidelines. Chest 126:72S–77S, 2004. 378. Fletcher EC, et al: Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 135:525–533, 1987. 379. Hawrylkiewicz I, et al: Pulmonary haemodynamics in patients with OSAS or an overlap syndrome. Monaldi Arch Chest Dis 61:148–152, 2004. 380. Kessler R, et al: Pulmonary hypertension in the obstructive sleep apnoea syndrome: Prevalence causes and therapeutic consequences. Eur Respir J 9:787–794, 1996. 381. Laks L, et al: Pulmonary hypertension in obstructive sleep apnoea. Eur Respir J 8:537–541, 1995. 382. Kessler R, et al: The obesity-hypoventilation syndrome revisited: A prospective study of 34 consecutive cases. Chest 120:369–376, 2001.

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383. Chaouat A, et al: Pulmonary hemodynamics in the obstructive sleep apnea syndrome. Results in 220 consecutive patients. Chest 109:380–386, 1996. 384. Bradley TD, et al: Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 131:835–839, 1985. 385. Weitzenblum E, et al: Daytime pulmonary hypertension in patients with obstructive sleep apnea syndrome. Am Rev Respir Dis 138:345–349, 1988. 386. Sajkov D, et al: Continuous positive airway pressure treatment improves pulmonary hemodynamics in patients with obstructive sleep apnea. Am J Respir Crit Care Med 165:152–158, 2002. 387. Alchanatis M, et al: Daytime pulmonary hypertension in patients with obstructive sleep apnea: The effect of continuous positive airway pressure on pulmonary hemodynamics. Respiration 68:566–572, 2001. 388. Denton CP, Black CM: Pulmonary hypertension in systemic sclerosis. Rheum Dis Clin North Am 29:335–349 vii, 2003. 389. Koh ET, et al: Pulmonary hypertension in systemic sclerosis: An analysis of 17 patients. Br J Rheumatol 35:989– 993, 1996. 390. Smith LJ, Lawrence JB, Katzenstein AA. Vascular sarcoidosis: A rare cause of pulmonary hypertension. Am J Med Sci 285:38–44, 1983. 391. Humbert M, et al: Short-term and long-term epoprostenol (prostacyclin) therapy in pulmonary hypertension secondary to connective tissue diseases: Results of a pilot study. Eur Respir J 13:1351–1356, 1999. 392. Preston IR, et al: Vasoresponsiveness of sarcoidosisassociated pulmonary hypertension. Chest 120:866– 872, 2001. 393. Barst RJ, Ratner SJ: Sarcoidosis and reactive pulmonary hypertension. Arch Intern Med 145:2112–2114, 1985. 394. Sturani C, et al: Pulmonary vascular responsiveness at rest and during exercise in idiopathic pulmonary fibrosis: Effects of oxygen and nifedipine. Respiration 50:117–129, 1986. 395. Olschewski H, et al: Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med 160:600–607, 1999. 396. Fedullo PF, et al: Chronic thromboembolic pulmonary hypertension. N Engl J Med 345:1465–1472, 2001. 397. Chin K, Fedullo PF: Chronic thromboembolic pulmonary hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 2006. 398. Pengo V, et al: Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 350:2257–2264, 2004. 399. Liu P, et al: Predictors of long-term clinical outcome of patients with acute massive pulmonary embolism after thrombolytic therapy. Chin Med J (Engl) 116:503–509, 2003.

Pulmonary Hypertension and Cor Pulmonale

400. Egermayerand A, Peacock J: Is pulmonary embolism a common cause of chronic pulmonary hypertension? Limitations of the embolic hypothesis. Eur Respir J 15:440–448, 2000. 401. Fedullo PF, et al: The natural history of acute and chronic thromboembolic disease: The search for the missing link. Eur Respir J 15:435–437, 2000. 402. Wartski M, Collignon MA: Incomplete recovery of lung perfusion after 3 months in patients with acute pulmonary embolism treated with antithrombotic agents. THESEE Study Group Tinzaparin ou Heparin Standard: Evaluation dans l’Embolie Pulmonaire Study. J Nucl Med 41:1043–1048, 2000. 403. Ribeiro A, et al: Pulmonary embolism: A follow-up study of the relation between the degree of right ventricle overload and the extent of perfusion defects. J Intern Med 245:601–610, 1999. 404. Moser KM, Bloor CM: Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 103:685– 692, 1993. 405. Auger W, Moser KM: Pulmonary flow murmurs: A distinctive physical sign found in chronic pulmonary thromboembolic disease. Clin Res 37:145A, 1989. 406. Worsley DF, Palevsky HI, Alavi A: Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med 35:793–796, 1994. 407. Ryan KL, et al: Perfusion scan findings understate the severity of angiographic and hemodynamic compromise in chronic thromboembolic pulmonary hypertension. Chest 93:1180–1185, 1988. 408. Bergin CJ, et al: Chronic thromboembolism: Diagnosis with helical CT and MR imaging with angiographic and surgical correlation. Radiology 204:695–702, 1997. 409. Bergin CJ, et al: Accuracy of high-resolution CT in identifying chronic pulmonary thromboembolic disease. AJR Am J Roentgenol 166:1371–1377, 1996. 410. Daily PO, et al: Modifications of techniques and early results of pulmonary thromboendarterectomy for chronic pulmonary embolism. J Thorac Cardiovasc Surg 93:221–233, 1987. 411. Moser KM, et al: Chronic thromboembolic pulmonary hypertension: Clinical picture and surgical treatment. Eur Respir J 5:334–342, 1992. 412. Kim NH, et al: Preoperative partitioning of pulmonary vascular resistance correlates with early outcome after thromboendarterectomy for chronic thromboembolic pulmonary hypertension. Circulation 109:18–22, 2004. 413. Jamieson SW, Kapelanski DP: Pulmonary endarterectomy. Curr Probl Surg 37:165–252, 2000. 414. Jamieson SW, et al: Pulmonary endarterectomy: Experience and lessons learned in 1500 cases. Ann Thorac Surg 76:1457–1462; discussion 1462–1464, 2003. 415. Kramm T, et al: Long-term results after thromboendarterectomy for chronic pulmonary embolism. Eur

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J Cardiothorac Surg 15:579–583; discussion 583–584, 1999. 416. Kapitan KS, Clausen JL, Moser KM: Gas exchange in chronic thromboembolism after pulmonary thromboendarterectomy. Chest 98:14–19, 1990. 417. Tanabe N, et al: The efficacy of pulmonary thromboendarterectomy on long-term gas exchange. Eur Respir J 10:2066–2072, 1997. 418. Menzel T, et al: Quantitative assessment of right ventricular volumes in severe chronic thromboembolic pulmonary hypertension using transthoracic threedimensional echocardiography: Changes due to pulmonary thromboendarterectomy. Eur J Echocardiogr 3:67–72, 2002. 419. Zoia MC, et al: Mid term effects of pulmonary thromboendarterectomy on clinical and cardiopulmonary function status. Thorax 57:608–612, 2002. 420. Archibald CJ, et al: Long-term outcome after pulmonary thromboendarterectomy. Am J Respir Crit Care Med 160:523–528, 1999. 421. Riedel M, et al: Long-term follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 81:151–158, 1982. 422. Lewczuk J, et al: Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 119:818–823, 2001. 423. Scelsi L, et al: Epoprostenol in chronic thromboembolic pulmonary hypertension with distal lesions. Ital Heart J 5:618–623, 2004. 424. Ghofrani HA, et al: Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 167:1139–1141, 2003. 425. Ono F, et al: Effect of orally active prostacyclin analogue on survival in patients with chronic thromboembolic pulmonary hypertension without major vessel obstruction. Chest 123:1583–1588, 2003.

426. Nagaya N, et al: Prostacyclin therapy before pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension. Chest 123:338–43, 2003. 427. Bresser P, et al: Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension. Eur Respir J 23:595–600, 2004. 428. Jeffery M, Taichman DB: Management of the acutely ill patient with pulmonary arterial hypertension, in Mandel J, Taichman DB (eds), Pulmonary Vascular Disease. Philadelphia, Elsevier Science, 2006. 429. Naeije R. Should pulmonary hypertension be treated in chronic obstructive pulmonary disease? in Weir EK, Archer SL, Reeves JT (eds), The Diagnosis and Treatment of Pulmonary Hypertension. New York, Futura Publishing, 1992, pp 209–239. 430. Kwak YL, et al: The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension. Anaesthesia 57:9–14, 2002. 431. Holloway EL, Polumbo RA, Harrison DC: Acute circulatory effects of dopamine in patients with pulmonary hypertension. Br Heart J 37:482–485, 1975. 432. Kerbaul F, et al: Effects of norepinephrine and dobutamine on pressure load-induced right ventricular failure. Crit Care Med 32:1035–1040, 2004. 433. Hoeper MM, et al: A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol 35:176–182, 2000. 434. Amato MB, et al: Beneficial effects of the “open lung approach” with low distending pressures in acute respiratory distress syndrome. A prospective randomized study on mechanical ventilation. Am J Respir Crit Care Med 152:1835–1846, 1995. 435. Hickey PR, et al: Pulmonary and systemic hemodynamic responses to fentanyl in infants. Anesth Analg 64:483–486, 1985.

82 Pulmonary Thromboembolic Disease Gordon L. Yung

Peter F. Fedullo

I. SOURCES OF EMBOLI II. PREDISPOSING FACTORS Acquired Risk Factor Inherited Conditions III. PATHOPHYSIOLOGY Hemodynamic Consequences Gas-Exchange Abnormalities Diagnosis of Pulmonary Embolism IV. TREATMENT Heparin Novel Agents Thrombolytic Therapy Interventional Radiology Techniques

Pulmonary thromboembolic disease refers to the condition in which blood clot(s) (thrombus or multiple thrombi) migrate from the systemic circulation to the pulmonary vasculature. Most of these blood clots arise from the “deep veins” of the lower and upper extremities (deep venous thrombosis, DVT). From the clinical standpoint, DVT and pulmonary embolism can be considered a continuum of the same disease, and the two terms are often collectively referred to as venous thromboembolism (VTE). This is distinct from cases of in situ thrombus formation in the pulmonary vascular tree, which is often part of a more complex condition such as idiopathic pulmonary arterial hypertension (primary pulmonary hypertension). Whereas in situ thrombus formation is a slow process, with typically subtle onset and progressive symptoms over a period of weeks to months, thrombus migration often results in dramatic and acute clinical changes. In some cases, unresolved pulmonary emboli can lead to a condition called chronic thromboembolism, with associated secondary pulmonary hypertension (chronic thromboembolic pulmonary hypertension). In a retrospective analysis of data involving 2218 Olmsted County residents over a ten year period, community

Pulmonary Embolectomy Long-Term Management Duration of Therapy Vena Cava Interruption and Vena Cava Filter Chronic Thromboembolism Prophylaxis Other Varieties of Embolic Disease Venous Air Embolism Fat Embolism Amniotic Fluid Embolism Septic Embolism Tumor Embolism Sickle Cell Disease Other Emboli

residents who were not hospitalized within a 90 days period had the incidence of pulmonary embolism of 3.6 (95 percent CI, 3.2–4.0) per 10,000 person-years. A slightly lower incidence of 2.3 per 10,000 person-years was also reported in an earlier study in Massachusetts. This translates to an annual incidence of approximately 100,000 cases in the United States. However, the true incidence of pulmonary embolism is likely to be much higher, since many cases remain undiagnosed. While 30 percent of patients with venous thrombosis (VTE) may develop symptomatic pulmonary embolism, an additional 40 percent may have asymptomatic disease noted on imaging studies. An earlier report estimated that as many as 630,000 patients develop pulmonary embolism every year in the United States with 200,000 related deaths, the majority in patients in whom the diagnosis was never made (Fig. 82-1). Although considerable effort is directed toward the development of new diagnostic techniques and therapeutic agents, a considerable impact on mortality related to the disease would arise from the routine use of prophylactic strategies, an understanding of the often subtle clinical presentation of the disease, and the appropriate application of existing diagnostic techniques.

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Figure 82-1 Estimated incidence and survival statistics for pulmonary embolism in the United States. (From Dalen JE, Alpert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17:259–270, 1975.)

SOURCES OF EMBOLI Most cases (80–95 percent) of pulmonary embolism occur as a result of thrombus originating in the lower extremity. Thrombus often begins at a site where blood flow is turbulent, such as at a venous bifurcation, or behind a venous valve (Fig. 82-2). When thrombus propagation exceeds the rate of thrombus organization and adherence to the endothelium, part or all of thrombus may break away and migrate via the venous system to the lungs. Most thrombi originate in the deep veins of the calf and propagate proximally to the popliteal and femoral veins. Calf-limited thrombi pose a minimal embolic risk while those that extend into and above the popliteal vein represent the most common source of acute symptomatic pulmonary embolism. Emboli may originate from other sources, most often from the pelvic veins in which case a predisposing factor such as pregnancy, pelvic thrombophlebitis or pelvic infection, prostate disease, or recent pelvic surgery can often be identified. Emboli may also originate from upper-extremity

thrombosis associated with central venous catheters or intravascular cardiac devices, or may be associated with thoracic outlet obstruction or effort thrombosis (Paget von Schroetter syndrome). A small number of patients with pulmonary embolism may have evidence of right ventricular thrombus at presentation and this has been associated with more hemodynamic instability and an increase in mortality. Although the majority of cases of pulmonary embolism are the result of thrombus migration (hence thrombo embolism), other materials may occasionally obstruct the pulmonary vascular bed. These include blood born parasites (such as schistosomiasis), sickle cell disease, and various “contaminants” of illicit injected drugs (talc, cloth fibers, etc). Air embolism is usually iatrogenic and typically enters the blood stream accidentally through a central venous catheter. Less commonly, a patient’s own tissues or cells may enter the blood stream and lodge in the pulmonary vasculature. Examples include amniotic fluid embolism, which can occur during or immediately after labor or late term abortion, fat embolism which is usually associated with long bone

Figure 82-2 Large, well-organized embolus representing ‘‘cast” of a lower extremity vein removed from pulmonary artery at pulmonary embolectomy.

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fractures, and tumor embolism. Pulmonary embolism due to sickle cell disease is caused by “clumping” of abnormal red blood cells in the setting of hypoxia and stress, and can cause both acute respiratory distress as well as a more progressive disease with secondary pulmonary hypertension.

PREDISPOSING FACTORS Ruldoph Virchow first described the phenomena of “embolism” and “thrombosis” in the mid-nineteenth century, and identified three main factors contributing to the formation of venous thrombosis (Virchow’s triad): venous stasis, hypercoagulability, and injury to the venous wall (endothelium). One hundred fifty years later, this basic classification remains useful in helping clinicians stratify individual patient’s risk of developing venous thromboembolism (Table 82-1). It is important to recognize that many of these clinical predisposing factors involve multiple mechanisms leading to deep venous thrombosis and/or pulmonary embolism and that multiple factors can often be found in individual patients.

Acquired Risk Factors General surgery represents a major risk factor for thrombosis. A high level of risk (30–50 percent) has been described in or-

Table 82-1 Virchow’s Triad: Clinical States Predisposing to Venous Thrombosis Stasis

Immobility Bed rest Anesthesia Congestive heart failure/cor pulmonale Prior venous thrombosis

Hypercoagulability

Malignancy Anticardiolipin antibody Nephrotic syndrome Essential thrombocytosis Estrogen therapy Heparin-induced thrombocytopenia Inflammatory bowel disease Paroxysmal nocturnal hemoglobinuria Disseminated intravascular coagulation Protein C and S deficiencies Antithrombin III deficiency

Vessel wall injury

Trauma Surgery

Pulmonary Thromboembolic Disease

thopedic, neurosurgical, gynecological, and urologic surgery. Major traumatic injuries, most notably those of the head, spine, and pelvis, are also associated with high risk. The basis for this risk is multifactorial, involving all three components of Virchow’s triad. Normally endothelium acts as a barrier between subendothelial connective tissue and various components of blood and plays an active role in preventing blood from clotting while circulating in the body. Thrombosis is an important part of normal wound healing after injury. As a result of direct endothelial disruption, subendothelial basement membrane and collagen are exposed to platelets and contact–phase coagulation proteins, thereby impairing normal antithrombotic mechanisms by stimulating prothrombotic ones. The endothelium is a very active tissue and endothelial injury can occur through a wide variety of mechanisms, from direct trauma to local inflammation. Although initially recognized and studied in surgical patients, it is now appreciated that hospitalized medical patients may be equally prone to develop deep venous thrombosis. In about 80 percent of the cases, one or more risk factors may be present when extensive investigative testing is performed. Major risk factors include New York Heart Association class III and IV congestive heart failure, chronic obstructive pulmonary disease, sepsis and other inflammatory disorders, advanced age, stroke, critical illness, and prolonged bed rest. Any prolonged period of immobilization may increase thromboembolic risk and explains the occurrence of thrombosis under such circumstances as paralysis, bed rest, and prolonged air travel. Long distance traveling (economy class syndrome) is associated with a 1.5- to threefold increase in thromboembolic risk, depending on the traveling distance. A flight time of more than 8 hours and a flight distance of more than 5000 miles have been associated with higher chance of venous thrombosis (1.6 and 5 percent for low and high-risk patients, respectively), even though the actual incidence of pulmonary embolism was still very low (2.57 and 1.5 cases of embolism per million passengers, respectively). Pregnancy is the most common cause of VTE in women less than 40 years old, and if untreated may account for 20 to 50 percent of all pregnancy-related deaths. It occurs three to six times more often than in age-matched women not on oral contraceptives. The increase may be a result of decreased mobility, pregnancy-related hypercoagulable state (increase in factor I, II, VII, VIII, IX, X, XII, fibrinogen, and activated protein C resistance), and venous obstruction from uterine compression. The incidence is between 1 in 500 to 2000 pregnancies and occurs in roughly equal distribution over all trimesters as well as during the postpartum period. Cesarean section, premature birth, multiple births, preeclampsia, advance maternal age, and maternal history of cardiac disease have all been identified as contributing factors. Interestingly, 90 percent of all deep venous thrombosis cases are noted in the left leg, presumably because of the anatomic relationship between the uterus and inferior vena cava. The use of oral contraceptive agents and hormonal replacement therapy has also been associated with an increased

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Disorders of the Pulmonary Circulation

risk of venous thromboembolism. In terms of oral contraceptive agents, the relative risk of developing venous thrombosis is a four- to sixfold increased risk. It should be noted that the absolute risk of thrombosis among young women is low and the overall influence of oral contraceptive agents on the overall occurrence of thrombosis is relatively low. Hormone replacement therapy appears to be associated with a two- to fourfold increased risk. Given that the baseline risk of thrombosis increases with age, the use of hormonal replacement therapy in a postmenopausal population has a considerably higher impact on absolute rates of thrombosis. Obesity has been associated with VTE, particularly in women. The Nurses’ Health Study found that a body mass index greater than or equal to 29 kg/m2 was an independent risk factor, and the Framingham Study confirmed that obesity is a risk factor for pulmonary embolism. The metabolic syndrome, defined by abdominal obesity, elevation of blood pressure, elevated fasting blood sugar and triglycerides, and low levels of high-density lipoprotein cholesterol, appears to be associated not only with an increased risk of atherosclerotic disease but also of venous thromboembolism. The risk of venous thromboembolism increases with age. A recent study, using hospital discharge surveys over a 21-year period, found that patients 70 years or older have an approximately 25-fold increased risk, compared with those 20 to 29 years of age. Presumably the difference may be due to decrease in mobility and increase in co-morbidities in this population. Elderly patients also appear to have a higher mortality due to PE, and PE is suspected less commonly prior to death in the elderly patient. Cancer patients, particularly those with primary malignancies from lung, pancreas, breast (mucin-secreting adenocarcinoma), prostate, stomach/colorectal and genitourinary tracts are at a high risk for VTE. Cancer is estimated to increase the risk of VTE by four- to sixfold. Patients with cancer also have a higher risk of thromboembolic recurrence and have a higher overall mortality rate than cancer patients without thrombosis. Multiple factors are probably involved and include the development of abnormalities in the hemostatic system related to the malignancy itself, hemostatic alterations induced by chemotherapeutic agents, immobility, infectious complications, and the presence of chronic indwelling central venous catheters. Although most instances of cancerassociated VTE occur after the diagnosis of the malignancy, approximately 5 to 10 percent of patients with “idiopathic” venous thrombosis have a malignancy diagnosed within the next 2 to 3 years. There is no evidence at this time to recommend an aggressive search for cancer in these patients, although recent data suggest that a limited approach (abdominal/pelvic CT, mammography, sputum cytology) may be cost effective. Various hematologic conditions such as polycythemia vera, essential thrombocytosis, and acute leukemia may result in significant overproduction of different cell lines, which in turn may increase the risk of VTE by increasing blood viscosity (hyperviscosity syndromes). This type of thrombosis seems to occur more frequently in the hepatic or portal veins

and may be the presenting symptoms of the underlying disorder. Paroxysmal nocturnal hemoglobinuria is a rare condition associated with an incidence of VTE of approximately 40 percent. Many cases involve non–lower extremity sites, particularly in the intra-abdominal vessels. The reason for thrombosis is not clear but may be related to a decrease in blood complement levels in these patients. The presence of antiphospholipid antibodies, including the lupus anticoagulant, appears to be an independent risk factor for VTE. Among patients with venous thrombosis, a lupus anticoagulant has been reported in 5 to 15 percent and this abnormality has been estimated to lead to a ninefold increased risk of thrombosis. The frequency of VTE in patients with nephrotic syndrome may be as high as 40 percent, but the occurrence of pulmonary embolism is probably quite rare. There is a higher tendency for the thrombosis to present in unusual locations such as the cerebral sinus or as arterial thrombosis. Rarely, thrombosis may also be the presenting symptom of the nephrotic syndrome. The mechanism for VTE in these patients is not clear but various factors such as functional or quantitative changes in coagulation factors, diminished fibrinolytic activity, platelet hyperreactivity, and increase blood viscosity have been proposed. Patients with inflammatory bowel disease are at substantially increased risk of both venous and arterial thrombosis. The exact pathogenetic mechanism remains unclear. The majority of thrombotic complications occur during an active phase of the disease and inflammatory mechanisms have been proposed.

Inherited Conditions Many patients who develop VTE are found to have an inherited risk factor due to either abnormal levels of or functional abnormalities in coagulation factors (inherited thrombophilia). The relative risk of thrombosis varies widely depending on the hemostatic defect. In general, this group of patients tends to be younger (less than 50 years) and has a tendency to develop recurrent VTE. The first known inherited thrombophilic trait was antithrombin III deficiency, originally described in 1965. Subsequently, a number of other genetic mutations associated with VTE have been reported. The most common of these inherited predispositions was first described in 1993 by Dahlbeck and designated as a Factor V Leiden mutation, is the consequence of a single point mutation on the factor V gene (adenine for guanine) resulting in factor Va with diminished sensitivity to the natural anticoagulant effect of activated protein C . Approximately five percent of Caucasians in Europe and North America are heterozygous for this genetic defect; lower rates of carrier frequency have been reported among Native-American, African, and Asian populations. The heterozygous state carries a five- to 10-fold increase in lifetime risk for venous thromboembolism, whereas the risk among patients homozygous for this mutation may be increased

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80-fold. Factor V Leiden mutation appears to be an important risk factor for venous thromboembolism during pregnancy, in the postpartum period, and during oral contraceptive use. Compared with women who do not use oral contraceptives and are not carriers of the Factor V mutation, the risk of thrombosis among those with both risk factors is increased approximately 30-fold. Another common mutation has been identified in the 3â&#x20AC;˛ untranslated region of the prothrombin gene (substitution of A for G at position 20210) and is present in 2 to 4 percent of the general population. This mutation results in an overproduction of prothrombin, which is otherwise normal. It is associated with a three- to fourfold increased risk of lower extremity venous thrombosis and appears to act in a synergistic manner with other forms of thrombophilia in increasing both the initial and recurrent thrombosis risk. In clinical practice, factor V Leiden mutation and prothrombin gene mutation are the most common inherited conditions and account for more than half of the cases of inherited thrombophilia-related VTE; three other conditions (deficiencies in antithrombin III, protein C, or protein S) account for most of the remainder. Occasionally one may also encounter VTE patients who may have other conditions, particularly related to dysfibrinogenemias. It is important to recognize that, when multiple inherited risk factors coexist (such as factor V Leiden and prothrombin gene mutation), the risk of recurrent VTE may increase substantially, and lifelong anticoagulation may be necessary in these patients. Similarly, isolated hyperhomocysteinemia may not be independently associated with thrombosis, even though the risk for thrombosis may be further increased in patients with coexisting factor V Leiden.

Pulmonary Thromboembolic Disease

sistance. Compensatory mechanisms exist that allow up to 70 percent obstruction of the pulmonary vascular bed before right ventricular failure develops. In the absence of preexisting cardiopulmonary disease, obstruction of less than 20 percent of the pulmonary vascular bed results in minimal hemodynamic consequences as a result of recruitment and distention of pulmonary vessels. When the degree of pulmonary vascular obstruction exceeds 30 to 40 percent, modest increases in right ventricular pressure occur, but cardiac output is maintained through an increase in heart rate and myocardial contractility. Compensatory mechanisms begin to fail when the degree of pulmonary artery obstruction exceeds 50 to 60 percent. Cardiac output begins to fall and right atrial pressure increases dramatically. Mixed venous oxygen saturation falls and a lactic acidosis may develop. With further acute obstruction, the right heart dilates, right ventricular wall tension increases, right ventricular ischemia may develop, the cardiac output falls, and systemic hypotension develops. In patients without prior cardiopulmonary disease, the maximal mean pulmonary artery pressure capable of being generated by the right ventricle appears to be 40 mmHg (pulmonary artery systolic pressure of approximately 70 mmHg). Other factors may affect the hemodynamic consequences of pulmonary embolism. Patients with preexisting cardiopulmonary disease often have diminished pulmonary vascular reserve and even a relatively minor embolus may result in significant hemodynamic instability (Fig. 82-3). Alternatively, if the right ventricle has had time (months to years) to hypertrophy in response to a gradual increase in demand (left ventricular disease, idiopathic pulmonary arterial

PATHOPHYSIOLOGY Once detached from their point of origin, emboli travel via the systemic venous system, through the right chambers of the heart, and eventually reach the pulmonary arterial system. The physiologic effects and clinical consequences of pulmonary thromboembolism vary widely, ranging from asymptomatic disease to hemodynamic collapse and death. Major factors that determine the outcome include: (1) size and location of emboli; (2) coexisting cardiopulmonary diseases; (3) secondary humoral mediator release and vascular hypoxic responses; and (4) the rate of resolution of emboli.

Hemodynamic Consequences Obstruction of the pulmonary vascular bed by embolism acutely increases right ventricular afterload. The normal pulmonary arterial system is a low-pressure system capable of accommodating substantial increases in blood flow with only modest increases in pressure. The thin-walled right ventricle is poorly equipped to generate the pressure necessary to overcome any significant increase in pulmonary vascular re-

Figure 82-3 Hemodynamic consequences of pulmonary embolism and the underlying state of the pulmonary vasculature. Patients in whom the pulmonary vasculature was previously normal (open circles) develop little increase in pulmonary vascular resistance (PVR) until the clot burden exceeds 50 percent. In those with antecedent cardiopulmonary disease (solid circles), the pulmonary vascular resistance increases appreciably with only modest clot burden. (From Sharma, McIntyre, Sharma, Sasahara: Clin Chest Med 5:421â&#x20AC;&#x201C;437, 1984.)

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hypertension, chromic thromboembolism, etc.) a significantly higher pulmonary artery pressure may been seen. Several observations suggest that other mechanisms are involved in hemodynamic consequences of acute pulmonary embolism. For example, patients develop only minimal hemodynamic instability during elective lobectomy, pneumonectomy, or even single lung transplantation despite complete and acute interruption of blood supple during cross clamping. In the experimental setting, cyproheptadine (a nonselective serotonin antagonist) and ketanserin (a selective serotonin antagonist) have been shown to diminish some of the hemodynamic and airway responses that occur after pulmonary embolization. Certain patients develop disproportionately large and fluctuating pulmonary hemodynamic changes in response to relatively small emboli, suggesting that other mechanisms such as reflex vasoconstriction and release of vasoactive compounds may also be involved. As expected, large or multiple emboli tend to cause more severe symptoms and changes in oxygenation and hemodynamics. Given the large surface area of the peripheral pulmonary vascular bed compared to the central, symptomatic improvement may occur when a large central embolus is fragmented by forces generated by cardiac contractions or even with chest compressions during cardiopulmonary resuscitation. Eventually, the emboli may either resolve by fibrinolysis, or organize and become scar-like tissue that adheres to the vascular endothelium (Fig. 82-4). Recent data suggest that complete resolution is uncommon and that as many as 50 percent of patients have some residual obstruction 6 months after the embolic event.

Gas-Exchange Abnormalities Hypoxemia is the most common immediate physiologic consequence of pulmonary embolism. Obstruction of the pulmonary vasculature prevents systemic venous blood from reaching the pulmonary capillaries of the involved vessels

Figure 82-4 Chronic thromboembolic material dissected from pulmonary arteries at pulmonary thromboendarterectomy. Resolution of emboli is occasionally complete but certain patients may be left with significant emboli residua.

and re-directs the blood flow to other parts of the pulmonary vascular bed. This results in an increase in intra-pulmonary shunting, ventilation-perfusion (V/Q) inequality, and decreases in the mixed venous O2 level, thereby magnifying the effect of the normal venous admixture. Further shunting and increase in alveolar dead space can also occur as a result of alveolar hemorrhage or to atelectasis related to loss of surfactant. Constriction of terminal bronchioles may further increase alveolar dead space as a result of regional hypocapnia and the release of vasoconstrictive substances from platelet aggregates and mast cells. Despite an increase in alveolar dead space, patients with pulmonary embolism often develop hypocapnia. This is thought to be due to hypoxia-induced intrapulmonary reflex vagal stimulation, with resulting hyperventilation. Finally, hypoxemia may lead to an increase in sympathetic tone, which in turn causes systemic vasoconstriction. Patients with no significant cardiopulmonary disease may then respond by a temporary compensatory increase in venous return and stroke volume. Finally, embolic events large enough to increase right atrial pressure may result in intracardiac right-to-left shunting through a patent foramen ovale. One uncommon consequence of pulmonary embolism is pulmonary infarction. Infarction is uncommon because the pulmonary parenchyma has three potential sources of oxygen: the pulmonary arteries, bronchial arteries, and airways. Two of these three sources apparently must be compromised before infarction develops (Fig. 82-5). Therefore, in a patient with no coexisting cardiopulmonary disease, infarction is rare. Infarction occurs in approximately 20 percent of patients with significant cardiac or pulmonary disease that compromise either bronchial arterial flow or airway patency. In patients with left ventricular failure, increased pulmonary venous pressure may decrease bronchial flow and infarction may occur.

Diagnosis of Pulmonary Embolism The diagnostic approach to pulmonary embolism has undergone a fundamental transition over the past decade. Ventilation-perfusion scanning, the mainstay of diagnosis for almost three decades, has been relegated to a secondary role. The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) trial demonstrated the shortcomings of this technique while providing valuable insight into the diagnostic utility of clinical assessment. Computed tomography, highly sensitive D-dimer assays, stratification according to clinical assessment, and the application of Bayesian analysis to the diagnostic pathway have become the cornerstones of the current diagnostic approach. What has not changed is the understanding that clinical evidence per se, although capable of raising suspicion of the disease, is incapable of reliably confirming or excluding the diagnosis in the absence of objective testing. Recognition of the clinical signs and symptoms associated with embolism is valuable because clinical findings and clinical suspicion represent an essential first step in the diagnostic pathway.

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Figure 82-5 Pulmonary angiogram demonstrating thromboembolic obstruction of left pulmonary artery with absent blood flow to lingula and lower lobe. Despite extension obstruction, infarction did not occur as a result of lungâ&#x20AC;&#x2122;s dual blood supply.

Clinical Presentation The mainstay for the diagnosis of pulmonary embolism is a high index of suspicion tempered by the reality that most patients with embolism have one or more factors predisposing them to the condition. These predisposing factors need not be major or readily apparent. Advancing age, a period of bed rest, a prolonged air flight, or a minor traumatic injury can result in the development of venous thromboembolism. The absence of a known clinical or thrombophilic predisposition, however, should not dissuade an objective evaluation if the clinical presentation is consistent with embolism. Although a somewhat arbitrary classification (as presenting symptoms and signs of embolism frequently overlap), the presentation of acute pulmonary embolism can be categorized into one of three clinical syndromes: (1) isolated dyspnea; (2) pleuritic pain or hemoptysis; and (3) circulatory collapse. Among patients without prior cardiopulmonary disease in the PIOPED study, the syndrome of pleuritic pain or hemoptysis was found to be the most common mode of presentation, occurring in approximately 60 percent of pa-

Pulmonary Thromboembolic Disease

tients; isolated dyspnea occurred in approximately 25 percent, whereas circulatory collapse occurred in 10 percent. Two additional modes of presentation are also possible. With the increasing use of computed tomographic studies, incidental emboli are occasionally found. Typically, these emboli are found in the peripheral segments of the pulmonary arterial vasculature and do not correlate with any clinical symptoms. At this time, the short- and long-term significance of these incidental findings is not clear. In patients who are known to be at high risk of recurrent disease, such as those with inherited thrombophilia and hormonal use, it is reasonable to consider treatment with anticoagulation or at least the use of more aggressive prophylactic therapies during at-risk situations, such as prolonged hospitalization or air travel. Complete anatomic resolution of pulmonary embolism appears to be uncommon. Given sufficient residual pulmonary vascular obstruction, some patients may develop chronic thromboembolic pulmonary hypertension (CTEPH). Although exact values for frequencies vary, it is estimated that approximately 1 percent of patients may develop this condition following a symptomatic episode of pulmonary embolism. Approximately 30 percent of patients who present with CTEPH do not have a history of precedent acute embolism and are diagnosed during the evaluative process for pulmonary hypertension. The most common presenting symptom of acute embolism is the sudden onset of dyspnea. However, dyspnea does not recur in approximately 25 percent of patients ultimately proven to have embolism. Other symptoms include pleuritic chest pain, cough, leg swelling or pain, and hemoptysis. The most common physical finding is unexplained tachypnea (respiratory rate greater than 20/minute) present in approximately 70 percent of patients with embolism. Less frequent physical findings include rales, tachycardia, and an increased pulmonic component of the second heart sound. Fever may develop some hours after the event and often reaches, but rarely exceeds, 38.3â&#x2014;Ś C. Obviously, these symptoms and signs are nonspecific (Table 82-2). In the PIOPED study, none of the presenting symptoms or signs with the exception of the presence of rales, a fourth heart sound, and an increased pulmonic component of the second heart sound could differentiate between those with positive and negative angiograms. Clinical Assessment A major advance in the diagnostic approach to pulmonary embolism has been a transition from a purely techniqueoriented approach to one that uses Bayesian analysis. In doing so, the pretest probability of the disease, calculated independently of a particular test result using either empiric means or a standardized prediction rule, is calculated. This pre-test probability aids in the selection and interpretation of further diagnostic tests to create a post-test probability of the disease. This post-test probability can then be used as a basis for clinical decision making. For pulmonary embolism,

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Table 82-2 Incidence of Signs and Symptoms of Pulmonary Embolism Massive PE (%)∗

Submassive PE (%)∗

PE Without Preexisting Cardiopulmonary Disease (%)†

Dyspnea

Pleuritic chest pain

Cough

Hemoptysis

Tachypnea

95 (>16/min)

87 (>16/min)

70 (>20/min)

Tachycardia (>100/min)

Increased P2

Rales

Phlebitis

∗ Source: † Source:

Data from NIH-Sponsored urokinase and streptokinase clinical trials. Am J Med 62:355–360, 1977. Data from NIH-sponsored PIOPED trial. Chest 100:598–603, 1991.

three such scores have been developed and validated (Tables 82-3 to 82-5). Wells and co-workers have prospectively tested a rapid seven-item bedside assessment to estimate the clinical pretest probability for PE. An alternative scoring system, the Geneva score, involved seven variables and required gas exchange and radiographic information. Recently, a revised Geneva score requiring eight clinical variables without gas exchange or radiographic information was validated and published. Although such scoring systems have not proved to be more accurate than clinical assessment, they do provide a method of standardization that compensates for variability in physician experience and judgment. Laboratory Data Routine laboratory testing is not useful in confirming or excluding the diagnosis of pulmonary embolism but may be helpful in suggesting other diagnoses. A modest leukocytosis may accompany embolism but rarely exceeds 20,000/mm3 . Hypoxemia is common in acute PE although the diagnosis of acute PE cannot be excluded based upon a normal PaO2 . The more massive the obstruction, the more severe the hypoxemia is likely to be. However, many other conditions also cause hypoxemia, and embolism often does not cause hypoxemia or even a widening of the (A-a) O2 gradient. Hypocapnia usually accompanies embolism. Hypercapnia, on the other hand, is rare and appears with embolism only in patients with marked antecedent ventilatory limitation

or when such limitation has been imposed because the patient is on controlled mechanical ventilation when embolism occurs. Electrocardiogram The electrocardiogram is nonspecific in the diagnosis of pulmonary embolism, and its major value may be in identifying other clinical disorders (e.g., acute myocardial infarction and pericarditis) that may be confused with pulmonary embolism. Findings in acute PE are generally nonspecific and include T-wave changes, ST-segment abnormalities, and left- or right-axis deviation (Fig. 82-6). Atrial arrhythmias may occur but appear to be more common in patients with underlying cardiopulmonary disease. The S1Q3T3 pattern, commonly considered to be specific for PE, is seen in only a minority of patients. Electrocardiographic findings can offer insight into the extent and hemodynamic consequence of the embolism. The electrocardiogram is rarely normal in the setting of embolism associated with right ventricular dysfunction. The presence of an S1Q3T3 pattern, right bundle branch block, or T-wave inversion in leads V1-V3 in a patient with embolism should suggest the presence of right ventricular dysfunction. Chest Radiography Most patients with pulmonary embolism have abnormal but nonspecific chest radiographic findings. Common radiographic findings include atelectasis, pleural effusion,

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Pulmonary Thromboembolic Disease

Table 82-3

Table 82-4

The Wells Clinical Prediction Score

The Original Geneva Clinical Prediction Score

Variable

Points

DVT symptoms/signs

3.0

PE al likely or more likely than alternative diagnosis

3.0

Heart rate >100

1.5

Immobilization/Surgery previous 4 weeks

1.5

Previous DVT or PE

Variable

Points Score

Age 60–79 years >80 years

1 2

Previous DVT or PE

Recent surgery

1.5

Pulse rate >100

Hemoptysis

1.0

Malignancy

1.0

PaCO2 , kPa (mmHg) <4.8 (36) 4.8–5.19 (36–38)

2 1

Total Score

Pretest Probability

<2.0

Low

2.0–6.0

Moderate

PaCO2 , kPa (mmHg) <6.5 (<48) 6.5–7.99 (48–60) 8.0–9.49 (61–71) 9.5–10.99 (72–82)

4 3 2 1

>6.0

High

Chest radiograph appearance Platelike atelectasis Elevated hemidiaphragm

1 1

Total Score

Pretest Probability

0–4

Low

5–8

Moderate

9–16

High

Dichotomized Score #4

PE unlikely

PE likely

Source: Wells PS, Anderson DR, Rodger M, et al.: Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: Increasing the models utility with the SimpliRED d-dimer. Thromb Haemost 83:416–420, 2000.

Source: Wicki J, Perneger TV, Junod AF, et al.: Assessing clinical probability of pulmonary embolism in the emergency ward. Arch Intern Med 161:92–97, 2001.

pulmonary infiltrates, and mild elevation of a hemidiaphragm. Classic findings of pulmonary infarction—such as Hampton’s hump or decreased vascularity (Westermark’s sign)—are suggestive but infrequent. There is some confusion about the diagnostic configuration of infiltrates due to embolism. These infiltrates, although usually abutting a pleural surface, can be of any shape, not necessarily wedge-shaped. Although pleural effusions occur in almost half of the patients, the majority of effusions are small and involve only blunting of the costophrenic angle. The main use of the chest radiograph in suspected embolism is to exclude diagnostic possibilities such as pneumothorax, which may simulate the disease. A normal chest radiograph in a patient with otherwise unexplained acute dyspnea or hypoxemia is strongly suggestive of embolism.

D-Dimer The development of a rapid and accurate blood test capable of diagnosing venous thromboembolism has been the subject of considerable investigative interest. A number of different hemostasiologic markers have been investigated. Of these, D-dimer, alone and in combination with other noninvasive studies has been subjected to the most rigorous clinical evaluation. D-dimer testing has proven to be highly sensitive but not specific. Increased levels are present in nearly all patients with thromboembolism, but also occur in a wide range of other circumstances, including advancing age, pregnancy, trauma, infections, the postoperative period, inflammatory states, and malignancy. Therefore, the

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Table 82-5 The Revised Geneva Clinical Prediction Score Variable

Points

Age >65 years

Previous DVT or PE

Surgery (under general anesthesis) or lower limb fracture within 1 month

Active malignancy (currently active or considered cured <1 year)

Symptoms Unilateral lower limb pain Hemoptysis

3 2

Clinical signs Heart rate: 75–94 beats/minute ∃ 95 beats/minute Pain on lower-limb deep venous palpation or unilateral edema

3 5 4

Total Score

Pretest Probability

0–3

Low

4–10

Moderate

∃ 11

High

Source: Le Gal G, Righini M, Roy P-M, et al.: Prediction of pulmonary embolism in the emergency department: The revised Geneva Score. Ann Intern Med 144:165–171, 2006.

role of D-dimer testing is limited to one of thromboembolic exclusion. Multiple assays for D-dimer have been developed with sensitivities that range from 80 to almost 100 percent. Highly sensitive assays such as the enzyme-linked immunosorbent assay (ELISA) are capable of excluding thromboembolism but are associated with such a high frequency of false-positive results, especially when applied to an inpatient population, as to limit their clinical utility. Less sensitive assays (e.g., latex agglutination, red cell agglutination) lack the ability to exclude thromboembolism in isolation but have been used successfully in combination with either a clinical probability estimate or noninvasive diagnostic study. D-dimer testing has been used successfully as part of a number of different diagnostic strategies. Negative results of standardized, highly sensitive assays (ELISA), using a cutoff value of 500 ng/ml, have proved capable of safely excluding pulmonary embolism in

outpatients presenting with a low or intermediate clinical likelihood of the disease. Certain non-ELISA assays are capable of excluding embolism as a stand-alone study in outpatients with a low probability of disease but are more appropriately used in a multi-branch diagnostic pathway. Computed Tomography Computed tomography (CT) has become the first-line imaging test for pulmonary embolism (Fig. 82-7). CT technology has evolved from single detector scanners to multi-row detectors and from 4- to 64-MDCT. Using the latest generation scanners, visualization of the entire chest with submillimeter resolution extending to the sixth generation arteries can now be performed within a single breath hold. Unfortunately, these technological advances have considerably outstripped substantiating research data. For example, the recently published PIOPED II trial, which used predominantly 4-MDCT technology and a composite reference standard, demonstrated sensitivity for the diagnosis of embolism of 83 percent, specificity of 96 percent, positive predictive value of 86 percent, and negative predictive value of 97 percent. The predictive value of CT varied substantially when clinical assessment was taken into account, with the major variance occurring when there was discordance between the clinical assessment and CT finding (Table 826). Both the positive predictive value in patients with a low clinical probability and the negative predictive value in those with a high clinical probability were in the range of 60 percent. At the present time, CT can be considered confirmatory in excluding embolism in patients with a low or intermediate likelihood of disease and confirming embolism in patients with intermediate or high probability of disease. When discordance exists between the clinical assessment and CT findings, additional studies should be performed. It is possible this recommendation will change as studies with 64-MDCT scanners are published. Ventilation-Perfusion Scanning Despite limitations, ventilation and perfusion lung scanning can provide valuable information if used and interpreted appropriately. A negative study rules out the diagnosis of pulmonary embolism with the same degree of certainty as a negative pulmonary angiogram and with a higher degree of certainty than can be achieved by a negative CT scan (Fig. 828). The positive predictive value of a “high probability” study (one characterized by multiple, segmental-sized, mismatched defects) approximates 88 percent (Fig. 82-9). Unfortunately, only 28 percent of patients in PIOPED had scans characterized as high probability or normal, the only categories that can be considered definitive. The majority of patients with embolism do not have a high probability scan, while the majority of those without embolism do not have a normal scan. The PIOPED study also undertook to correlate the clinical impression of the likelihood of pulmonary embolism with

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Figure 82-6 Electrocardiogram demonstrating findings consistent with embolism including sinus tachycardia, incomplete right bundle branch block, S1Q3T3 pattern, and inverted precordial T waves.

the interpretation of the lung scan (Table 82-7). When interpretation of the lung scan and clinical assessment were concordant (both high and low probability), diagnostic accuracy was greater than that of the lung scan alone. In contrast, when interpretation of the lung scan and clinical assessment were discordant, the predictive value of the lung scan was decreased. In as many as two-thirds of patients suspected of pulmonary embolism, the combination of the lung scan and clinical assessment were either discordant or indeterminate and failed to diagnose or exclude pulmonary embolism.

Figure 82-7 Computed tomographic angiogram demonstrating nearly occlusive thrombus in both lower lobe pulmonary arteries (arrows).

Echocardiogram Echocardiography may serve a valuable role in the diagnostic approach to pulmonary embolism. Under appropriate clinical circumstances, the detection of unexplained right ventricular volume or pressure overload should suggest the possibility of embolism and lead to confirmatory testing. Properly performed transesophageal echocardiography has demonstrated sensitivity and specificity exceeding 90 percent in the detection of proximal emboli involving the pulmonary trunk and the right and left main pulmonary arteries. Echocardiography also may prove valuable in the evaluation of competing diagnostic possibilities such as right ventricular infarction, endocarditis, pericardial tamponade, and aortic dissection in patients with unexplained shock and evidence of elevated central venous pressure. The overall sensitivity of transthoracic echocardiography in pulmonary embolism approximates 50 percent. Therefore, it cannot be considered a primary diagnostic technique. Consideration can be given to its use in that subset of patients with suspected massive pulmonary embolism who are too ill for transportation or have an absolute contraindication to the administration of a contrast agent. Lower Extremity Evaluation Duplex ultrasonography, which refers to the combination of Doppler venous flow detection and real-time B-mode imaging, has assumed a central role in the noninvasive diagnosis of symptomatic lower extremity deep venous thrombosis. A number of criteria are used to diagnose venous thrombosis, the most reliable of which is non-compressibility of a venous segment. Secondary, less reliable criteria include the presence of echogenic material within the venous lumen, venous distention, and loss of phasicity, response to Valsalva, and augmentation of spontaneous flow. The absence of an echogenic luminal mass cannot be considered useful in excluding the diagnosis of venous thrombosis because acute thrombus may

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Table 82-6 Prevalence of Pulmonary Embolism in PIOPED II: Value of Correlating CT Interpretation with Clinical Assessment Clinical Assessment

CT scan interpretation

PPV of CTA PPV of CTA-CTV NPV of CTA NPV of CTA-CTV

High No./Total/%

Intermediate No./Total/%

Low No./Total/%

22/23 (96%) 27/28 (96%) 9/15 (60%) 9/11 (82%)

93/101 (92%) 100/111 (90%) 121/136 (89%) 114/124 (92%)

23/38 (58%) 24/42 (57%) 158/164 (96%) 146/151 (97%)

Source: Stein PD, Fowler SE, Goodman LR, et al.: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 354:2317â&#x20AC;&#x201C;2327, 2006.

not demonstrate echogenicity. Multiple studies over the past decade have demonstrated sensitivities and specificities exceeding 95 percent in symptomatic patients with proximal venous thrombosis. Although simplified compression examinations limited to the symptomatic leg or to the common femoral and popliteal veins (rather than the entire lower extremity venous system) have been suggested, the time saved with such approaches is limited and a number of isolated superficial femoral vein or calf-limited thrombi may be overlooked. Asymptomatic thrombi in the contralateral leg can be detected in approximately 5 to 10 percent of patients presenting with symptomatic acute venous thrombosis. Although the detection of asymptomatic, contralateral thrombi has little impact on the immediate management of the patient, it may have long-term consequences when recurrence is suspected. A more prudent approach appears to be a complete exami-

nation extending from the inguinal ligament to the popliteal vein and examination of the contralateral extremity if thrombus is detected in the symptomatic leg. Impedance plethysmography (IPG), an indirect technique which measures the rate of venous outflow, has been well standardized and carefully validated against contrast venography. False-positive studies may result from conditions that diminish arterial inflow (congestive heart failure, shock, peripheral arterial disease) or that impede venous return (right ventricular failure, obstructive lung disease), thereby lowering the specificity of the technique. Early studies reported sensitivities of approximately 90 percent in symptomatic patients with proximal venous thrombosis. Calf thrombi are detected in approximately 25 percent, a figure that reflects the lesser degree of venous obstruction in most (though not all)

Figure 82-8 Normal 6-view perfusion scan. Such a scan finding has a negative predictive value equivalent to a negative pulmonary angiogram and higher than that of a negative computed tomographic study.

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Figure 82-9 ‘‘High probability” ventilation/perfusion scan demonstrating normal ventilation and multiple mismatched segmental and larger defects.

calf thrombi. Subsequent studies of IPG accuracy have raised questions regarding the ability of IPG to detect even symptomatic, proximal vein thrombosis. Reported sensitivities in these studies have been in the range of 65 to 75 percent. The low sensitivity of IPG in these studies may result from its use in patients with less severe symptoms because these patients are more likely to have small, nonocclusive, or distal thrombi that IPG cannot readily detect. The role of computed CT venography as a stand alone test for venous thrombosis is limited. The sensitive and specificity of CT venography appear to be comparable to ultra-

sonography, but mandates contrast injection with its associated risks and radiation exposure. Potential advantages of CT venography include the ability to visualize the pelvic veins and vena cava. The concept of combined CT pulmonary angiography and venography is attractive. Such an approach would provide visualization of the embolus and its source in a single study as well as potentially increase diagnostic yield in comparison with the use of CT angiography alone. However, the absolute increase in diagnostic yield appears to be modest and comes at the cost of increased expense, substantial pelvic radiation exposure, and the risk of hemorrhagic

Table 82-7 Prevealence of Pulmonary Embolism in PIOPED: Value of Correlating Lung Scan Interpretation with Clinical Assessment Clinical Assessment

Lung scan interpretation

High probability Intermediate probability Low probability

High No./Total/%

Intermediate No./Total/%

Low No./Total/%

96% (28/29) 66% (27/41) 40% (6/15)

88% (70/80) 28% (66/236) 16% (30/191)

56% (5/9) 16% (11/68) 4% (4/90)

Source: The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis. JAMA 263:2753–2759, 1990.

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complications from providing anticoagulation to patients with false-positive studies. Magnetic Resonance Imaging Magnetic resonance imaging (MRI) techniques for detecting venous thrombosis and pulmonary embolism have been investigated. Preliminary reports suggest that MRI is at least as sensitive and specific as duplex ultrasonography in detecting venous thrombosis. A potential advantage of MRI is that the entire length of the venous system, including the pelvic veins, can be evaluated. MR angiography appears to be as sensitive as 16-MDCT in detecting emboli. Disadvantages associated with MRI include cost, limited access, motion artifacts related to the time necessary to perform the study, and a high degree of expertise required to properly perform and interpret the studies. Pulmonary Angiogram Pulmonary angiography remains the accepted â&#x20AC;&#x153;gold standardâ&#x20AC;? for PE diagnosis although it has a number of limitations as a gold standard (Fig. 82-10). It requires expertise in study performance and interpretation; it is invasive and has associated risks, although published studies suggest that the use

Figure 82-10 Conventional contrast pulmonary angiogram demonstrating extensive embolus within the left main pulmonary artery and extending into lobar branches.

of modern techniques and contrast materials has reduced the reality of that risk well below its lingering perception. Only two angiographic findings are diagnostic of acute embolism: the filling defect and abrupt cutoff of a vessel. Technical adequacy of the angiogram is critical to accurate identification of both. Flow artifacts can falsely suggest a filling defect. It is essential that good vessel opacification be obtained and that the filling defects be identified as real on a sequence of films. Angiography is reserved for the small subset of patients in whom the diagnosis of embolism cannot be established or excluded by less invasive means. Even under this defined circumstance, angiography appears to be underused. Diagnostic Approach The diagnostic approach to pulmonary embolism should be targeted toward the patient population being studied (Figs. 82-11 and 82-12). For outpatients, the use of a clinical prediction rule coupled with D-dimer testing can substantially reduce the number of imaging studies performed. The specificity of D-dimer testing in inpatients is so low as to render the utility of the study nearly meaningless. Furthermore, the presence of co-morbid conditions substantially limits the utility of clinical prediction rules. In an outpatient setting, D-dimer testing should be the initial diagnostic study, except in patients with a high clinical probability of disease. In the latter group, D-dimer results would not alter the need for an objective imaging study. In patients with a low or intermediate clinical likelihood of embolism, a negative D-dimer study is sufficient to exclude the possibility of embolism, assuming a highly sensitive assay is used. CT angiography should be performed in all patients with a high probability of disease as well as those with a low or intermediate probability whose D-dimer tests are positive. In patients with a high or intermediate clinical probability, a positive CT angiogram confirms the diagnosis. In patients with a low or intermediate clinical probability, a negative CT angiogram excludes the diagnosis. The only patients who require additional testing (duplex ultrasonography and/or conventional angiography) are those in whom the clinical assessment and CT findings are discordant (low clinical probability and positive CT scan or high clinical probability and negative CT scan), unless the CT scan is of adequate quality and demonstrates evidence of embolic disease in the main or lobar arteries in a patient with a low clinical probability assessment. If readily available, duplex ultrasonography should be considered prior to chest imaging. Although not confirming the diagnosis of embolism, a positive study has the same therapeutic implication and avoids the need for contrast administration and radiation exposure. A negative study, however, is incapable of excluding the disease. A ventilation/perfusion (V/Q) scan approach can be used in settings such as pregnancy, contrast allergy, or renal insufficiency. Lower extremity evaluation should be considered prior to chest imaging given the likelihood that the V/Q scan will not be diagnostic. A negative V/Q scan is

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Figure 82-11 Current diagnostic strategies capable of excluding diagnosis of pulmonary embolism.

capable of excluding the diagnosis regardless of the clinical assessment. A high probability scan is capable of confirming the diagnosis in patients with a high clinical suspicion. All other circumstances (high clinical probability with low or intermediate V/Q result, intermediate clinical probability regardless of V/Q result, and low clinical probability with a high or intermediate V/Q scan result) require additional testing. Whatever approach is undertaken, the treating physician should be aware of the type of D-dimer assay, discriminant value of that particular assay, and generation of CT scanner used. â&#x20AC;&#x153;Negativeâ&#x20AC;? findings on a low-sensitivity D-dimer assay or a single-row CT scanner have very different implica-

tions than similar findings using a highly sensitive D-dimer assay or 64-MCTD CT scanner. As noted, the role of D-dimer testing and clinical assessment in hospitalized patients is limited. Approximately 90 percent of hospitalized patients have a positive highly sensitive D-dimer result, and co-morbid conditions affect the clinical likelihood assessment. Therefore, a far higher proportion of embolic suspects require an imaging study to confirm or exclude the diagnosis. In patients with limited cardiopulmonary reserve, high clinical probability assessment, and negative CT scan, pulmonary angiography should be strongly considered given the potentially fatal consequences of a recurrent embolic event. In patients with adequate cardiopulmonary reserve, a

Figure 82-12 Current diagnostic strategies capable of confirming diagnosis of pulmonary embolism.

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strategy incorporating sequential lower extremity evaluation can be undertaken.

TREATMENT Management of acute pulmonary embolism consists of a systematic approach that involves early intervention, patient risk stratification, selection of therapy, and determination of treatment duration. The goals of therapy in PE are severalfoldâ&#x20AC;&#x201D;to assure adequate oxygenation, provide hemodynamic support, and prevent thrombus propagation and embolic recurrence. When a diagnosis of VTE is suspected, empiric treatment should be considered until the diagnosis is either objectively excluded or confirmed. Given the ready availability of rapid D-dimer assays and computed tomography, diagnostic confirmation should require a relatively short period of time. Early empiric treatment should be initiated if diagnostic tests are not readily available. An exception can be made in those patients with a low clinical likelihood of disease, adequate cardiopulmonary reserve, and a high risk of bleeding complications. The availability of low-molecular-weight heparin potentially allows selected patients to be managed in the outpatient setting. Although there are good data to support treating uncomplicated cases of venous thrombosis entirely in the outpatient setting, most physicians still advocate a short period of hospitalization in patients with newly diagnosed acute pulmonary embolism. Hospitalization should be mandatory for older patients who may have less cardiopulmonary reserve, or significant co-existing illnesses, or those who may not be able to follow instructions or have adequate follow-up. Other indications for hospitalization include hypoxemia, hypotension, or hemodynamic instability.

Heparin Anticoagulation with heparin remains the standard initial therapy. The major anticoagulant effect of heparin is to reduce thrombus propagation and prevent embolic recurrence. Choices include either intravenous unfractionated heparin (UFH) or subcutaneous low-molecular-weight heparin (LMWH) preparations. Given that failure to achieve rapid therapeutic levels of anticoagulation appears to be associated with an increased recurrence rate, it seems reasonable to attempt to ensure adequate anticoagulation as soon as possible. Physician practices in the administration of intravenous unfractionated heparin have often resulted in substantial delays before adequate prolongation of the aPTT was achieved. To overcome these problems, standardized protocols for heparin administration and monitoring have been recommended. One commonly employed dosing regimen using an initial intravenous bolus of 80 units of heparin per kilogram followed by a continuous infusion initiated at 18 units per kilogram per hour has been demonstrated to reach ther-

apeutic thresholds more quickly than regimens using fixed dosing. The heparin drip is adjusted based on monitoring of the activated partial thromboplastin time (aPTT), drawn 6 hours after the initial bolus dose, then 6 hours after each dose adjustment, with a target aPTT ratio of 2.0 to 3.5. More recently, an approach using a fixed dose of subcutaneous unfractionated heparin, administered as an initial dose of 333 U/kg followed by a dose of 250 U/kg every 12 hours, has been demonstrated to be as safe and effective as low-molecular-weight heparin in patients presenting with venous thrombosis and pulmonary embolism. With the exception of special circumstances, lowmolecular-weight heparin preparations have displaced unfractionated heparin as the anticoagulant of choice in uncomplicated venous thromboembolism. Situations in which the use of UFH is appropriate include renal insufficiency, extremes of body weight, hypertensive crisis, and circumstances in which a rapid adjustment of anticoagulation is needed, such as women in the late stage of pregnancy who may need Caesarian sections, patients with recent surgery or recent history of bleeding, and hemodynamically unstable patients with VTE who may need surgical procedures such as emergency embolectomy. Available evidence suggests that LMWH is at least as effective as UFH in treating acute pulmonary embolism. Advantages of LMWH compared with UFH include: (1) longer half-life and ease of use; (2) ability to consistently achieve early therapeutic anticoagulation; (3) no need to monitor anticoagulant effects; and (4) reduced incidence of major bleeding complications. There are few data comparing different LMWH preparations. Even though there are differences in their FDA-approved indications in the United States, it is not clear if their actions differ significantly. At this time, enoxaparin and tinzaparin are indicated for treatment of established DVT in the outpatient setting or for DVT (with or without PE) in the inpatient setting, and dalteparin is approved for prevention of venous thrombosis and acute pulmonary embolism. In general, therapeutic monitoring is not needed with LMWH, but there are situations where the therapeutic effects may be less predictable and monitoring with anti-Xa levels is indicated. Typical examples include: (1) patients with antiphospholipid antibodies or other circulating anticoagulants who have elevated baseline aPTT; (2) extremes of body weight (less than 40 kg and greater than 150 kg); (3) significant renal disease (creatinine clearance less than 30 ml/min); (4) pregnancy; and (5) unexplained bleeding or recurrent thrombosis during therapy. A therapeutic target range for anti-Xa levels ranges from 0.6 to 1 U/mL, four hours after administration. Prophylactic anti-Xa levels are lower, ranging from 0.1 to 0.3 U/mL.

Novel Agents Fondaparinux, a synthetic pentasaccharide, represents the first in a new class of antithrombotic agents. Unlike heparin and low-molecular-weight heparins, the antithrombotic

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properties of fondaparinux are selective for factor Xa. By binding rapidly and strongly to antithrombin, fondaparinux catalyzes specifically the inhibition of factor Xa, which results in inhibition of thrombin generation. It does not bind to other plasma components or platelets, has a half-life of approximately 17 hours, and is excreted almost completely by the kidneys. It has been approved for prophylaxis in patients undergoing hip, knee, and abdominal surgery as well as for treatment of venous thrombosis and pulmonary embolism in conjunction with warfarin. Direct thrombin inhibitors (bivalirudin, lepirudin, argatroban) represent another new class of anticoagulant agents. Their mechanism of action differs from that of heparin and the synthetic pentasaccharides in that they directly inhibit the active site of thrombin and do not require interaction with antithrombin to produce an anticoagulant effect. Argatroban is a synthetic agent derived from arginine. It has a half-life of approximately 45 minutes and is cleared by the liver. Lepirudin is a recombinant polypeptide similar to hirudin. It has a half-life of 40 to 60 minutes and is cleared by the kidneys. Both agents are administered by continuous intravenous infusion and dose adjustments made with monitoring of the aPTT. Both agents affect the international normalized ration (INR), thereby complicating the transition to oral warfarin therapy. Both drugs have been approved for the management of patients with heparin induced thrombocytopenia.

Thrombolytic Therapy Unlike anticoagulants, thrombolytic drugs cause direct lysis of thrombi by increasing plasmin production through plasminogen activation. The potential benefits, however, are often offset by the relatively high incidence of hemorrhagic complications. Multiple thrombolytic agents are available, and the most studied include streptokinase, recombinant tissue plasminogen activator (rt-PA), and urokinase, all of which are FDA approved for use in the United States. Streptokinase, a polypeptide derived from beta-hemolytic streptococci, was the least expensive agent but was occasionally associated with severe side effects such as anaphylaxis and hypotension. Urokinase is obtained from cultures of neonatal kidney cells while rt-PA is produced by recombinant DNA technology. Through different mechanisms, these agents convert circulating plasminogen to plasmin. Streptokinase must first bind to circulating plasminogen before becoming an enzyme capable of cleaving additional plasminogen; urokinase is itself a plasminogen activator. Doses of streptokinase and urokinase sufficient to cause fibrinolysis of thrombi also generate circulating free plasmin that overwhelms and depletes Îą2 antiplasmin and other plasma inhibitors. As a result, systemic hemostasis is impaired because of degradation of circulating fibrinogen and other coagulation proteins and because of an increase in fibrin degradation products. In physiological amounts, t-PA does not bind to circulating plasminogen. Therefore, it does not produce circulating plasmin, which would induce systemic fibrinolysis or fibrinogenolysis; nor are

Pulmonary Thromboembolic Disease

circulating inhibitors of plasmin, particularly aÂ´ 2 -antiplasmin, depleted by the clot-selective action of t-PA. In principle, tPA, because of its intense affinity for fibrin, should have its lytic effects restricted to fibrin in thrombi. At pharmacologic doses, however, some degree of systemic fibrinolysis is the rule. The exact role of thrombolytic agents in acute pulmonary embolism remains controversial. While thrombolytic therapy does appear to accelerate the rate of thrombolysis, there is no convincing evidence to suggest that it decreases mortality, increases the ultimate extent of embolic resolution when measured at 7 days, reduces thromboembolic recurrence rates, improves symptomatic outcome, or decreases the incidence of thromboembolic pulmonary hypertension. The one issue about which there can be little controversy is that the use of thrombolytic agents is associated with a substantially increased risk of bleeding, including intracranial hemorrhage. Intracranial hemorrhage has occurred in 0.5 to 2.0 percent of patients treated with thrombolytic agents in trials evaluating the use of these agents in both pulmonary embolism and myocardial infarction. Based on these data, and assuming there is no contraindication to its use, the use of thrombolytic therapy in pulmonary embolism is appropriate when an accelerated rate of thrombolysis may be considered lifesaving; that is, in patients with pulmonary embolism who present with hemodynamic compromise, patients who develop hemodynamic compromise during conventional therapy with heparin, and patients with embolism associated with intracavitary right heart thrombi. The role of thrombolytic therapy in patients with anatomically massive embolism or echocardiographic evidence of right ventricular dysfunction in the absence of systemic hypotension is less well defined. Risk stratification approaches using echocardiography, troponin or BNP levels are currently under investigation and may help resolve this area of controversy. At the present time, the finding of right ventricular dysfunction on echocardiography in the absence of hemodynamic instability would not appear to serve as a justification for the routine use of thrombolytic therapy. Approximately 40 to 50 percent of patients with symptomatic pulmonary embolism have echocardiographic evidence of right ventricular dysfunction. Patients with evidence of right ventricular dysfunction, as determined by echocardiography or elevated BNP or troponin levels in the absence of systemic hypotension, appear to be at risk for an adverse outcome when compared with patients without right ventricular dysfunction. However, until criteria have been established that more clearly define that subset of patients who will benefit from thrombolytic therapy, there is little basis for exposing all such patients to the considerable risk of hemorrhagic complications associated with this intervention. Because of the side effects and the prolonged period of infusion required, many physicians are reluctant to use thrombolytics in cases of venous thrombosis, whether delivered systemically or by local catheter-directed infusion. In selected patients with symptomatic ileo-femoral thrombosis,

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catheter directed thrombolysis either alone or combined with angioplasty or stent placement may result in increased venous patency and may improve quality of life. Catheter-directed techniques have been successfully employed in the setting of acute ileo-femoral DVT using doses of urokinase ranging from 1.4 to 16 million units delivered over an average of 30 hours. Results from a national registry of patients with ileo-femoral thrombosis treated with local, catheter-directed therapy indicates that this approach is frequently successful and may improve health-related quality of life.

Interventional Radiologic Techniques Interventional thrombus fragmentation represents a potential alternative to systemic thrombolysis or surgical embolectomy. If the bleeding risk it not exceedingly high, catheter fragmentation may be combined with local or systemic thrombolysis. A wide variety of fragmentation and embolectomy devices designed to either fragment and/or remove fresh embolic material have been tested in patients with pulmonary embolism. In general, the devices use either pressured saline or a rotating impeller to fragment central thrombi. The fragments are either aspirated through a separate port on the catheter or allowed to migrate distally. Most of the devices appear to be effective, safe, and potentially life-saving in the presence of central, acute clots. However, none of the devices has been investigated in a large controlled trial, and all commercially available devices have important limitation. There limitations, including a risk of paradoxical embolism from the clot fragments. Therefore, the intervention is contraindicated in patients who have an intracardiac communication, such as a patent foreman ovale.

Pulmonary Embolectomy Embolectomy has been used for the emergency removal of pulmonary emboli. Small observational studies comparing surgical embolectomy and thrombolytics did not show significant advantage using embolectomy, although there was a trend toward better survival and lower bleeding rates in the surgical group. Based on current data, it is therefore reasonable to consider surgical embolectomy in patients with persistent hypotension, shock, or cardiac arrest who either failed thrombolysis or have contraindications to thrombolytics. Its use has also been advocated in patients who are at high risk of paradoxical embolism and who are not candidates for thrombolytics, although further validation for this indication is needed.

Long-Term Management Anticoagulation Oral Anticoagulant

Recurrence is common following an acute thromboembolic event. Therefore, treatment should be continued until the

benefits of ongoing therapy no longer outweigh the potential risks. Oral anticoagulation using warfarin, a vitamin K antagonist, is generally used for long term treatment of VTE because of its proven efficacy. Warfarin inhibits gamma carboxylation activation of coagulation factors II, VII, IX, and X as well as proteins C and S. With proper monitoring, less than three percent of patients using warfarin develop significant bleeding. The drug is usually started soon after the initiation of heparin therapy. Use of warfarin without heparin is strongly discouraged as it generally takes 3 to 5 days of warfarin to achieve full therapeutic efficacy. In patients with protein C deficiency, skin necrosis or paradoxical thrombosis may occur in the absence of concurrent heparin therapy. Warfarin has a narrow therapeutic index and patients are generally monitored closely by measuring the prothrombin time corrected to the reagent being used (the International Normalized Ratio or INR). To maximize efficacy while minimizing side effects, an INR range between 2 and 3 is recommended for most patients. Recent data suggested that, even in patients with a high risk of thrombosis, an INR over 3 may not confer significant additional protection, whereas a higher incidence of bleeding was observed. Besides bleeding complications, warfarin has been associated with fetal abnormalities particularly when given during the sixth to 12th weeks of gestation. Another rare complication of warfarin use is cholesterol microembolism (â&#x20AC;&#x153;purple toesâ&#x20AC;? syndrome), which is thought to be due to cholesterol crystal release from ulcerated intravascular plaques. Individuals metabolize warfarin differently and age, genetic variations in CYP2C9 alleles, nutritional factors, and concomitant medications can affect anticoagulant levels significantly. Multiple mechanisms of drug interaction are possible including alterations of absorption (cholestyramine), induction of hepatic CYP450 (barbiturates, carbamazepine), inhibition of CYP3A4 (amiodarone), inhibition of CYP2C9 (metronidazole, clotrimazole), and displacement of protein bound warfarin (phenytoin). Suggested dosing regimens involve an initial daily dose of 5 or 10 mg with use of a standardized nomogram to dose adjust based on INR values obtained on days 3 and 5. Once the therapeutic range of INR is reached, monitoring is then done at 1- to 2-week interval, depending on the stability of INR results. Elderly malnourished and debilitated patients tend to require less warfarin and the initial dose should be lowered accordingly. Some medical conditions, such as concomitant liver or kidney failure, alcoholism, malignancy, and recent history of gastrointestinal bleeding or trauma, are additional factors that may predict dose titration difficulties and higher risk of bleeding To minimize potential subtherapeutic anticoagulation, it is generally recommended that patients should receive at least 5 days of combined heparin and warfarin therapy, including at least 2 days in which the INR is in a therapeutic range prior to stopping heparin. Specialized anticoagulation clinics have been shown to provide a safe and effective means

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to adjust warfarin dose for patients requiring anticoagulant therapy. In carefully selected patients, self-management of warfarin therapy using INR measurement with â&#x20AC;&#x153;point of careâ&#x20AC;? devices may also be done. There are occasional instances in which heparin should be considered for long-term anticoagulation, despite the cost and inconvenience associated with subcutaneous or intravenous administration. Because of the teratogenic potential of warfarin, UFH or LMWH should be used in pregnant women who developed VTE in the first and possibly early second trimesters. Since the risk of venous thromboembolism may be highest in the postpartum period, anticoagulation should be continued for at least 3 to 6 months, including a minimum of 4 to 6 weeks after delivery. Patients with cancer complicated by thromboembolism appeared to have fewer recurrent thromboembolic events when treated with LMWH compared with warfarin. Whether this affect is intrinsic to the drugs or simply a reflection of fluctuating INR levels in patients with cancer treated with warfarin is uncertain.

Duration of Therapy Over the past decade, data have emerged that have significantly changed our recommendation regarding duration of anticoagulation after VTE. Central to this change has been awareness that venous thromboembolism often represents a recurrent disease and that the risk for recurrence is based on the initiating factors, persistence or resolution of those factors, and anatomic consequences of the initial event. Patients with venous thromboembolism associated with a temporary risk factor appear to be at the lowest risk of recurrence. However, the risk of recurrent disease after 3 months of anticoagulation is still in the region of 10 percent; therefore, patients should be treated with warfarin for 3 to 6 months. Patients with idiopathic thromboembolism have a substantially higher rate of recurrence, one that approaches 30 percent following 3 months of anticoagulation. In these patients, anticoagulation may simply delay subsequent recurrent thromboembolic events and ongoing risk factors may be present that have yet to be identified. Therefore, it is recommended that this group of patients be treated with at least 6 to 12 months of anticoagulation and consideration given to lifelong therapy in those with a low risk of bleeding complications. In certain patients it is reasonable to consider a 6to 12-month course of therapy and to counsel about shortcourse prophylaxis when additional risk may be encountered in the future (such as pregnancy and prolonged air travel). In patients with VTE associated with an irreversible risk factor, the absolute recurrence risk depends on the underlying disease or condition. Patients with heterozygous Factor V Leiden mutation do not appear to benefit from prolonged anticoagulation, while those with homozygous disease or a combined thrombophilia (e.g., heterozygous Factor V Leiden combined with heterozygous prothrombin mutation) do benefit. Patients with antiphospholipid antibody syndrome are at considerable risk for thromboembolic recurrence, and a minimum of 12 months of therapy is recommended with

Pulmonary Thromboembolic Disease

consideration given to lifelong therapy. In patients with two or more episodes of recurrent VTE, the current recommendation is to consider life-long anticoagulation with interval re-assessment of the risk-benefit ratio. Determining which patients remain at increased risk of thromboembolic recurrence is the target of ongoing investigative efforts. A number of clinical and serologic factors have been identified that predict a higher likelihood of recurrent venous thromboembolism following an initial course of therapy. These include pulmonary embolism as the initial presenting manifestation, evidence of residual lower extremity venous thrombosis by ultrasonography, elevated D-dimer levels, elevated Factor VIII levels, and an abnormally short activated partial thromboplastin time. How such findings apply to an anticoagulation withdrawal decision-making strategy in an individual patient remains to be determined.

Vena Cava Interruption and Vena Cava Filter The concept of vena cava interruption came from the historical practice of surgical ligation (by complete vascular ligation or partial interruption using surgical suture) of the inferior vena cava in an attempt to prevent thrombus migration. A variety of vena cava filters are now available, both permanent and temporary, and surgical ligation is rarely performed in the modern era The reason for inferior vena cava (IVC) filter placement is to prevent pulmonary embolism in patients who either have a contraindication to anticoagulation or develop recurrent VTE while on adequate anticoagulation. Filters are sometimes placed in patients who have documented massive pulmonary embolism, and those in whom embolism occurs in the setting of residual lower extremity venous thrombosis and poor cardiopulmonary reserve. Based on these principles, the prophylactic use of IVC filters may also be appropriate in trauma or high-risk orthopedic patients, patients with cancer and a history of VTE, and prior to anticipated pulmonary embolectomy or pulmonary thromboendarterectomy. Many case reports have documented the potentially life-saving benefits of IVC filters. However, long-term studies suggest that IVC filters, although capable of preventing short-term embolic recurrence, are associated with a longterm increase in the incidence of venous thromboembolism. Similarly, although IVC filters have been associated with short-term (90 days) reduction in mortality, this benefit may be lost in the long run. This observation, together with the many long-term side effects of IVC filters led to the recent development of retrievable filters. Four different retrievable vena caval filters have received approval by the FDA (Gunther tulip filter, ALN filter, Recovery filter, OptEase filter). Because of endothelialization of the filters at the point of vascular contacts, the rate of successful retrieval may decrease significantly over time.

Chronic Thromboembolism Anatomic resolution of pulmonary embolism is rarely complete. However, resolution in most patients suffices not to

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Disorders of the Pulmonary Circulation

impair pulmonary hemodynamics or exercise tolerance. In a few the residual thromboembolic burden is sufficiently extensive to cause thromboembolic pulmonary hypertension (CTEPH). Estimates of the incidence of CTEPH range from 0.5 to 3.8 percent following an initial episode of embolism, to 13.4 percent following recurrent episodes of venous thromboembolism. Approximately 30 percent of patients who develop chronic thromboembolic pulmonary hypertension have no documented history of acute DVT or PE, and this feature greatly impedes the diagnosis. Anticardiolipin antibodies or a lupus anticoagulant have been detected in approximately 10 percent of patients and elevated Factor VIII levels detected in 40 percent. No other defined thrombophilic or fibrinolytic abnormality has been encountered in this population. The mortality of untreated CTEPH is high, with a 5-year survival of only about 10 percent in those who have a mean pulmonary artery pressure of over 50 mmHg. The treatment of choice for CTEPH is surgery (pulmonary thromboendarterectomy or PTE), which involves the dissection of endothelialized thrombi under cardiopulmonary bypass and deep hypothermia. For the majority of patients, successful PTE is considered curative. However, the hemodynamic outcome is incomplete in approximately 20 percent of patients. These patients have been treated with medical therapies that are used in patients with idiopathic pulmonary arterial hypertension. Indications for medical therapy in chronic thromboembolic pulmonary hypertension include: (1) “inoperable” cases of CTEPH in patients who have either distal disease or significant secondary vasculopathy; (2) as a “bridge” to thromboendarterectomy in patients with severe right ventricular dysfunction; and (3) persistent or recurrent pulmonary hypertension after PTE. Patients with

inoperable CTEPH or persistent pulmonary hypertension despite PTE may be considered for lung transplantation. Because thromboendarterectomy is performed by way of a sternotomy, single lung transplantation is usually performed to minimize scar dissection. In selected patients, the survival of these patients after transplantation may be comparable to those with other diseases.

Prophylaxis Although the efficacy of mechanical and pharmacological prophylaxis is well documented, the incidence of VTE does not appear to have changed during the past few decades, suggesting a failure in effective use of prophylaxis in at-risk patients. Initial assessment should focus on the following questions: (1) What is the risk of VTE in this patient? (2) What type(s) and intensity of prophylaxis should be used? (3) When is the best time to use prophylaxis? Because a patient’s thrombotic risk may change over time, periodic assessment of the best prophylactic strategy should also be done (Table 82-8). Several risk scores have been proposed in an attempt to objectively and quantitatively describe the relative risk of VTE in hospitalized patients. It is important to stress that none of these methods has been validated prospectively. Most hospitalized patients are at risk of VTE and should receive some form of VTE prophylaxis unless its use is contraindicated. Prophylaxis may not be necessary in rare instances, as in the case of a young (less than 40 years) ambulatory patient who is admitted for a short (less than 48 to 72 hours) hospital stay without prior VTE history or recent surgery. Three categories of drugs have been used successfully, all administered subcutaneously: UFH (5000 units two or

Table 82-8 Example of a Risk Stratification Approach to Assist in Determining the Intensity of Thrombosis Prophylaxis Degree of Risk

Age

Surgery

Risk Factors

Prophylactic Options

Low

<40

Minor

Early ambulation

Moderate

<40 40–60 Any age

Major Minor Minor

No No Yes

UFH (q12h) LMWH IPC or GCS

High

>40 >60

Major Major

Yes No

UFH (q8hr) ± IPC or GCS LMWH + IPC or GCS

Very High

Any age

Major

Multiple

LMWH + IPC or GCS Warfarin Fondaparinux (orthopedic) IVC filter

UFH = unfractionated heparin; LMWH = low molecular weight heparin; IPC = intermittent pneumatic compression devices; GCS = graduated compression stockings.

1443 Chapter 82

three times daily), LMWH (Enoxaparin, either 40 mg once daily or 30 mg twice daily; Dalteparin, 2500 or 5000 units once daily), and Fondaparinux (2.5 mg once daily). When administered correctly in appropriate patients, prophylactic anticoagulation is safe and effective with an absolute reduction in the incidence of VTE in the range of 40 to 50 percent. Major bleeding complications occur in less than 1 percent of patients. Prevention of venous thromboembolism may also be achieved by the use of mechanical devices. These devices fall into two categories, graduated compression stockings and intermittent pneumatic compression stockings. Although studied less rigorously than pharmacologic methods of prophylaxis, the use of pneumatic compression has been shown in selected patients to be as effective as subcutaneous unfractionated heparin in preventing thrombosis. Mechanical methods of prophylaxis are especially useful in patients at bleeding risk and as an adjunct to pharmacologic methods in patients at high risk of thrombosis. Whatever form of prophylaxis is used, its intensity should be based on a patientâ&#x20AC;&#x2122;s thrombotic risk determined by both personal and clinical circumstances. Prophylaxis adequate for a 41-year-old patient undergoing an elective appendectomy would be inadequate for a 70-year-old patient with cancer undergoing hip replacement surgery. Recommended prophylactic strategies for a variety of different clinical circumstances have been published by the American College of Chest Physicians. It should also be recognized that thromboembolic risk does not necessarily end at the time of hospital discharge. The trend toward early hospital discharge has only served to transfer risk to the outpatient setting. Whether on an inpatient or outpatient basis, prophylaxis should continue until the thrombotic risk has resolved. The potential for bleeding complications associated with prophylaxis is a common dilemma in surgical or trauma patients where bleeding may occur from the surgical site, especially in the immediate postoperative period. On the other hand, effective prophylaxis depends on timely administration of therapy before a thrombus develops. Recommendations can be drawn from multiple studies with regard to the appropriate timing for anticoagulation in different surgical settings. In cases in which anticoagulation may be delayed, it is customary to use either graduated compression stockings or pneumatic compression devices either before surgery begins or as soon a surgery is completed. In high-risk patients in whom pharmacologic prophylaxis is contraindicated, it is reasonable to obtain serial lower extremity ultrasonography, and consideration should be given to the placement of a retrievable IVC filters.

Other Varieties of Embolic Disease Because the lung receives all of the blood flow returned from the venous system, the pulmonary vascular bed serves as a â&#x20AC;&#x153;sieveâ&#x20AC;? for all particulate substances entering the venous blood and is the first vascular bed to be exposed to any toxic substance injected intravenously. As a result of its strategic

Pulmonary Thromboembolic Disease

position, the pulmonary vascular bed is, therefore, exposed to a wide variety of potentially obstructing and injurious agents.

Venous Air Embolism An increasingly common form of non-thrombotic embolism in the United States is venous air embolism. The increasing frequency of the problem reflects the wide variety of invasive surgical and medical procedures now available, the broad use of indwelling central venous catheters, the use of positive pressure ventilation with high levels of positive endexpiratory pressure, and the frequency of thoracic and other forms of trauma. The simple inadvertent transection or loss of closure of a large-bore intravenous catheter, particularly in the jugular or subclavian vein, can result in ingress of substantial quantities of air. Air bubbles enter the pulmonary vascular bed and, from there, can enter the arterial system and be diffusely distributed throughout the body by way of either an intracardiac shunt (atrial septal defect, patent foramen ovale) or, more likely, through microvascular pulmonary shunts. Physiologic consequences include an abrupt rise in pulmonary artery pressure. Non-cardiogenic pulmonary edema may develop, lung compliance falls, and hypoxemia ensues. The symptoms of venous air embolism are variable and nonspecific, and may include alterations in sensorium, chest pain, dyspnea, or a sense of impending doom. These and other consequences appear to be due to two phenomena: actual lodgement of the bubbles in capillary beds that interfere with nutrient supply to the affected organs, and the formation of platelet-fibrin aggregates, creating diffuse microthrombi. Thrombocytopenia may be seen as a consequence of this latter event. The most serious consequences result from cerebral or coronary artery air embolism, the severity of the consequences depending upon the rate and volume of air gaining access to the circulation. The best approaches to air embolism are prevention and early detection. Treatment consists of measures designed to restore flow and promote reabsorption of the intravascular air. Measures designed to restore flow include patient positioning (Trendelenburg position with the left side down), removal of air through central venous catheters or direct needle aspiration, and closed chest cardiac massage. Measures designed to increase absorption include the use of 100 percent oxygen and hyperbaric oxygen therapy. Using such aggressive measures, mortality from venous air embolism has been dramatically reduced.

Fat Embolism Another reasonably frequent and dramatic form of nonthrombotic embolism is fat embolism. A rather characteristic syndrome follows entry of neutral fat into the vascular system, consisting of the onset of dyspnea, hypoxemia, petechiae, and mental confusion. Seizures and focal neurologic deficits have been described. There is a variable lag time of 24 to 72 hours in the onset of the syndrome following the inciting event;

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Disorders of the Pulmonary Circulation

rarely, cases occur within 12 hours or as late as 2 weeks after the event. By far, the most common inciting event is traumatic fracture of long bones, with incidence rising with the number of fractures. However, orthopedic procedures and trauma to other fat-laden tissues (e.g., fatty liver) occasionally can be followed by the same syndrome. Although considerably less common, fat embolism syndrome has been reported following both liposuction and lipoinjection procedures. The basis for the variability in the incidence and severity of the syndrome after apparently comparable injuries has not been well defined; neither has the reason for the delay in clinical presentation been explained. The pathophysiologic consequences appear to derive from two events: (1) actual vascular obstruction by neutral particles of fat; and (2) the injurious effects of free fatty acids released by the action of lipases on the neutral fat. The latter effect is probably the more important, causing diffuse vasculitis with leakage from cerebral, pulmonary, and other vascular beds. The time necessary to produce toxic intermediaries may explain the delay from the inciting event to clinical presentation. The diagnosis of fat embolism syndrome is a clinical one suggested by the onset of dyspnea, neurologic abnormalities, petechiae, and fever in the proper clinical context. Petechiae, typically distributed over the head, neck, anterior chest, and axillae, are present in only 20 to 50 percent of cases. Therefore, their absence should not preclude consideration of the disease. No laboratory test is diagnostic of the syndrome. Fat can be demonstrated in the serum of a majority of fracture patients with evidence of fat embolism syndrome. The finding of lipid-laden cells in bronchoalveolar lavage fluid appears to occur commonly in patients with traumatic injuries irrespective of the presence of fat embolism syndrome. Although a variety of treatments have been suggested (e.g., intravenous ethanol, albumin, dextran, heparin), none has proved effective. The role of corticosteroid therapy to prevent the onset of fat embolism syndrome after an inciting event remains controversial. Supportive treatment, including mechanical ventilatory support when necessary, is the primary approach, and survival is now the rule with meticulous support.

Amniotic Fluid Embolism Another special form of embolism is amniotic fluid embolism, a rare but unpredictable and catastrophic complication of pregnancy that represents the third leading cause of maternal mortality. This disorder occurs during or after delivery when amniotic fluid gains access to uterine venous channels and, therefore, to the pulmonary and general circulations. The delivery may be either spontaneous or by Cesarean section and usually has been uneventful. Most cases occur during labor, but delayed onset of symptoms up to 48 hours after delivery can occur. Advanced maternal age, multiparity, premature placental separation, fetal death, and meconium staining of amniotic fluid have been associated with increased risk of amniotic fluid embolism.

Amniotic fluid embolism syndrome is primarily a clinical diagnosis. There is unexpected sudden onset of severe respiratory distress, cyanosis, hypotension, cardiovascular collapse and, often, disseminated intravascular coagulation. Occasionally, seizure activity occurs. It has been postulated that there is a biphasic pattern of hemodynamic disturbance: an initial period of pulmonary hypertension, commonly seen in animal models, followed by left ventricular dysfunction and cardiogenic shock. Patients who survive the first several hours develop noncardiogenic pulmonary edema coincident with improvement in left ventricular dysfunction. Amniotic fluid contains particulate materials that can cause pulmonary vascular obstruction, but the major pathogenetic mechanism of the syndrome remains uncertain. Amniotic fluid has thromboplastic activity that leads to extensive fibrin deposition in the lung vasculature and, occasionally, other organs. As a consequence of fibrin deposition, severe consumptive coagulopathy develops, including marked hypofibrinogenemia and thrombocytopenia. Following the acute event, an enhanced fibrinolytic state often occurs. The diagnosis of amniotic fluid embolism is based on a compatible clinical picture, often enhanced by finding amniotic fluid components in the pulmonary circulation. The presence of squamous cells in pulmonary arterial blood, once considered pathognomonic, has proved to be a nonspecific finding. Serological assays and immunohistochemical staining techniques have been described as having high sensitivity for amniotic fluid embolism. Although various forms of therapy have been suggested (e.g., antifibrinolytic agents such as aminocaproic acid, cryoprecipitate), the best approach is supportive. Pulmonary artery catheterization is useful to monitor left ventricular function and volume status and to guide the appropriate use of inotropic and vasoactive agents. Even in the setting of aggressive supportive measures, however, maternal mortality has approached 80 percent.

Septic Embolism Septic embolism is another special disorder that, unfortunately, is also increasing in frequency owing to widespread intravenous drug abuse and the expanding use of indwelling intravenous catheters. Previously, septic embolism was almost exclusively a complication of septic pelvic thrombophlebitis due to either septic abortion or post-puerperal uterine infection. However, almost any venous structure can be involved, either as a focus of primary infection or from intravascular or contiguous spread; septic cavernous sinus thrombosis resulting from meningitis, sinusitis, or facial cellulitis; septic portal venous thrombosis resulting from diverticulitis or liver abscess; septic tonsillar or internal jugular venous thrombosis (Lemierreâ&#x20AC;&#x2122;s syndrome) resulting from oropharyngeal infection. Increasingly common causes are those related to intravenous drug use and those that are iatrogenic; namely, infections secondary to indwelling catheters inserted for a variety of diagnostic or therapeutic purposes. Microscopically, septic phlebitis consists of purulent material admixed with fibrin thrombus. Embolization from

1445 Chapter 82

such material does occur and can result in obstruction of small pulmonary vessels, but the major consequence is pulmonary infection. Characteristically, the chest roentgenogram displays scattered pulmonary infiltrates that undergo cavitation. An increasing number of such infiltrates develops over periods of hours to a few days. Symptoms and signs include a septic temperature course, dyspnea, cough, pleuritic chest pain, and hemoptysis. Initial treatment consists of appropriate antimicrobial drugs. If an indwelling catheter is the source of the infection, it should be removed. If there is not a prompt response to this regimen, surgical isolation of the septic vein, if present, should be considered. The role of systemic anticoagulation remains uncertain. Endocarditis may complicate septic phlebitis, or mimic it, particularly in drug addicts.

Tumor Embolism Involvement of the pulmonary vascular bed by tumor cells is not unusual given the frequency with which circulating tumor cells can be identified in patients with a wide range of malignancies and the frequency with which tumor emboli are discovered as an incidental finding at autopsy. Tumor embolism becomes clinically apparent, however, in only a minority of patients with malignancy. Microvascular tumor embolism is associated with a wide range of malignancies, the most common sites of origin being the breast, lung, prostate, stomach, and liver. Tumor embolism of large fragments occurs rarely and may mimic acute thromboembolic disease. In this setting, survival following tumor embolectomy has been reported. The clinical presentation of microvascular tumor embolism is typically subacute and involves progressive dyspnea, tachycardia, and tachypnea. Jugular venous distention, a prominent P2, tricuspid regurgitation or a right-sided S3 may be present on physical examination if the extent of pulmonary vascular obstruction is sufficient to cause pulmonary hypertension. The development of pulmonary hypertension is a common accompaniment of symptomatic, microvascular tumor embolism and remains a major cause of mortality. Pulmonary hypertension appears to result from both an obliteration of the pulmonary vascular bed by an admixture of tumor cells and thrombus as well as the development of medial hypertrophy, intimal fibrosis, and fibrinoid necrosis encountered in other etiologies of pulmonary hypertension. Hypoxemia and a compensated respiratory alkalosis are commonly present. The chest radiograph is most often normal but focal or diffuse infiltrates, which may be fleeting, have been described. Ventilation-perfusion scanning most commonly demonstrates a mottled appearance or peripheral, subsegmental defects; segmental or larger defects, indistinguishable from those associated with thromboembolic embolism, may occur in those rare instances of large-vessel involvement. CT may demonstrate peripheral, wedge-shaped defects consistent with infarcts; a pattern of multifocal dilatation and beading of the peripheral pulmonary arteries has been described.

Pulmonary Thromboembolic Disease

Pulmonary angiographic findings may include delayed vascular filling, pruning and tortuosity, similar to that seen in other forms of small-vessel pulmonary hypertension. The angiographic findings in large fragment tumor embolism may be indistinguishable from those seen in acute thromboembolic disease. Pulmonary microvascular cytology on specimens aspirated through a wedged pulmonary artery catheter may demonstrate malignant cells. Positive cytologies, however, can also be obtained in the setting of lymphangitic carcinomatosis. The misidentification of megakaryocytes obtained in this manner has been reported to lead to false-positive results. Although diagnosis by transbronchial biopsy has been reported, diagnostic confirmation may require open-lung biopsy. Before proceeding to that step, however, it must be stressed that the impact of early diagnosis on outcome is uncertain. This intervention should only be considered in the setting of a primary malignancy for which effective chemotherapeutic options are available. The differential diagnosis of tumor embolism includes thrombotic embolism, parenchymal metastasis, lymphangitic carcinomatosis, malignant pericardial effusion, and chemotherapy-related lung toxicity. The premortem diagnosis is often one of exclusion. Parenchymal metastasis, lymphangitic carcinomatosis and chemotherapy-related lung toxicity can be differentiated from tumor embolism by findings on high-resolution CT. Differentiation of tumor embolism from thrombotic embolism may be somewhat more problematic, especially if there is large vessel involvement.

Sickle Cell Disease Sickle cell disease affects the lungs by causing local thrombosis and occasionally by embolization of bone marrow elements. Small pulmonary arteries, arterioles, and capillaries are generally affected. Thrombosis in the pulmonary circulation is part of the general proclivity of red blood cells containing S hemoglobin to sickle under appropriate circumstances, particularly hypoxia; stagnation and clotting follow sickling. In some instances, the thrombus organizes, vascular lumen is obliterated, and perivascular fibrosis ensues in the adjacent lung; in others, the thrombus recanalizes. Occasionally, infarction occurs. Of the factors that predispose in thrombosis in the lungs in sickle cell disease, the most important is the low Po2 of mixed venous blood. Not only is the mixed venous Po2 inordinately low but also the O2 dissociation curve is shifted to the right, thereby handicapping O2 uptake in the lungs. Any pulmonary disease that causes alveolar hypoventilation or hypoxemia of blood in the lungs of persons with sickle cell disease favors sickling and thrombosis. Since patients with sickle cell disease are prone to intercurrent pulmonary infections, particularly pneumonia and tuberculosis, they are predisposed to local areas of alveolar hypoventilation and hypoxia. Patients with severe sickle cell anemia and large fractions of hemoglobin S in their red blood cells are particularly susceptible to intense sickling and thrombosis anywhere, including the lungs. However, vulnerability is not restricted

1446 Part IX

Disorders of the Pulmonary Circulation

to states of hemoglobin S. In some heterozygous sickle states—e.g., hemoglobin SC, S-thalassemia, and hemoglobin SA—enough hemoglobin S is present to cause extensive thrombosis and infarction during an episode of severe hypoxemia, acidosis, or septicemia associated with fever and leukocytosis. The clinical picture of pulmonary infarction in patients with sickle cell disease can mimic or coexist with bronchopneumonia. The latter may promote local hypoxia, which leads to in situ pulmonary thrombosis. An episode often begins with poorly defined or pleuritic chest pain, fever, and sputum that is blood streaked but fails to disclose any specific bacterial cause. A fleeting episode of breathlessness is usually overlooked. Cyanosis is rare because of the severe anemia. The subsequent course is characterized by an unconvincing response to antibiotics and slow clearing; often a linear scar in the lungs remains as a residue of the infarction. Suspicion of infarction should be high in any black person with hemoglobin S and in white people of Greek or Italian descent with S-thalassemia. Sometimes, occlusive disease is sufficiently extensive to cause pulmonary hypertension and cor pulmonale. For this sequence to evolve, many severe episodes of sickling are required. The cor pulmonale that results is unusual because of its association with a high cardiac output (due to the anemia) and with the intrinsic myocardial damage that generally complicates sickle cell disease. Management of the patient with pulmonary thrombosis and infarction in sickle cell disease relies heavily on experience with the disease. Few specific measures can be advocated other than conventional supportive treatment. Distinguishing between in situ thrombosis and thromboembolism can be difficult clinically and even with invasive procedures such as angiography, although in situ thrombosis tends to be in small, distal vessels. Moreover, because radiographic contrast materials may promote sickling, they have to be used cautiously. To complicate matters, some patients with sickle cell disease are also at increased risk of thromboembolus because of predisposing factors, such as bed rest, congestive heart failure, and dehydration. Anticoagulants are generally not used in sickle cell disease, since there are no data to substantiate their effectiveness in treating in situ thrombosis.

Other Emboli Because of its sieve function, the lung may also be embolized on occasion by a wide variety of other materials. Trophoblastic tissue can escape the uterus and lodge in the pulmonary circulation during pregnancy. After head trauma, brain tissue has been found in the lungs; the same is true of liver cells following abdominal trauma and bone marrow after cardiopulmonary resuscitation. Finally, in this era of intravenous drug abuse, noninfectious vasculitic-thrombotic complications are being seen with increasing frequency in association with the intravenous use of drugs intended for oral use. Medications associated

with pulmonary complications include methylphenidate hydrochloride, oral opiates (pentazocine, meperidine), and antihistamines. Particulate and irritant drug carriers (e.g., talc, cellulose) and occasionally the drugs themselves may cause vascular inflammation and secondary thrombosis. The clinical presentation may be diverse and includes lower lobe emphysema, diffuse interstitial fibrosis, and progressive massive fibrosis. Repetitive insults may lead to severe and irreversible pulmonary hypertension. In many intravenous drug users, perfusion scans demonstrate segmental or smaller defects. Distinguishing these defects from those due to venous thromboembolism may be difficult. The diagnosis is often suggested by the clinical history. Radiographic findings include small, diffuse well-defined nodular densities. These nodules can progress and massive fibrosis may ensue. Lower lobe emphysematous changes may also be present. Diagnostic confirmation often requires lung biopsy, either open or transbronchial. The prognosis is poor with progressive pulmonary disease being the rule.

SUGGESTED READING Agnelli G: Prevention of venous thromboembolism in surgical patients. Circulation 110:IV-4–IV-12, 2004. Alikhan R, Cohen AT, Combe S, et al.: Risk factors for venous thromboembolism in hospitalized patients with acute medical illness. Analysis of the Medenox Study. Arch Intern Med 164:963–968, 2004. Anderson DR, Lensing AWA, Wells PS, et al.: Limitations of impedance plethysmography in the diagnosis of clinically suspected deep-vein thrombosis. Ann Intern Med 118:25– 30, 1993. Aryal KR, Al-khaffal H: Venous thromboembolic complications following air travel: What’s the quantitative risk? A literature review. Eur J Vas Endov Surg 31:187–199, 2006. Auger WR, Kim NH, Kerr KM, et al.: Thromboembolic pulmonary hypertension. Clin Chest Med 28:255–269, 2007. Becattini C, Agnelli G, Pesavento R, et al.: Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 130:172–175, 2006. Blom JW, Doggen CJ, Osanto S, et al.: Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 293:715–722, 2005. Buller HR, Agnelli G, Hull RD, et al.: Antithrombotic therapy for venous thromboembolic disease: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:401S–428S, 2004. Buller HR, Davidson BL, Decousus H, et al.: Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 349:1695–1702, 2003. Dalen JE, Alpert JS: Natural history of pulmonary embolism. Prog Cardiovasc Dis 17:259–270, 1975.

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Dalen JE, Alpert JS, Hirsch J: Thrombolytic therapy for pulmonary embolism. Is it effective? Is it safe? When is it indicated? Arch Intern Med 157:2550–2556, 1997. Fedullo PF, Auger WR, Kerr KM, et al.: Chronic thromboembolic pulmonary hypertension. Semin Respir Crit Care Med 24:273–286, 2003. Geerts WH, Pineo GF, Heit JA, et al.: Prevention of venous thromboembolism: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:338S– 401S, 2004. Geibel A, Zehender M, Kasper W, et al.: Prognostic value of the ECG on admission in patients with acute pulmonary embolism. Eur Respir J 25:843–848, 2005. Goldhaber SZ, Grodstein F, Stampfer MJ, et al.: A prospective study of risk factors for pulmonary embolism in women. JAMA 277:642–645, 1997. Gomes MPV, Deitcher SR: Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy. Arch Intern Med 164:1965– 1976, 2004. Han D, Soo Lee K, Franquet T, et al.: Nonthrombotic pulmonary embolism. Spectrum of imaging findings. Radiographics 23:1521–1539, 2003. Heit JA, Kobbervig CE, James AH, et al.: Trends in the incidence of venous thromboembolism in pregnancy or postpartum: A 30-year population-based study. Ann Intern Med 143:697–706, 2005. Heit JA, Melton J III, Lohse CM, et al: Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin Proc 76:1102–1110, 2001. Hirsh J, Raschke R: Heparin and low-molecular-weight heparin. Chest 2004;126:188S–203S. Joffe HV, Goldhaber SZ: Upper-extremity deep venous thrombosis. Circulation 106:1874–1880, 2002. Kearon C, Ginsberg JS, Julian JA, et al.: Unfractionated heparin and low-molecular weight heparin for acute treatment of venous thromboembolism. JAMA 296:935–942, 2006. Kluge A, Luboldt W, Bachmann G: Acute pulmonary embolism to the subsegmental level: diagnostic accuracy of 3 MRI techniques compared with 16-MDCT. AJR 187:W7– W14, 2006. Kucher N, Goldhaber SZ: Risk stratification of acute pulmonary embolism. Semin Thromb Hemost 32:838–847, 2006. Le Gal G, Righini M, Roy P-M, et al.: Prediction of pulmonary embolism in the emergency department: The revised Geneva Score. Ann Intern Med 144:165–171, 2006. McRae SJ, Ginsberg JS: New anticoagulants for venous thromboembolic disease. Curr Opin Cardiol 20:502–508, 2005. Mewissen MW, Seabrook GR, Meissner MH, et al.: Catheterdirected thrombolysis for lower extremity deep venous thrombosis: Report of a national multicenter registry. Radiology 211:39–49, 1999. Minter KR, Gladwin MT: Pulmonary complications of sickle cell anemia. A need for increased recognition, treatment and research. Am J Resp Crit Care Med 164:2016–2019, 2001.

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Mirski M, Lele AV, Fitzsimmons L, et al.: Diagnosis and treatment of vascular air embolism. Anesthesiology 106:164– 177, 2007. Moore J, Baldsseri MR: Amniotic fluid embolism. Crit Care Med 33:S279–S285, 2005. Raschke RA, Reilly BM, Guidry JR, et al.: The weight based heparin dosing nomogram compared with a “standard care” nomogram: A randomized controlled study. Ann Intern Med 119:874–881, 1993. Roberts KE, Hamele-Dena B, Saqi A, et al.: Pulmonary tumor embolism: A review of the literature. Am J Med 115:228– 232, 2003. Rodger MA, Carrier M, Jones GN, et al.: Diagnostic value of arterial blood gas measurement in suspected pulmonary embolism. Am J Resp Crit Care Med 162:2105–2108, 2000. Roy PM, Colombet I, Durieux P, et al.: Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. Br Med J 331:259–268, 2005. Schoepf UJ, Costello P: CT angiography for diagnosis of pulmonary embolism. State of the art. Radiology 230:329–337, 2004. Simioni P, Tormene D, Spiezia L, et al.: Inherited thrombophilia and venous thromboembolism. Semin Thromb Hemost 32:700–708, 2006. Stein PD, Fowler SE, Goodman LR, et al.: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 354:2317–2327, 2006. Stein PD, Henry JW: Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest 112:974–979, 1997. Stein PD, Hull RD, Kayali F, et al.: Venous thromboembolism according to age: The impact of an aging population. Arch Intern Med 164:2260–2265, 2004. Stein PD, Hull RD, Patel KC, et al.: D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: A systematic review. Ann Intern Med 140:589–602, 2004. The PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis. JAMA 263:2753–2759, 1990. The PREPIC Study Group: Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism. Circulation 112:416–422, 2005. Uflacker R: Interventional therapy for pulmonary embolism. J Vasc Interv Radiol 12:147–164, 2001. Wells PS, Anderson DR, Rodger M, et al.: Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: Increasing the model’s utility with the SimpliRED d-dimer. Thromb Haemost 83:416–420, 2000. Wicki J, Perneger TV, Junod AF, et al.: Assessing clinical probability of pulmonary embolism in the emergency ward. Arch Intern Med 161:92–97, 2001. Wood KE: Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 121:877–905, 2002.

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83 Pulmonary Vasculitis Ulrich Specks

I. NOMENCLATURE AND DEFINITIONS II. EPIDEMIOLOGY III. ANCA-ASSOCIATED VASCULITIS Wegener’s Granulomatosis: Clinical Presentation and Diagnosis Microscopic Polyangiitis: Clinical Presentation and Diagnosis Churg-Strauss Syndrome: Clinical Presentation and Diagnosis Path ophysiology of ANCA-Associated Vasculitis Treatment of ANCA-Associated Vasculitis Treatment of Wegener’s Granulomatosis and Microscopic Polyangiitis Treatment of Churg-Strauss Syndrome

NOMENCLATURE AND DEFINITIONS Pulmonary vasculitis is usually a manifestation of a systemic disorder leading to inflammation of vessels of different sizes by a variety of immunologic mechanisms. Vasculitis can be separated into primary and secondary vasculitis. The primary systemic vasculitides are a heterogeneous group of syndromes of unknown etiology, which share a clinical response to immunosuppressive therapy (Table 83-1). Their wide spectrum of frequently overlapping clinical manifestations is defined by the size and location of the affected vessels as well as the nature of the inflammatory infiltrate. Secondary vasculitis may represent significant management problems in the context of a well-defined underlying disorder, such as diffuse alveolar hemorrhage caused by systemic lupus erythematosus. Alternatively, secondary vasculitis may be an incidental histopathological finding, for instance, in the context of an infection or necrotizing sarcoid granulomatosis.

IV. OTHER DISORDERS PRESENTING WITH PULMONARY VASCULITIS Giant Cell Arteritis Takayasu’s Arteritis Classic Polyarteritis Nodosa Behc¸et’s Disease Idiopathic Pauci-immune Pulmonary Capillaritis Systemic Lupus Erythematosus and Other Collagen Vascular Disorders Antiphospholipid Syndrome Antiglomerular Basement Membrane Disease Henoch-Sch¨onlein Purpura Drug-Induced Vasculitis Pulmonary Capillaritis after Lung Transplantation Necrotizing Sarcoid Granulomatosis

Classification schemes and definitions of the various forms of vasculitis have evolved over the past decades. Historically, the classification of the vasculitides has been based on the size of the most prominently affected vessels. The primary purpose of classification and nomenclature is to standardize communication between clinicians and investigators and to facilitate more uniform treatment approaches. Ideally, they reflect the current understanding of pathogenesis. Two schemes of classification and definitions are currently in use. In 1990, the American College of Rheumatology (ACR) developed criteria for the classification of the vasculitides. The ACR effort identified clinical features that allow separation of one form of vasculitis from another. The 1990 ACR criteria have several major drawbacks for clinical practice. First, the underlying data were collected before testing for antineutrophil cytoplasmic antibodies (ANCA) became available. Second, these criteria precede the acknowledgment of the concept of microscopic polyangiitis, which has been widely accepted in Europe for many decades. In the U.S. literature preceding the

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Table 83-1 Chapel Hill Consensus Nomenclature of the Primary Systemic Vasculitides Name

Respiratory Presence Manifestations of ANCA

Large vessel vasculitis Giant cell arteritis Takayasu’s arteritis

Rare Frequent

Medium-sized vessel vasculitis Classic polyarteritis Rare nodosa Kawasaki’s disease No Small vessel vasculitis Wegener’s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Henoch-Sch¨onlein purpura Essential cryoglobuinemic vasculitis

No No

Frequent

>80%

Frequent Frequent Rare

>80% >50% IgA-ANCA reported No

1990s, cases with microscopic polyangiitis were either referred to as “hypersensitivity vasculitis” or lumped with classic polyarteritis nodosa. An international consensus conference on the nomenclature of systemic vasculitides held in 1992 in Chapel Hill aimed to reconcile definitions and classification schemes used by European and American investigators. The resulting nomenclature and definitions are based mainly on histopathological criteria, particularly the size of the vessels involved. However, radiographic and clinical surrogates may be used to fulfill the definitions. Although the Chapel Hill consensus nomenclature takes the presence or absence of ANCA into account, the presence of ANCA is not required for the diagnosis of an “ANCA-associated vasculitis,” such as Wegener’s granulomatosis or microscopic polyangiitis. Finally, the conference acknowledged the occasional need to change the diagnosis in certain patients as their clinical presentations change over time. For instance, a patient originally diagnosed as having microscopic polyangiitis may have to be diagnosed as having Wegener’s granulomatosis when characteristic necrotizing granulomas develop. In this chapter, the specific definition of each form of vasculitis is discussed in detail as part of the description of the clinical manifestations and differential diagnosis of each entity. The Chapel Hill nomenclature has been criticized for a variety of reasons. However, from a pulmonologist’s perspective, it represents the clinically most useful attempt to

Figure 83-1 Cytoplasmic indirect immunofluorescence (CANCA) pattern in ethanol-fixed neutrophils caused by ANCA reacting with PR3.

categorize the primary systemic vasculitides. The categories reflect the clinical and histopathological pulmonary features, are in accordance with the ANCA data, and facilitate the therapeutic approach to individual patients. The three small vessel vasculitides that present most often with respiratory symptoms are Wegener’s granulomatosis, MPA, and the ChurgStrauss syndrome. Most patients with these syndromes have ANCA detectable in the serum at the time of initial presentation. Consequently, this group of small vessel vasculitides is frequently referred to in cumulo as “ANCA-associated vasculitis.” Clinicians convinced of the pathogenic significance of these antibodies even prefer the term “ANCA vasculitis.” In patients with vasculitis, two types of ANCA are of clinical significance. In more than 80 percent of patients with Wegener’s granulomatosis (Fig. 83-1), ANCA occurs and is associated with a cytoplasmic immunofluorescence pattern (CANCA) on ethanol-fixed neutrophils that react with the neutrophil granule enzyme, proteinase 3 (PR3-ANCA). In contrast, ANCA that causes a perinuclear immunofluorescence pattern (P-ANCA) on ethanol-fixed neutrophils and reacts with myeloperoxidase (MPO-ANCA) occurs in fewer than 10 percent of patients with Wegener’s granulomatosis but in the majority of patients with microscopic polyangiitis (Fig. 83-2). MPO-ANCA are also the predominant type of ANCA encountered in patients with Churg-Strauss syndrome, in which PR3-ANCA is the exception. Despite these circulating autoantibodies, hardly any immunoglobulin deposits can be detected in the tissue lesions of ANCA-associated vasculitis, and they are consequently called “pauci-immune” lesions.

EPIDEMIOLOGY The primary systemic vasculitides are rare and few epidemiologic studies have been conducted, mostly in ethnically homogenous populations. Giant-cell arteritis is the most

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Figure 83-2 Perinuclear indirect immunofluorescence (P-ANCA) pattern in ethanol-fixed neutrophils caused by ANCA reacting with MPO.

frequent form of systemic vasculitis with an annual incidence of 13 per million adults (40 per million over the age of 60). It appears to be increasing in frequency and becoming cyclical over time. The latter observation has been interpreted as possibly suggesting a relationship with infections. Respiratory manifestations rarely represent significant management problems in these patients. Various studies from different regions of the world report a fairly uniform incidence of one to two cases per million for Takayasu’s arteritis. Pulmonary vascular complications occur in about half of the afflicted patients. The estimated annual incidence of Wegener’s granulomatosis has been rising over the decades from 0.5 to 0.7 per million during the 1970s and early 1980s to current estimates of about 10 to 12 per million. Similar increases in annual incidence have been observed for microscopic polyangiitis and Churg-Strauss syndrome. The average frequency of microscopic polyangiitis is similar to that of Wegener’s granulomatosis; for the Churg-Strauss syndrome it is estimated to be of the order of one to three per million. The ANCA-associated vasculitides have different ethnic predilections: Wegener’s granulomatosis affects predominantly whites, and northern Europeans appear more prone to develop Wegener’s granulomatosis. In contrast, individuals of southern European and Mediterranean descent appear to be relatively more apt to develop microscopic polyangiitis. Wegener’s granulomatosis and microscopic polyangiitis can affect individuals of any age. However, the incidence of Wegener’s granulomatosis plateaus after age 50, whereas the likelihood of developing microscopic polyangiitis continues to increase with age. The annual incidence of the secondary vasculitides varies widely. The reported frequencies for rheumatoid vasculitis and vasculitis in systemic lupus erythematosus are 12.5 per million and 3.6 per million, respectively. Behc¸et’s disease has a peculiar geographic distribution along the old Silk Road, with the highest prevalence being reported from Turkey, central and far-eastern Asia, where the frequencies

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range from 100 to 380 per 100,000, compared with only one per 100,000 in western Europe. The available population-based studies need to be interpreted with some caution because they do not distinguish between whether the observed increased incidence of systemic vasculitis is true, or the result of more frequent recognition of the disease. Moreover, whether individual diagnoses are accurate is challenged by the changing definitions of the syndromes. For instance, if the ACR 1990 criteria for polyarteritis nodosa (PAN) are applied, the incidence of PAN would be 2.4 per million annually. In contrast, application of the definitions of the Chapel Hill Consensus Conference has resulted in the almost complete disappearance of PAN, whereas the incidence of microscopic polyangiitis would seem to be 3.6 per million annually. Finally, the advent of ANCA testing may have affected the apparent incidences of Wegener’s granulomatosis and microscopic polyangiitis.

ANCA-ASSOCIATED VASCULITIS Wegener’s Granulomatosis: Clinical Presentation and Diagnosis Wegener’s granulomatosis is the most common form of vasculitis to involve the lung. The Chapel Hill Consensus Conference defined Wegener’s granulomatosis as “granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels.” However, it is important to recognize that Wegener’s granulomatosis is a systemic disease that can affect almost any organ (Table 83-2). The most frequently involved sites are the upper airways, lungs, and kidneys. Symptoms and clinical disease manifestations are the result of necrotizing granulomatous inflammation and small vessel vasculitis that occur in variable degrees of combination. In the 1960s the term “limited Wegener’s granulomatosis” was introduced to indicate those patients who lacked renal disease. The use of this term and its implications have evolved over the last two decades. Even in the absence of renal involvement, patients may have life-threatening pulmonary or neurological disease requiring aggressive immunosuppressive treatment. For instance, a patient who “only” has alveolar hemorrhage in the absence of glomerulonephritis should never be classified as having “limited Wegener’s granulomatosis.” Consequently, today, the use of the term “limited Wegener’s granulomatosis” implies that: (a) the pathology is predominantly a necrotizing granulomatous and the vasculitis seen on biopsy is of lesser clinical significance; and (b) there is no immediate threat either to the patient’s life or that the affected organ is at risk for irreversible damage. In this sense, limited Wegener’s granulomatosis is distinguished from severe Wegener’s granulomatosis, which by definition either threatens the patient’s life (alveolar hemorrhage) or a vital organ with the risk of irreversible damage (rapidly progressive glomerulonephritis, scleritis, or mononeuritis

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Table 83-2 Organ Systems Affected by ANCA-Associated Vasculitis Feature

Wegener’s Granulomatosis

Microscopic Polyangiitis

Churg-Strauss Syndrome

Upper airway disease

90–95%

50–60%

Pulmonary parenchymal disease

54–85%

20%

30%

Alveolar hemorrhage

5–15%

10–50%

<3%

Glomerulonephritis

51–80%

60–90%

10%–25%

Gastrointestinal tract

<5%

30%

30–50%

Eyes

35–52%

<5%

Nervous system

20–50%

60–70%

70%–80%

Heart

8–16%

10–15%

Skin

33–46%

62%

50–60%

Eosinophilia

Rare

Yes

Asthma

No∗

Yes

Granulomatous inflammation

Yes

∗ Not

more than general population.

multiplex). These definitions and distinctions form the basis for stratification of current standard therapy. Over 90 percent of patients with Wegener’s granulomatosis first seek medical attention for symptoms arising from either the upper and/or lower airway. Nasal and sinus disease is characterized by congestion and epistaxis due to mucosal friability, ulceration, and thickening. Patients may also have features of chronic sinusitis and recurrent or chronic serous otitis. Perforation of the nasal septum and/or saddle nose deformity may result from ischemia of the nasal cartilage (Fig. 83-3). Oral manifestations include gingival hyperplasia (Fig. 83-4) and oropharyngeal ulcerations. Subglottic stenosis occurs in approximately 20 percent of patients and can cause life-threatening compromise of the airway. Subglottic stenosis may occur in the absence of other features of active Wegener’s granulomatosis, and its symptoms may be nonspecific, e.g., dyspnea, hoarseness, cough or stridor; the latter is occasionally mistaken for wheezing. Wegener’s granulomatosis involving the lower airways can affect the pulmonary parenchyma, the bronchi, and rarely the pleura. Presenting features of parenchymal involvement may include cough, dyspnea, chest pain, or hemoptysis. However, some patients may be completely asymptomatic. Patients with diffuse alveolar hemorrhage usually present with

progressive dyspnea and anemia (Fig. 83-5). Hemoptysis is absent in about one-third of patients. Patients with diffuse alveolar hemorrhage may deteriorate rapidly and experience respiratory failure, which has a mortality rate of 50 percent. The clinical presentation of alveolar hemorrhage is caused by pulmonary capillaritis (Fig. 83-6). The predominant inflammatory cells are neutrophils. However, eosinophils or monocytes may also be present. Capillaritis usually causes fibrinoid necrosis of alveolar and vessel walls and may culminate in the destruction of the underlying architecture of the lung. An important hallmark of capillaritis is the presence of pyknotic cells and nuclear fragments from neutrophils undergoing apoptosis, a feature called leukocytoclasis. This hallmark enables distinction between true capillaritis and margination of neutrophils related to surgical trauma. Depending on the acuteness and duration of alveolar hemorrhage, hemosiderin-laden macrophages and interstitial hemosiderin deposits may be present. The most common form of pulmonary involvement in Wegener’s granulomatosis is that of nodules or mass lesions, which may cavitate (Figs. 83-7, 83-8, and 83-9). Frequently, these lesions are incidental findings on thoracic imaging studies as they cause little symptoms and do not result in significant abnormalities of pulmonary function. These lesions are

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Figure 83-5 Chest radiograph of a patient with Wegener’s granulomatosis displaying an alveolar filling pattern indicative of diffuse alveolar hemorrhage.

Figure 83-3 Saddle nose deformity of Wegener’s granulomatosis.

caused by necrotizing granulomatous inflammation. Prominent air-fluid levels can be seen when the necrotic center of the inflammatory lesion gets superinfected (Fig. 83-8). These necrotizing granulomatous lesions are a disease-defining feature of Wegener’s granulomatosis. Their presence easily separates Wegener’s granulomatosis from microscopic polyangiitis. In the absence of other features of small vessel vasculitis in other organs, the differential diagnosis of these lesions consists primarily of infections, particularly caused by fungal or mycobacterial organisms, and less likely of malignancies or necrotizing sarcoid granulomatosis. The lung nodules of Wegener’s granulomatosis have very characteristic histopathological features. Small necrotiz-

Figure 83-4 Strawberry or mulberry gums in a patient with Wegener’s granulomatosis.

ing microabscesses appear to be the earliest lesion. They enlarge and coalesce until the typical geographic and basophilic appearance of the necrosis has developed (Fig. 83-10). The necrotic center is surrounded by palisading histiocytes and scattered giant cells. Occasionally the necrosis may be bronchocentric. When this type of necrotizing granulomatous inflammation extends into the walls of small vessels it is referred to as granulomatous vasculitis (Fig. 83-11). In contrast to capillaritis, this type of vasculitis seems to be a secondary phenomenon of the necrotizing granulomatous inflammation affecting the lung parenchyma. The inflammatory background of the granulomatous necrosis and vasculitis consists of a mixed cellular infiltrate containing lymphocytes, plasma cells, scattered giant cells, and eosinophils. It may cause extensive parenchymal consolidation mimicking organizing pneumonia. Well defined sarcoidlike non-necrotizing granulomas are not found in Wegener’s granulomatosis. Inflammation and stenosis of the tracheobronchial tree occurs in at least 15 percent of patients with lung involvement. Endobronchial disease may be an incidental finding on bronchoscopy or present with cough, hemoptysis, wheezing, dyspnea, or symptoms related to parenchymal collapse or postobstructive infection. Spirometry including inspiratory and expiratory flow-volume loops may show characteristic abnormalities indicative of degree and location of airway narrowing. Subglottic stenosis represents a fixed airway obstruction resulting in flattening of both the inspiratory and expiratory loops. If the intrathoracic trachea, or more commonly, one or both mainstem bronchi are affected, flattening of the expiratory curve can be found. Pleural effusions may occur, but are usually small, asymptomatic, and incidental findings (Fig. 83-9). Other thoracic manifestations of Wegener’s granulomatosis include inflammatory pleural pseudotumors or hilar

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Figure 83-6 Alveolar capillaritis causing pulmonary hemorrhage in Wegener’s granulomatosis.

adenopathy. The latter should raise the suspicion of infection, sarcoidosis, or lymphoma. Glomerulonephritis is among the most concerning disease manifestations of Wegener’s granulomatosis as it can progress to complete renal failure in the absence of symptoms. It is usually detected by the presence of abnormal laboratory results such as active urine sediment with microscopic

hematuria and red cell casts, proteinuria, and declining renal function. Continued vigilance for glomerulonephritis is essential as it is present at diagnosis in less than half of all patients. However, over the course of their disease, the kidneys are affected in 80 percent of patients.

Figure 83-7 Chest radiograph of a patient with Wegener’s granulomatosis displaying multiple nodules with and without cavitation.

Figure 83-8 Chest radiograph of a patient with Wegener’s granulomatosis showing multiple large cavities, some with air-fluid levels.

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Figure 83-9 Computed tomography scan of a patient with Wegener’s granulomatosis showing multiple nodules, some with cavitation. There are also small bilateral pleural effusions.

A renal biopsy is useful to establish a diagnosis of ANCA-associated vasculitis and to determine the renal prognosis. The glomeruli are not affected uniformly (focal) by segmental, necrotizing inflammation (Fig. 83-12), and cellular crescents (Fig. 83-13) are frequently found. The number of glomeruli affected, degree of crescent formation, and destruction of individual glomeruli as well as the amount of sclerosis found determine the chance of recovery of renal function. Direct immunofluorescence reveals no or only scant immune deposits (pauci-immune glomerulonephritis). Granulomatous inflammation affecting the renal parenchyma and tubulointerstitial nephritis can also be found rarely. A wide spectrum of ocular manifestations has been observed in Wegener’s granulomatosis, which may threaten vision by affecting the eye directly or involving its contiguous structures. Manifestations may include conjunctivitis, epis-

cleritis, scleritis, keratitis, corneal ulceration, uveitis, and retinal vasculitis. Involvement of the lacrimal system may result in epiphora, dacryocystitis, and fistula. Retro-orbital inflammatory pseudotumors may affect one or both eyes, threaten the vision, and represent the most difficult challenge in the management of Wegener’s granulomatosis (Figs. 83-14 and 8315). Any patient with Wegener’s granulomatosis who presents with eye pain or redness, proptosis, change in visual acuity, diplopia, or loss of visual field should be referred for emergent ophthalmologic consultation. Nervous system involvement may occur in up to onethird of patients. Mononeuritis multiplex of the peripheral nervous system caused by inflammation of the vasa nervorum as well central nervous system vasculitis and pachymeningitis represent severe disease manifestations with substantial risk of irreversible damage, persisting even after the acute inflammation is adequately controlled.

Figure 83-10 Geographic basophilic necrosis with palisading histiocytes and giant cells from a lung nodule in a patient with Wegener’s granulomatosis.

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Figure 83-11 Granulomatous vasculitis with giant cells in a lung biopsy of a patient with Wegener’s granulomatosis.

Cardiac involvement may be occult. Regional wall motion abnormalities with a noncoronary distribution pattern are frequent echocardiographic findings. It is unclear whether this type of cardiomyopathy is the result of small vessel disease or inflammatory infiltration of the cardiac muscle. Pericarditis, valvulitis, and inflammatory pseudotumor have also been described. A wide spectrum of cutaneous manifestations may be observed in Wegener’s granulomatosis. Leukocytoclastic vasculitis presenting as palpable purpura is most common, followed by pyoderma gangrenosum-like lesions (Fig. 83-16) and so-called Churg-Strauss granulomas.

Figure 83-12 Focal necrotizing glomerulitis of Wegener’s granulomatosis.

Figure 83-13 Rapidly progressive crescentic glomerulonephritis in Wegener’s granulomatosis.

Microscopic Polyangiitis: Clinical Presentation and Diagnosis Histopathologically, the necrotizing small vessel vasculitis of microscopic polyangiitis including necrotizing crescentic glomerulonephritis and pulmonary capillaritis are indistinguishable from that encountered in Wegener’s granulomatosis. Consequently, there is substantial overlap in organ manifestations and symptoms between microscopic polyangiitis and Wegener’s granulomatosis (Table 83-2). A timely diagnosis of microscopic polyangiitis may be delayed by a gradual onset or the nonspecific nature of symptoms such as fever, malaise, and weight loss. All organ systems may be involved. The kidneys are most commonly affected in up to 80 percent

Figure 83-14 External ophthalmoplegia of the left eye due to orbital involvement with Wegener’s granulomatosis.

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Figure 83-15 Computed tomography scan of the orbits in a patient with Wegener’s granulomatosis showing a mass in the right orbit causing external ophthalmoplegia.

of patients. Other commonly encountered disease manifestations include diffuse alveolar hemorrhage due to pulmonary capillaritis affecting 10 to 30 percent of patients. Microscopic polyangiitis is the most frequent cause of pulmonary-renal syndrome. Several cases of microscopic polyangiitis in association with a variety of nonvasculitic pulmonary disorders including pulmonary fibrosis, severe obstructive airways disease, and bronchiectasis, have also been described. Palpable purpura caused by leukocytoclastic vasculitis of the skin, and musculoskeletal complaints, such as arthralgias and myalgias, are also common. Gastrointestinal involvement occurs in about one-third of patients. This is in contrast to Wegener’s granulomatosis, in which gastrointestinal involvement is very rare. Visceral angiography is generally not helpful for the evaluation of abdominal symptoms as the vessels involved are too small to be visualized. CT with or without contrast injection may be more helpful if gastrointestinal involvement is suspected. However, the use of contrast is relatively con-

Figure 83-16 Pyoderma gangrenosum of the leg in a patient with Wegener’s granulomatosis.

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traindicated in patients with active renal involvement. Sinusitis and asthma are rarely found in microscopic polyangiitis, and should lead to the consideration of an alternative diagnosis. Most patients with microscopic polyangiitis have ANCA, and in 40 to 80 percent they are of the P-ANCA variety, reacting with MPO. C-ANCA reacting with PR3 is seen less frequently. Occasionally patients with microscopic polyangiitis later develop granulomatous inflammation and are reclassified as having Wegener’s granulomatosis; this is more likely to occur in patients with C-ANCA. As in Wegener’s granulomatosis, a histopathological diagnosis should be obtained before the patient is committed to prolonged immunosuppressive therapy. The biopsy specimen should be sought from the most accessible site. Renal biopsy shows pauci-immune focal segmental necrotizing glomerulonephritis, with extracapillary proliferation forming crescents. In contrast to Wegener’s granulomatosis, granulomatous inflammation is not a feature of microscopic polyangiitis. All other histopathological features are indistinguishable from those of Wegener’s granulomatosis. Treatment of microscopic polyangiitis should follow the principles applied to the management of Wegener’s granulomatosis. Consequently, most cases of microscopic polyangiitis require immunosuppressive therapy used for patients with severe Wegener’s granulomatosis.

Churg-Strauss Syndrome: Clinical Presentation and Diagnosis Churg-Strauss syndrome is the third type of vasculitis that commonly affects the lung. The Chapel Hill Consensus definition for the disease is “eosinophil-rich and granulomatous inflammation involving the respiratory, and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia.” The inclusion of Churg-Strauss syndrome among the ANCA-associated vasculitides remains controversial, as only 40 to 70 percent of patients with active Churg-Strauss vasculitis are ANCA positive. Churg-Strauss syndrome is primarily distinguished from Wegener’s granulomatosis and microscopic polyangiitis by a high prevalence of asthma and peripheral blood and tissue eosinophilia. Three distinct disease phases of the disease have been described. The first is a prodromal allergic phase with asthma. This phase may last for a number of years. The second is an eosinophilic phase with prominent peripheral and tissue eosinophilia. This phase may also last a number of years and the manifestations may remit and recur over this time period. The differential diagnosis for patients in this phase of the disease includes parasitic infection and chronic eosinophilic pneumonia. The third vasculitic phase consists of systemic vasculitis and may be life threatening. The three phases are not seen in all patients and do not necessarily occur in this order; they may even concur. However, asthma usually predates vasculitic symptoms by a mean of 7 years (range 0 to 61). Formes frustes of Churg-Strauss syndrome have also been described with eosinophilic vasculitis and/or

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Figure 83-17 Chest radiographs of patients with Churg-Strauss syndrome: A. Nonspecific gnomonic infiltrates. B . Multiple vague, patchy infiltrates. (Reproduced by permission from Mayo Clin Proc 52:482, 1977.) Chumbley LC, Harrison EG, DeRemee RA: Allergic Granulomatosis and angiitis (Churg-Strauss syndrome): Report and analysis of 30 cases. Mayo Clin Proc 52: 477–484, 1977.

eosinophilic granulomas in isolated organs without evidence of systemic disease. Pulmonary parenchymal involvement occurs in 38 percent of patients. Transient alveolar-type infiltrates are most common (Fig. 83-17). These have a predominantly peripheral distribution and are indistinguishable from infiltrates seen in chronic eosinophilic pneumonia. Occasionally, nodular lesions may be seen in Churg-Strauss syndrome. In contrast to Wegener’s granulomatosis and microscopic polyangiitis, alveolar hemorrhage is exceedingly rare. Renal involvement in Churg-Strauss syndrome is less prominent than in Wegener’s granulomatosis and microscopic polyangiitis and does not

generally lead to renal failure. In contrast, peripheral nerve involvement, typically in the form of mononeuritis multiplex, is more frequent. Skin, heart, central nervous system, and abdominal viscera may also be involved. The classic histopathological picture consists of necrotizing vasculitis, eosinophilic tissue infiltration, and extravascular granulomas. However, not all features are found in every case, and they are not pathognomonic of the condition. Particularly the finding of a “Churg-Strauss granuloma” on skin biopsy should not be confused with the diagnosis of ChurgStrauss syndrome. While this type of necrotizing extravascular granuloma may be seen in Churg-Strauss syndrome, it may occur in other systemic autoimmune diseases, including Wegener’s granulomatosis and rheumatoid arthritis. If ANCA are present, they are usually P-ANCA reacting with MPO. The ANCA status appears to correlate with disease activity. Recent studies suggest a more vasculitic disease phenotype in the presence of ANCA, but not all studies have found this, and there remains substantial overlap of organ manifestations between patients with Churg-Strauss syndrome who are ANCA positive and those who are ANCA negative. In recent years significant attention has been devoted to Churg-Strauss syndrome detected in patients using leukotriene receptor antagonists. Available case studies and limited population-based incidence estimates suggest that these agents may lead to unmasking of vasculitic symptoms in asthmatics, by allowing dose reductions or discontinuation of oral glucocorticoid therapy. There is no evidence suggesting that these agents cause Churg-Strauss syndrome. The prognosis of Churg-Strauss syndrome is better than that of Wegener’s granulomatosis or microscopic polyangiitis, as the overall mortality is lower and not significantly different from the normal population. Most deaths are secondary to cardiac involvement.

Pathophysiology of ANCA-Associated Vasculitis The etiology of ANCA-associated vasculitis remains unknown. A genetic predisposition for autoimmunity is suspected. An association with the major histocompatibility complex documented for several autoimmune disorders has not been identified in AAV. Nevertheless, skewing in polymorphisms of immune response genes and genes encoding for ANCA target antigens and α1 -proteinase inhibitor with potential effects on disease outcome have been reported. Many clinical observations suggest that the presence or absence of ANCA as well as the specific type of ANCA (PR3ANCA versus MPO-ANCA) define the disease phenotype. Patients with limited Wegener’s granulomatosis who remain ANCA negative rarely develop systemic vasculitic disease manifestations. Patients with glomerulonephritis and PR3ANCA loose their renal function much more rapidly than patients with MPO-ANCA. Patients with PR3-ANCA also have a higher relapse rate than patients with MPO-ANCA. Experimental data and animal models support a pathogenic role of ANCA in the development of vasculitis. A couple of recent

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studies have also suggested a different clinical phenotype of ANCA-positive patients with Churg-Strauss syndrome compared with ANCA-negative patients. In Wegener’s granulomatosis, the presence of PR3ANCA appears most closely related to the development of vasculitic complications. Furthermore, systemic vasculitic relapses without recurrence of ANCA are extremely rare. Yet, remission may be maintained for extended periods of time in up to one-half of the patients despite the presence of ANCA. These clinical observations suggest that ANCA alone are not sufficient to cause disease activity, but ANCA seem to be required for the development of vasculitic complications of Wegener’s granulomatosis and systemic relapses. Many in vitro studies have demonstrated proinflammatory effects of PR3-ANCA and MPO-ANCA on neutrophils, monocytes, and endothelial cells, which enhance and perpetuate endothelial cell and tissue damage. ANCA may increase the adhesion of neutrophils to endothelial cells by enhancing the expression of cell adhesion molecules on endothelial cells. ANCA can activate primed neutrophils, resulting in the release of oxygen radicals and proteolytic enzymes. The latter may in turn induce endothelial cell apoptosis. ANCAmediated neutrophil activation involves both Fc-γ -receptor engagement and recognition of expressed target antigen on the surface of primed neutrophils. ANCA may also cause endothelial cell damage by direct cytotoxicity or localized immune complex formation with target antigens bound to the endothelial cell surface. The latter may initiate localized complement activation. Finally, ANCA are thought to contribute to the recruitment of more inflammatory cells to the area of tissue injury by stimulating the release of chemotactic chemokines and agents from neutrophils, monocytes, and endothelial cells. For a detailed description of pathways and mechanisms by which ANCA may directly and indirectly contribute to damage of the vascular endothelium, the reader is referred to other recent reviews. Many patients with ANCA-associated vasculitis relate the onset or recurrence of their disease to preceding infectious episodes. The following link to infection has been hypothesized. Most ANCA-mediated effects on neutrophils and monocytes require priming of the cells. This cytokinedependent process is not unique to vasculitis. Cytokine stimulation of neutrophils and monocytes, typically by tumor necrosis factor (TNF), with resulting increased surface expression of ANCA target antigens, occurs normally in the context of infections. Patients with active vasculitis have indeed been shown to have both increased expression of ANCA target antigens on the surface of their neutrophils and elevated levels of TNF. In combination, these observations allow the hypothesis that neutrophil priming, which occurs in response to cytokine stimulation during infection, enables ANCA to interact with their target antigen on the neutrophil surface. This in turn sets the documented proinflammatory effects of ANCA in motion, which aggravate and perpetuate the inflammatory reaction at the endothelial cell interphase. Rodent models of MPO-ANCA associated vasculitis support this hypothesis of a pathogenic role of ANCA. They

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clearly indicate that ANCA contribute directly to the development of vasculitis and glomerulonephritis, and that the interaction of ANCA with its target antigen is required for the development of lesions. Furthermore, the localization of lesions is determined by the site of this interaction. At the same time, animal models support the significance of genetic determinants for the development of autoimmunity, vasculitis, and a specific phenotype with characteristic organ involvement and histopathological features. Finally, animal model studies indicate that infections may be significant disease modifiers. Even though proinflammatory effects of murine PR3-ANCA could also be documented in vivo, the animals did not develop organ pathology typical for Wegener’s granulomatosis or microscopic polyangiitis, and good animal model for PR3ANCA associated vasculitis remains elusive. This may be due to substantial differences between human and murine PR3, as the latter behaves more like human elastase than human PR3. To date, the causes of the production and persistence of ANCA remain poorly understood. Yet infections may be instrumental for the development of this specific type of autoimmunity. ANCA directed against a broad variety of target antigens have been documented in association with viral, fungal, bacterial, and protozoal infections. In the rare instances of C-ANCA/PR3-ANCA observed in infections, the ANCA disappeared with appropriate antimicrobial therapy. These observations may suggest that ANCA can occur transiently in the setting of infection, and that the persistent ANCA response in patients with vasculitis may be the result of molecular mimicry in susceptible hosts. Subsequent diversification of T- and B-cell responses (“epitope spreading”) may lead to responses against different epitopes on the same target molecule (intramolecular spreading) or extend to other molecules (intermolecular spreading). Bacterial superantigens have also been implicated in the pathogenesis of ANCA-associated vasculitis. Wegener’s granulomatosis patients colonized with superantigen-producing S. aureus are at high risk for relapse. Wegener’s granulomatosis patients had expansion of T cell clones expressing Vβ genes specific for S. aureus superantigens more frequently than controls. This supports the theory that S. aureus contributes to the pathogenesis of vasculitis. By inducing potent T- and Bcell activity, superantigens produced during an S. aureus infection could initiate and maintain both ANCA production and cytokine release, thought to be required for the cascade that results in necrotizing granulomatous inflammation and vasculitis.

Treatment of ANCA-Associated Vasculitis Treatment of Wegener’s Granulomatosis and Microscopic Polyangiitis The first goal of therapy for patients with ANCA-associated vasculitis is to induce a remission as quickly as possible, so that irreversible organ damage is minimized. To this end, early diagnosis and prompt application of an appropriate immunosuppressive regimen are crucial. At the same time the treatment plan needs to include the prevention of

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treatment-related toxicity. Once remission has been induced, the second goal of therapy is to maintain remission with as few side effects as possible. Finally, once the patient has enjoyed a stable remission, surgical interventions aiming to repair damage may proceed as necessary. Remission Induction Therapy Remission induction therapy is best tailored to the patient’s degree of disease severity, extent, and acuity. Patients who present with indolent Wegener’s granulomatosis localized to the upper and/or lower airways and who are ANCA negative can be treated with trimethoprim/sulfamethoxazole (T/S) at a dose of 160/800 mg twice daily. The mechanism of action of T/S is unclear, but possibly related to antimicrobial effects on Staphylococcus aureus, the organism most frequently cultured from the nostrils of patients with Wegener’s granulomatosis. It is also possible that this agent has some immunemodulatory effects not shared with other antibiotics. T/S monotherapy should never be used alone in the setting of glomerulonephritis or any other severe disease manifestation, and patients treated with T/S need continued long-term observation, as some will later develop more severe disease manifestations requiring immunosuppressive therapy. Standard remission induction therapy for most patients with limited Wegener’s granulomatosis consists of oral prednisone at doses of 0.5 to 1 mg/kg per day (generally not to exceed 80 mg/day) in combination with methotrexate with a target dose of 20 to 25 mg once a week. This dose can be applied orally or subcutaneously. To minimize toxicity and the risk of Pneumocystis pneumonia (PCP), this immunosuppressive regimen should be supplemented by folic acid, 1 mg/day and standard PCP prophylaxis. Standard remission induction therapy for patients with severe disease consists of oral prednisone and oral cyclophosphamide at a dose of 2 mg/kg daily. With this regimen, remission can be achieved in up to 90 percent of patients. To minimize the risk of bone marrow toxicity the dose of cyclophosphamide should be adjusted in patients with impaired renal function, and the patient’s complete blood counts need to be monitored at least biweekly for the duration of therapy. Optimal dosing with cyclophosphamide is achieved when the lymphocyte count is reduced, but the total white blood count is maintained above 3500. To avoid bladder toxicity of cyclophosphamide, the entire dose is applied in the morning and patients are instructed to drink at least three liters of fluid per day. In patients with rapidly progressive fulminant disease, such as those presenting with alveolar hemorrhage or rapidly deteriorating renal function, intravenous methylprednisolone, 1000 mg per day for 3 to 5 days may be necessary for effective control of inflammation. If this therapy does not generate the desired effects, plasma exchange should be implemented. Remission Maintenance Therapy Once remission has been induced the prednisone dose is tapered gradually over the course of 5 to 6 months with the

goal of complete discontinuation. Patients with limited disease should be maintained on methotrexate for remission maintenance. Patients treated with cyclophosphamide for remission induction should be switched to either methotrexate or azathioprine for remission maintenance. Azathioprine is preferred in patients with any degree of renal insufficiency. Mycophenolate mofetil is an alternative for patients who can not tolerate either methotrexate or azathioprine for remission maintenance. Remission maintenance therapy is continued for at least 12 months beyond achievement of remission, and longer in patients who have suffered relapses. Early discontinuation of immunosuppressive therapy is associated with an unduly high relapse rate. Long-term remission maintenance therapy with T/S beyond immunosuppression may also be beneficial. In one study, patients who received T/S at a dose of 160/800 mg twice daily had a lower rate of disease relapse than those who received placebo. Treatment of Patients Refractory to Standard Therapy About 10 percent of patients do not respond adequately to standard therapy and fail to achieve remission. These patients are particularly challenging. Initial enthusiasm about the adjunct use of anti-TNF-α agents in such patients has vanished over the course of the last few years. The Wegener’s granulomatosis Etanercept Trial, the first multicenter, double-blind, placebo-controlled, randomized trial conducted in this disease, has shown no efficacy of etanercept when added to standard therapy. Moreover, a higher frequency of malignancies was observed in the treatment arm compared with the control arm of that trial. All patients with malignancies had also received cyclophosphamide. For this reason, the use of etanercept in patients who have received cyclophosphamide is now strongly discouraged. Smaller, uncontrolled open-label studies with infliximab conducted in Europe have suggested some efficacy of that agent, but many complicated infections were observed in these patients. Based on very encouraging preliminary results in patients with refractory Wegener’s granulomatosis who were treated with rituximab, which depletes B lymphocytes selectively, a large multicenter trial is currently being conducted that evaluates this agent as a potential alternative to cyclophosphamide for remission induction in ANCA-associated vasculitis. Supportive Therapy PCP still carries a mortality of up to 35 percent. Therefore, PCP with T/S is recommended for all non–sulfa allergic Wegener’s granulomatosis patients receiving immunosuppressive therapy. Patients who have a sulfa allergy manifesting itself with a skin rash can be desensitized against the drug. Those who fail this approach or have other contraindications for the use of this drug should be given other agents for PCP prophylaxis. Patients receiving methotrexate for remission induction or maintenance should also receive PCP. This can be safely accomplished with T/S at recommended doses for this purpose, provided that folic acid, 1 mg daily, is also given. Patients undergoing intense immunosuppression

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during the remission induction phase may also benefit from prophylactic antifungal therapy. Finally, every patient treated with glucocorticoids for ANCA-associated vasculitis should receive osteoporosis prophylaxis with calcium and vitamin D supplements and possibly bisphosphonates.

Treatment of Churg-Strauss Syndrome Even though mortality of Churg-Strauss syndrome is lower than that of Wegener’s granulomatosis or microscopic polyangiitis, the management of Churg-Strauss syndrome remains a challenge. Systemic glucocorticoids remain the mainstay of therapy. There are no clinical trials that provide clear guidance. The reports from the French Vasculitis Study Group are difficult to interpret with respect to this disease, because patients with Churg-Strauss syndrome were not separated from those with polyarteritis nodosa and microscopic polyangiitis, two diseases with distinct clinical manifestations, pathophysiology, and prognosis. Yet, these studies suggest that it is appropriate to treat Churg-Strauss syndrome according to the principles applied to the management of ANCA-associated vasculitis. Accordingly, cyclophosphamide should be added to glucocorticoids for remission induction in all patients with disease manifestations that threaten the patient’s life or the function of a vital organ, i.e., particularly those with central or peripheral nerve involvement, glomerulonephritis, heart involvement, or alveolar hemorrhage. Methotrexate, azathioprine, and mycophenolatemofetil have been used as glucocorticoid-sparing agents in less severe disease and for remission maintenance. Refractory disease and disease dominated by difficult-to-control eosinophilic inflammation may respond to interferon-α therapy. However, continued long-term interferon-α therapy may be necessary, and this treatment carries the risk of substantial toxicity.

OTHER DISORDERS PRESENTING WITH PULMONARY VASCULITIS

Pulmonary Vasculitis

identifiable cause, and it is reasonable to measure the erythrocyte sedimentation rate in such patients. Isolated cases with pleural effusion or multinodular pulmonary lesions have also been reported in giant cell arteritis. Such cases are difficult to interpret. Particularly in the latter situation, Wegener’s granulomatosis should be considered in the differential diagnosis, because it may also present with temporal arteritis.

Takayasu’s Arteritis Takayasu’s arteritis is a large vessel vasculitis affecting predominantly the aorta and its major branches in young patients. Pulmonary complications are the result of a unique arteriopathy predominantly of the large- and medium-size pulmonary vessels. Progressive defects in the outer media of the arteries and ingrowth of granulation tissue-like capillaries associated with thickened intima and subendothelial smooth muscle proliferation lead to pulmonary artery stenoses and occlusion as well as pulmonary hypertension in up to onehalf of all patients. The involvement of pulmonary arteries is common but often asymptomatic. It is detectable by conventional angiography, perfusion scan, or magnetic resonance angiography. CT may show areas of low attenuation as a result of regional hypoperfusion, subpleural reticulolinear changes, and pleural thickening. Fistula formation between pulmonary artery branches and bronchial arteries, as well as nonspecific inflammatory interstitial lung disease, has also been reported. Therapy for Takayasu’s arteritis consists primarily of immunosuppression with glucocorticoids. Other immunosuppressive agents, including methotrexate are used as in conjunction with glucocorticoids for remission induction and as glucocorticoid-sparing agents for remission maintenance. Unfortunately, many patients relapse when the glucocorticoid dose is reduced below 15 mg daily. Most recently, the use of antitumor necrosis factor-α agents has been reported as beneficial in patients who are refractory to standard therapy. Vascular bypass procedures may be beneficial in severe disease.

Giant-Cell Arteritis Giant-cell arteritis is a generalized inflammatory disorder involving large and medium-sized arteries. It is the most common form of vasculitis in the white population, and appears to affect predominantly elderly patients. Respiratory symptoms have been reported in up to 25 percent of patients. However, pulmonologists rarely see patients with giant-cell arteritis for the management of its respiratory complications. Cough, hoarseness, and throat pain usually resolve promptly with prednisone therapy. Chest roentgenograms and pulmonary function tests rarely show abnormalities attributable to the disease. Occasionally respiratory symptoms are the initial manifestations of giant-cell arteritis. Therefore, this possibility should be considered in any elderly patient with new onset of cough, hoarseness, or throat pain without other

Classic Polyarteritis Nodosa Since its formal separation from microscopic polyangiitis, this form of vasculitis affecting predominantly medium-sized vessels is diagnosed rarely. Because it does not affect capillaries, it does not cause either glomerulonephritis or alveolar hemorrhage. However, classic polyarteritis nodosa can affect the bronchial or bronchiolar arteries on rare occasions. Most cases of classic polyarteritis nodosa diagnosed today are associated with viral infections, specifically hepatitis B and C. Consequently, antiviral therapy plays a prominent role in the management of such cases in addition to immunosuppression. Classic polyarteritis nodosa is far less likely to relapse than microscopic polyangiitis, and therefore can generally be treated with a shorter course of immunosuppression.

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Behçet’s Disease Behçet’s disease is a rare chronically relapsing systemic inflammatory disorder characterized by aphthous oral ulcers and at least two or more of the following: aphthous genital ulcers, uveitis, cutaneous nodules or pustules, or meningoencephalitis. Respiratory manifestations are common in Behçet’s disease and include cough, hemoptysis, chest pain, and dyspnea. Hemoptysis is often massive and fatal. The vasculitis of Behçet’s disease is immune complex–mediated, and may affect vessels of all sizes. If the veins are affected secondary thrombosis with major venous occlusion can occur. This type of thrombosis may not be preventable by anticoagulation, but the use of aspirin 80 mg/day has been advocated. Massive hemoptysis is the result of destruction of the elastic lamina of pulmonary arteries leading to the characteristic aneurysm formation, secondary erosion of bronchi, and arterial-bronchial fistulae. Pulmonary artery aneurysms are detectable by CT or MR angiography, and pulmonary angiography is no longer necessary. Recurrent pneumonia as well as bronchial obstruction as a consequence of mucosal inflammation has also been described. Therapy of the underlying disease consists of immunosuppression. Prednisone alone may not be sufficient to control the vasculitis. The addition of other drugs, such as colchicine, chlorambucil, methotrexate, cyclosporin, or azathioprine is recommended. The addition of azathioprine or cyclophosphamide to glucocorticoids has resulted in resolution of pulmonary aneurysms. Once pulmonary arteritis has been identified in these patients, anticoagulation should be avoided. The prognosis of pulmonary involvement is poor. About one-third of patients die within 2 years of developing pulmonary involvement, most from fatal pulmonary hemorrhage. Embolization therapy may be used as treatment and prevention of hemorrhage from pulmonary artery aneurysms.

Idiopathic Pauci-immune Pulmonary Capillaritis Diffuse alveolar hemorrhage as a result of capillaritis in the absence of symptoms or serologic evidence of any detectable underlying systemic disorder may occur rarely. Direct immunofluorescence studies of the lung tissue did not reveal any immune deposits. This isolated pauci-immune pulmonary capillaritis is histopathologically indistinguishable from that of ANCA-associated vasculitis. It is a diagnosis of exclusion, and such patients are best treated with an immunosuppressive regimen according to the guidelines for severe Wegener’s granulomatosis or microscopic polyangiitis.

Systemic Lupus Erythematosus and Other Collagen Vascular Disorders The disease manifestations of systemic lupus erythematosus (SLE) are highly variable. Pulmonary capillaritis leading to diffuse alveolar hemorrhage is rare in patients with SLE. However, it represents one of the most serious complications

Figure 83-18 Lung biopsy of a patient with lupus erythematosus and alveolar hemorrhage showing so-called lumpy, bumpy deposition of immune complexes as demonstrated by direct immunofluorescence.

of the disease. In contrast to the pauci-immune pathology of ANCA-associated vasculitis, prominent immune complex deposits can be detected by direct immunofluorescence in the affected tissue of patients with SLE (Fig. 83-18). Hence, the development of pulmonary capillaritis in systemic lupus erythematosus is thought to be immune complex mediated. The onset of diffuse alveolar hemorrhage in patients with SLE is usually abrupt, and it is seldom the first sign of SLE. In the overwhelming majority of patients the rapid development of pulmonary infiltrates is associated with fever. Hemoptysis may be absent in up to one-half of the patients. Consequently, the differentiation of diffuse alveolar hemorrhage from infection may be difficult in patients with SLE, and may require a diagnostic bronchoalveolar lavage. Mechanical ventilation, infection, and cyclophosphamide therapy were identified as negative prognostic factors in one cohort. However, no multivariate analysis was performed, and these factors may simply identify patients with more severe disease. The reported mortality from diffuse alveolar hemorrhage in SLE varies widely, between 0 and 90 percent. Treatment consists of glucocorticoids and cyclophosphamide. The use of plasma exchange has been suggested, but its benefit remains unproved. Respiratory complications are very common in all other types of collagen vascular or connective tissue disorders. However, pulmonary capillaritis presenting as diffuse alveolar hemorrhage is rare. Isolated cases have been reported with polymyositis, rheumatoid arthritis, and mixed connective tissue disease. Consequently, serologic testing performed as part of an evaluation of diffuse alveolar hemorrhage should

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include studies aimed at the identification of these potential underlying disease entities.

Antiphospholipid Syndrome Antiphospholipid syndrome is defined by arterial and venous thromboses, or recurrent miscarriages occurring in patients with antiphospholipid antibodies (anticardiolipin antibodies, lupus anticoagulant, or both). If antiphospholipid syndrome in the context of another autoimmune disease, malignancy, or drug exposure, it is labeled secondary antiphospholipid syndrome. In the absence of other coexisting disorders, it is considered primary. Hypercoagulability can cause pulmonary embolism and infarction, pulmonary microthrombosis, and pulmonary arterial thrombosis with secondary pulmonary hypertension as consequence. However, primary pulmonary hypertension has also been reported in antiphospholipid syndrome. Acute respiratory distress syndrome (ARDS) is another possible complication of antiphospholipid syndrome. Antiphospholipid syndrome can also be complicated by diffuse alveolar hemorrhage, presenting with cough, dyspnea, fever, and bilateral pulmonary infiltrates. Because of this nonspecific clinical presentation, the possible occurrence of diffuse alveolar hemorrhage in the context of ARDS, and the lack of hemoptysis in over one-half of the reported antiphospholipid syndrome patients with alveolar hemorrhage, and early bronchoalveolar lavage may help in the differential diagnosis. Tissue necrosis from microthrombosis as well as pulmonary capillaritis has been implicated as the cause of alveolar hemorrhage in antiphospholipid syndrome. As in SLE, the capillaritis of antiphospholipid syndrome appears to be immune complex–mediated. Most patients respond to glucocorticoids. Yet, the coexistence of thrombosis and capillaritis with alveolar hemorrhage represents a therapeutic dilemma, as anticoagulation may need to be interrupted to control the hemorrhage. Early plasma-exchange in addition to immunosuppressive therapy should be considered in patients with antiphospholipid syndrome and alveolar hemorrhage.

Antiglomerular Basement Membrane Disease Historically the syndrome of alveolar hemorrhage and glomerulonephritis has been called Goodpasture’s syndrome. Today’s terminology restricts the use of the term Goodpasture’s disease to alveolar hemorrhage or necrotizing glomerulonephritis caused by autoantibodies directed against the NC1-domain of the α3 chain of basement membrane collagen type IV. This epitope is only accessible for autoantibodies in the basement membranes of kidneys and lungs. Diffuse alveolar hemorrhage is common in anti-GBM disease, but is thought to require an additional inhalational injury, particularly smoking for the development of the pulmonary manifestation of this disease. Isolated alveolar hemorrhage in the absence of renal disease is rare in anti-GBM disease. The finding of circulating anti-GBM autoantibodies in the serum may facilitate the early implementation of appropriate ther-

Figure 83-19 Kidney biopsy of a patient with Goodpasture’s syndrome showing linear immunofluorescence of the glomerular basement membrane due to fixation of IgG anti-GBM antibodies.

apy. However, methods used for their detection are of highly variable sensitivity and specificity, and a definitive diagnosis depends on the documentation of linear anti-GBM deposits in the kidney or lung (Fig. 83-19). In most patients, tissue from the kidney is more easily accessible for histopathological evaluation than lung tissue. Anti-GBM is arguably not a vasculitis. Bland pulmonary hemorrhage is the most frequently described histopathological pattern in diffuse alveolar hemorrhage associated with anti-GBM disease. However, capillaritis as a secondary histopathological feature has been encountered in some patients. Early implementation of immunosuppressive therapy in conjunction with plasma exchange is the key to a favorable outcome in patients with anti-GBM disease.

Henoch-Schönlein Purpura Pulmonary manifestations of Henoch-Schönlein purpura are rare. Only 26 cases have been reported to date, and capillaritis has been documented histopathologically only in a minority of them. IgA deposits along the pulmonary capillary walls, analogous to those found in vessels of the skin and glomeruli of affected kidneys are pathognomonic features of Henoch-Schönlein purpura, detectable by direct immunofluorescence.

Drug-Induced Vasculitis The list of drugs described in association with vasculitis includes a long list of therapeutic agents as well as drugs of abuse. The clinical spectrum of drug-induced vasculitis ranges from isolated and mild vasculitis of the skin to severe multiorgan system disease. Small to medium-sized vessels are usually affected. Based on clinical manifestations, drug-induced vasculitis cannot be distinguished from the primary vasculitis syndromes.

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Figure 83-20 Low-power photomicrograph of lung revealing coalescing necrotizing granulomas in a patient with necrotizing sarcoid granulomatosis.

The following drug-induced syndromes merit special attention. First, a variety of drugs including propyl-thiouracil, d-penicillamine, hydralazine, sulfasalazine, minocycline, allopurinol, and others can induce an ANCA-associated vasculitis. Pulmonary capillaritis as a manifestation of an ANCA-associated vasculitis induced by these agents is well documented. Drug-induced ANCA-associated vasculitis should be treated with immunosuppression according to the principles for primary ANCA-associated vasculitis. However, once the offending drug has been eliminated, the likelihood of a relapse seems low. The use of all-trans-retinoic acid in acute promyelocytic leukemia can cause a syndrome of fever, leukocytosis, fluid retention, hemorrhage, thrombosis, and organ failure. Pulmonary complications of this syndrome are frequent, and pulmonary capillaritis has been reported in this context. Some chronic nasal cocaine abusers develop severe midline destructive lesions. In its early stage, such a lesion is clinically and histopathologically difficult to differentiate from limited Wegener’s granulomatosis, particularly in patients who do not volunteer the history of abuse. The presence of ANCA reacting with human neutrophil elastase appears to be an immunologic marker separating patients with cocaine-induced midline destructive lesions from those with Wegener’s granulomatosis.

Pulmonary Capillaritis after Lung Transplantation Five cases of acute rejection after lung transplantation with prominent pulmonary capillaritis, histopathologically distinct from typical rejection, have been reported. In these cases, the capillaritis was thought to represent a form of severe, acute vascular rejection. Early histologic diagnosis and aggressive immunosuppression, possibly in conjunction with plasma

exchange, was suggested to control the inflammatory activity and prevent relapses.

Necrotizing Sarcoid Granulomatosis Vasculitis is a prominent histopathological feature of necrotizing sarcoid granulomatosis. The disease is usually limited to the lungs. The characteristic pulmonary nodules are bilateral, and may be an incidental finding in asymptomatic patients. Alternatively, patients may complain of cough, dyspnea, or phlegm production. Generalized constitutional symptoms occur rarely. The differential diagnosis of necrotizing sarcoid granulomatosis includes primarily infectious processes. Special sputum and tissue stains and cultures should always be obtained to exclude mycobacterial or fungal disease. Clinically, these patients are difficult to differentiate from limited Wegener’s granulomatosis. Histopathologically, there are characteristic necrotizing epithelioid granulomas that may form aggregates (Fig. 83-20). In contrast to Wegener’s granulomatosis, these granulomas are well circumscribed. Vasculitis is a central histopathological feature of necrotizing sarcoid granulomatosis. Liebow originally described three types of vasculitis: an epithelioid-granulomatous form, a form reminiscent of giant-cell arteritis with prominent histiocytes and multinucleated giant cells in the inflammatory infiltrate of the vessel wall, and a lymphocytic form lacking granuloma formation and giant cells. The separation from sarcoidosis remains controversial. Yet, the extensive vasculitis and necrosis seen in necrotizing sarcoid granulomatosis are unusual for sarcoidosis. The chest roentgenographic appearance of pulmonary nodules, or masses and pleural involvement are also atypical for sarcoidosis. Finally, extrapulmonary involvement has only rarely been documented in necrotizing sarcoid granulomatosis. It is debatable whether necrotizing sarcoid granulomatosis should be included with the systemic vasculitides.

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Most authors would argue against this inclusion because of its limitation to the lungs and good prognosis (spontaneous remission may occur). Therapeutically, necrotizing sarcoid granulomatosis can be approached as cases with chronic pulmonary sarcoidosis. Decisions about the use of oral glucocorticoid therapy should be individualized based on symptoms, pulmonary function data, and their evolution over time.

SUGGESTED READING Boomsma MM, Stegeman CA, van der Leij MJ, et al: Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels. A prospective study. Arthritis Rheum 43:2025–2033, 2000. Capizzi SA, Specks U: Does infection play a role in the pathogenesis of pulmonary vasculitis? Semin Respir Infect 18:17– 22, 2003. Choi HK, Merkel PA, Walker AM, et al: Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: Prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum 43:405– 413, 2000. Daum DE, Specks U, Colby TV, et al: Tracheobronchial involvement in Wegener’s granulomatosis. Am J Respir Crit Care Med 151:522–526, 1995. De Groot K, Rasmussen N, Bacon PA, et al: Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52:2461– 2469, 2005. Espinosa G, Cervera R, Font J, et al: The lung in the antiphospholipid syndrome. Ann Rheum Dis 61:195–198, 2002. Guillevin L, Durand-Gasselin B, Cevallos R, et al: Microscopic polyangiitis: Clinical and laboratory findings in eighty-five patients. Arthritis Rheum 42:421–430, 1999. Hunder GG, Arend WP, Bloch DA, et al: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 33:1065–1067, 1990. Jayne D, Rasmussen N, Andrassy K, et al: A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 349:36–44, 2003. Jennette JC, Falk RJ, Andrassy K, et al: Nomenclature of systemic vasculitides: The proposal of an international consensus conference. Arthritis Rheum 37:187–192, 1994.

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Jennings CA, King TE Jr, Tuder R, et al: Diffuse alveolar hemorrhage with underlying isolated, pauciimmune pulmonary capillaritis. Am J Respir Crit Care Med 155:1101– 1109, 1997. Keogh KA, Specks U. Churg-Strauss syndrome. Clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 115:284–290, 2003. Keogh KA, Ytterberg SR, Fervenza FC, et al: Rituximab for refractory Wegener’s granulomatosis: Report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 173:180–187, 2006. Levy JB, Turner AN, Rees AJ, et al: Long-term outcome of antiglomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 134:1033–1042, 2001. Nadrous HF, Yu AC, Specks U, et al: Pulmonary involvement in Henoch-Sch¨onlein purpura. Mayo Clin Proc 79:1151– 1157, 2004. Santos-Ocampo AS, Mandell BF, Fessler BJ: Alveolar hemorrhage in systemic lupus erythematosus: Presentation and management. Chest 118:1083–1090, 2000. Seo P, Stone JH: Large-vessel vasculitis. Arthritis Rheum 51:128–139, 2004. Sinico RA, Di Toma L, Maggiore U, et al: Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum 52:2926– 2935, 2005. Specks U: Antineutrophil cytoplasmic antibodies: Are they pathogenic? Clin Exp Rheumatol 2004;22:S7–12. Specks U: Methotrexate for Wegener’s granulomatosis: What is the evidence? Arthritis Rheum 52:2237–2242, 2005. Stegeman CA, Cohen Tervaert JW, et al: Trimethoprimsulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. N Engl J Med 335:16–20, 1996. Trimarchi M, Gregorini G, Facchetti F, et al: Cocaineinduced midline destructive lesions: Clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener granulomatosis. Medicine (Baltimore) 80:391–404, 2001. Uzun O, Akpolat T, Erkan L: Pulmonary vasculitis in Behc¸et disease: A cumulative analysis. Chest 127:2243–2253, 2005. Watts RA, Scott DG: Epidemiology of the vasculitides. Semin Respir Crit Care Med 25:455–464, 2004. The WGET Research Group: Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351– 361, 2005.

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84 Pulmonary Arteriovenous Malformations Daniel M. Goodenberger

I. HISTORY II. PATHOPHYSIOLOGY Structure Number Size Location Causes and Disease Associations Other Associations III. GENETICS

V. CLINICAL DIAGNOSIS Evaluation of a Radiographic Abnormality Screening of Probands or Relatives VI. COMPLICATIONS Pulmonary Complications Central Nervous System Complications Miscellaneous Complications VII. TREATMENT VIII. PROGNOSIS

IV. CLINICAL PRESENTATION

HISTORY Pulmonary arteriovenous malformations (PAVMs) were first described relatively recently in medical history; Churton reported the autopsy findings in a young boy with cyanosis in 1897. PAVMs were first diagnosed during life in 1939. As in many later cases, clubbing and polycythemia were present in a 40-year-old man. Based on the correlation of physical with postmortem findings, the triad of cyanosis, clubbing, and polycythemia was identified with PAVM in 1932. Hereditary hemorrhagic telangiectasia (HHT) was first connected to pulmonary arteriovenous malformation in 1938. As described in the following, HHT is often intimately related to PAVMs—a fact that prompts the subsequent discussion of the history of HHT. Hereditary epistaxis was first described in 1864, although neither that nor Babbington’s description a year later reports an association with telangiectasia. These reports were not generally recognized; nor were subsequent descriptions of telangiectasia, hereditary transmission, and epistaxis by Legg in 1876, or a similar kindred reported by Chiari in 1887. The first widely recognized connection of epistaxis to telangiectasia was made by Rendu in 1896. Osler added three cases, and recognized familial occurrence in 1901. Weber elu-

cidated the familial nature and lack of coagulation abnormality, and thus earned his eponymic association. By precedence of description, this eponym should be Rendu-Osler-Weber, even though Osler-Weber-Rendu is the most common usage. Hanes was responsible for naming the syndrome hereditary hemorrhagic telangiectasia, the designation now most often preferred, in 1909.

PATHOPHYSIOLOGY Structure By far the most common form of PAVM has a pulmonary arterial supply and pulmonary venous drainage. In one series, 60 of 63 PAVMs had a pulmonary arterial blood supply. This is similar to our experience, although we have been consulted on two patients with PAVMs in whom the arterial supply originated from the internal mammary artery. Approximately 80 percent of PAVMs have a single feeding and a single draining vessel; the remaining 20 percent are complex, with two or more of each. PAVMs appear to develop between precapillary arterioles and venules, with intervening epithelial dysplasia. After development, they are clusters of dilated,

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tortuous vessels with both arterial and venous elements with no intervening capillary beds.

Number In one series, more than one-third of the patients had two or more PAVMs. In general, multiple PAVMs correlate with HHT; in the experience of our clinic, most patients with HHT have more than one PAVM. A small percentage have diffuse, multilobar PAVMs.

many as 44 to 60 percent may have positive contrast echocardiography indicative of intrapulmonary shunt; many of these patients have shunt eliminated by liver transplantation. A PAVM of significant size, known as a Rasmussen aneurysm, may also develop as a result of tuberculosis. Metastatic thyroid carcinoma, a highly vascular tumor, may mimic pulmonary arteriovenous fistula.

GENETICS Size PAVMs may vary from malformations too small to be seen by radiography or angiography to those greater than 5 cm in diameter.

Location Up to 65 percent of PAVMs are located in the lower lobes—a phenomenon that may be due to the increased pulmonary blood flow and pressure, and subsequent “stretch” due to hydrodynamic forces. This location is probably the cause of the often associated orthodeoxia (desaturation in an upright position) and platypnea (dyspnea in an upright position). These symptoms may also occur with cirrhosis, which evidences the pulmonary vascular abnormalities described in the following. Location may also account for an increase in right-to-left shunt which occurs at total lung capacity. PAVMs have been observed to increase in size during pregnancy (Fig. 84-1). This supports the blood flow hypothesis, due to the increased blood volume and hyperdynamic state of pregnancy, although endocrine factors may also have an influence.

Causes and Disease Associations Early observers thought that all PAVMs were due to HHT. The estimates of frequency of PAVMs due to HHT have varied substantially, from 36 to 95 percent. Estimates of the percentage of patients with HHT who have associated PAVMs have varied widely. Various series have reported frequencies of 15, 20, 24, 33, 49, and 57 percent. As noted, the proportion of PAVMs that are multiple has been reported to be approximately one-third; multiple PAVMs are highly associated with HHT. Of note is that the homozygous form of HHT appears to be lethal, resulting either in miscarriage or neonatal death, associated with explosive growth of mucocutaneous telangiectasias and diffuse PAVMs.

Other Associations Cirrhosis may result in diffuse small arteriovenous connections. Nearly all such patients have cutaneous spider angiomas. The right-to-left shunt is probably due not to true PAVMs but, rather, to vasodilation of pleural vessels, which resemble the cutaneous spiders, and increased numbers of peripheral small arteriolar branches with precapillary arterioleto-venous connections in the peripheral respiratory lobule. As

The genetic basis, if any, of isolated PAVMs remains unknown. HHT is an autosomal dominant disease. Its frequency was believed until relatively recently to be less than 3 per 100,000 people. Newer studies suggest a much higher prevalence. The highest frequency reported, 1:1331, occurs in the AfroCaribbean population of the Netherlands Antilles, presumably due to a founder effect. Other estimates vary geographically; 1:6410 in Denmark, 1:8,000 in Japan, and 1:16,500 in Vermont. Phenotypic variation is extreme, ranging from asymptomatic to severely symptomatic, and from cases with no or few mucocutaneous lesions to those with diffuse cutaneous telangiectasias. For many patients, the disease remains undiagnosed by their primary care physicians, suggesting that disease frequency may be greater than reported, and that some patients with “isolated” PAVMs may actually have HHT. A gene for HHT was first localized to chromosome 9, region q33−34 (9 q33−34 ). Investigation revealed the protein product to be endoglin, which associates with different signaling receptors and can modify TGF-β-1 signaling. The same work showed the disease to be genetically heterogeneous, with multiple mutations in the responsible gene. It rapidly became clear that there were other chromosomal mutations resulting in the same syndrome, and the endoglin mutation disease was designated HHT-I. It was noted to be associated more often with PAVMs than were those with non-9q3 mutations. A haploinsufficient mouse model also demonstrated phenotypic heterogeneity that was very dependent on the genetic background. The activin receptor-like kinase 1 gene (ALK-1 or ACVRL1) on chromosome 12 is the second locus for hereditary hemorrhagic telangiectasia. It produces a transforming growth factor (TGF)-β superfamily type I receptor. Mice heterozygous for a loss-of-function mutation in ALK-1 develop age-dependent vascular lesions in the skin, extremities, oral cavity and in the lung, liver, intestine, spleen and brain, similar to those seen in HHT patients. Disease resulting from mutations in this gene has been designated HHT-2. A small number of patients with juvenile polyposis also have hereditary hemorrhagic telangiectasia.This appears to be due to mutations in MADH4 (encoding SMAD4); SMAD proteins influence the cellular response to TGF-β. A fourth gene abnormality producing clinical HHT in a family on has been described on chromosome 5. The gene product is as yet unidentified.

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Figure 84-1 Pulmonary arteriovenous fistulas in a pregnant 24-year-old woman with hereditary hemorrhagic telangiectasia. A. Before pregnancy. Small nodular densities are seen at both bases and in the left hilus. The shunt was estimated to be 49 percent of the cardiac output. B. Arteriogram before pregnancy demonstrates arteriovenous fistulas of both lower lobes. C. Seven months pregnant, the patient was admitted to the hospital with hemoptysis and left hemothorax. The enlargement of the arteriovenous fistulas is striking. The pregnancy was terminated. D. Two weeks after termination of pregnancy, the nodular densities have decreased in size. (Courtesy of Dr. M. Rossman.)

A fifth genetic abnormality in a family with HHT has been described on the short arm of chromosome 7. The gene product of this mutation is also unknown at present. Most HHT appears to be caused by mutations in endoglin and ALK-1. Mutations can be identified in up to 88 percent affected individuals; in one series, 61 percent were in endoglin, 37 percent in ALK-1, and 2 percent in MADH4. ALK-1 mutations appear to be more common in France and Italy, with endoglin mutations more frequent in northern

Europe and North America. Pulmonary arteriovenous malformations are more frequent and on the average of larger size in HHT1.

CLINICAL PRESENTATION The occurrence and frequency of symptoms related to PAVMs depend on how the patients are found; that is, whether they

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present with manifestations of disease or they are discovered as a result of screening. The asymptomatic state is most common when screening is the method of detection, with an incidence typically between 25 and 59 percent. The age at onset is usually in the third or fourth decade. The mean age at detection in various series is remarkably constant at 38 to 40 years. In one series, the patients ranged in age from 5 to 76 years, with a mean of 36; 26 percent presented at an age less than 21 years. However, PAVMs are uncommon in childhood; only 4 percent of affected persons are under 10. Twenty-five to fiftyeight percent of patients are asymptomatic. Pulmonary symptoms include dyspnea on exertion, with a frequency ranging from 27 to 71 percent. Platypnea and orthodeoxia also may occur. Hemoptysis ranges in frequency from 4 to 18 percent. Extrapulmonary symptoms include chest pain in 6 percent and epistaxis (largely seen in HHT), ranging from 32 to 85 percent. The mean age at onset of epistaxis in HHT is 12 years, with 54 percent of patients presenting by age 10. Severity of epistaxis ranges from mild to severe, with up to 45 episodes per month. Headache is also remarkably common in HHT patients, occurring in 43 percent. Transient ischemic attack occurs in up to 57 percent of patients with PAVM, and symptomatic cerebrovascular accident in 18 percent. Physical signs caused by the PAVM itself are relatively uncommon. As many as 25 percent of patients may exhibit no findings at all. Hypoxemia, when present, is secondary to the right-to-left shunt, and may result in cyanosis and secondary polycythemia. This tends to occur in advanced disease, and has been reported in 9 to 73 percent (mean, 30 percent). The frequency of clubbing has been reported in an average of 32 percent; it is much less common in our experience. Clubbing is nearly always associated with cyanosis. Clubbing may resolve after the PAVM is removed or occluded. A pulmonary bruit, which is often described, is also variable; its frequency, probably influenced by selection bias, ranges from less than 10 percent to 58 percent. Telangiectasia have been reported in up to 66 percent of patients with PAVM, depending on the frequency of HHT. These small red vascular blemishes occur most frequently on the face, followed in descending order by the lips, nares, tongue, ears, hands, chest, and feet. They often increase in size and number with age, and cutaneous telangiectasias are seldom identifiable until the second or third decade. We have been struck by the frequency with which classic tongue and lip telangiectasias have been passed off as nonspecific blemishes by primary care physicians. Laboratory results are nonspecific. A complete blood count may show polycythemia, although this tendency may be overshadowed by iron deficiency anemia in patients with HHT. Anemia was present in 94 of 292 (34 percent) in our series. This was more often due to GI bleeding when severe. GI blood loss of variable severity was present in 65 of 292 (22 percent). The severely affected person may have arterial hypoxemia at rest; those less severely affected may have orthodeoxia documented by supine and upright arterial blood gases. Ar-

terial blood gases, determined on blood samples drawn while the patient is breathing room air, followed by 100 percent oxygen, may reveal a significant right-to-left shunt.

CLINICAL DIAGNOSIS Early in the history of this disorder, the diagnosis was made only when it was advanced, when polycythemia and clubbing were present, or after death. Currently, making the diagnosis requires clinical suspicion in the appropriate clinical setting. Diagnosis is approached differently in the two most common situations.

Evaluation of a Radiographic Abnormality Earlier techniques for determining that a pulmonary nodule detected as an incidental finding was a pulmonary arteriovenous malformation were principally radiographic. Fluoroscopy might reveal the nodule to be pulsatile; a MÂ¨uller maneuver might cause the lesion to decrease in size, and a Valsalva maneuver might cause it to increase in size. Laminography typically revealed the lesion to be a grapelike cluster, with visible feeding and draining vessels. Computed tomography (CT) scan of the chest with contrast enhancement may show the typical lesion with feeding and draining veins (Fig. 84-2), but vascular tumors may cause false-positive results. A perfusion lung scan may detect a right-to-left shunt. Ordinarily, 95 percent of the technetiumlabeled macroaggregated albumin, with an average diameter of approximately 35 Âľ, is trapped in the pulmonary capillaries. When there is an intracardiac or intrapulmonary shunt, unusually large amounts may pass through the lung and travel to the brain and kidneys, resulting in excess radioactivity in those areas. However, this method cannot differentiate intracardiac from intrapulmonary shunt. Echocardiography, using indocyanine green as a contrast material, was found to be effective in the diagnosis of intrapulmonary shunt, with delayed appearance of the contrast material in the left side of the heart. This was rapidly improved by the use of agitated saline as contrast (Fig. 84-3). The intrapulmonary nature of the shunt can be determined by the delay, averaging four to five cardiac cycles, of left heart contrast appearance; when the echo is performed transesophageally, the region of a radiographically undetectable PAVM may be inferred by the appearance of contrast in one or another pulmonary vein. If contrast echocardiography is negative, a PAVM is very unlikely, and an alternative cause of the pulmonary nodule should be sought. On rare occasions, if the PAVM is fed by a systemic artery, the contrast echocardiogram is negative, and pulmonary angiography should be undertaken if suspicion is high. If the contrast echocardiogram is positive, the definitive test is pulmonary angiography. Angiography is 100 percent sensitive in our experience, with correct application of the appropriate views, for vessels of 2 mm or more. However, experience elsewhere has not always been concordant with ours (vide infra).

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Figure 84-2 Characteristic CT image appearance of PAVM in left hemithorax. Portions of two PAVMs are seen in right hemithorax.

Figure 84-3 Echocardiographic images using saline contrast: A. Before contrast. B. Right-sided chamber opacification. C. Delayed high-degree left-sided chamber opacification indicative of large intrapulmonary shunt.

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Figure 84-3 (Continued)

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enabled identification of more than 98 percent of PAVMs and was superior to pulmonary angiography. CT has also been advocated for pre-therapy planning. Our experience has been somewhat less favorable; among 15 patients with CTs showing PAVMs, 20 percent had PAVMs missed, representing 42 percent of PAVMs in those patients. CTs interpreted as negative were falsely negative in 6 of 9 patients, representing 10 PAVMs. Gradient-echo magnetic resonance imaging (MRI) shows promise, but it can mistake tumors for PAVMs. Gadolinium contrast-enhanced pulmonary magnetic resonance angiography (CEMRA) detected 79 percent of PAVMs found by helical CT, and all of those with a feeding artery diameter of at least 3 mm (i.e., PAVMs with clinical consequences). Arterial blood gases, determined on samples drawn while the patient is supine and upright, have been advocated for screening. However, this technique has not proved

Figure 84-4 Example of PAVM not seen on standard chest radiography. Right pulmonary angiogram showing small PAVM (arrow).

Screening of Probands or Relatives Because the majority of PAVMs occur in HHT, it is important to evaluate individuals with PAVMs for HHT, and to screen individuals with HHT for PAVMs. Criteria for diagnosis of HHT include: (1) spontaneous and recurrent epistaxis; (2) multiple characteristic telangiectasia (typically found on lips, tongue, malar eminence, pinnae, and digits); (3) visceral lesions (gastrointestinal telangiectasia with or without gastrointestinal bleeding, pulmonary arteriovenous malformations, hepatic arteriovenous malformations, and cerebral arteriovenous malformations); (4) family history with a first-degree relative with HHT. In addition, relatives of patients with HHT should be evaluated for that diagnosis and screened for PAVMs. The best approach to screening is a subject of considerable discussion in the literature, and the approach at HHT centers of excellence varies somewhat. The discussion that follows summarizes the evidence for various screening tests, and is followed by a description of the approach at the Washington University HHT Center. The reported sensitivity of chest radiographs varies widely, depending on whether they are used for screening or in patients with symptomatic disease. Rates of abnormality on the chest radiograph range from 41 to 100 percent. In our experience, chest radiography does not reliably detect PAVMs less than 20 mm in size (Fig. 84-4), and it may miss larger PAVMs when they are located in radiographically inopportune places, such as the costophrenic sulci, the retrocardiac region, or the proximal hila (Fig. 84-5). The sensitivity and specificity of chest CT are unknown, although this modality appears to be more sensitive than are chest radiographs. One early study suggested that CT

Figure 84-5 Example of patient with PAVMs that were not seen on standard radiography but were detected by echocardiographic screening: A. Before embolization. B. Angiogram. C. After embolization, showing both coil and balloon emboli.

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Figure 84-5 (Continued)

useful. Various combinations of shunt measurement using albumin microspheres labeled with 99m Tc, PaO2 on room air, shunt measurement in subjects breathing 100 percent oxygen, and erect oxygen saturation measurement have been used, but all have insufficient sensitivity, specificity, or both. Contrast echocardiography is more sensitive than symptoms, plain radiography, measurements of SaO2 , PaO2 on room air, and Pa O2 breathing 100 percent oxygen. It is positive in 55 to 73 percent of patients. and may be the only positive screening study in 31 percent of patients. Up to 80 percent have persistently positive contrast echo findings after undergoing embolotherapy. In patients with diffuse small PAVMs or telangiectasia, transephogeal contrast echocardiographymay provides the definitive evidence. Based on this information, a screening algorithm based on contrast echocardiography and anteroposterior chest radiograph, followed by chest CT if ei-

ther test is positive, is used in many centers. This algorithm is based on studies in which CT without contrast was used as the gold standard, with confirmatory pulmonary angiogram only if positive. However, for many years our center has followed a scheme in which patients with HHT are screened with saline contrast echocardiography. Those with positive findings undergo pulmonary angiography. This approach identified PAVMs in 57 percent of patients screened. In combination with our observations regarding false-negative chest CT, we believe the frequency of PAVMs identified greater than in any other series justifies this approach. In approximately 15 percent of patients with angiographically detectable PAVMs using this approach, no therapeutic embolization results. These PAVMs represent an opportunity to more fully understand the natural history and complication rates of PAVMs.

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Figure 84-6 Aâ&#x20AC;&#x201C;C Three-dimensional reconstruction of PAVMs on 64-row multidetector array CT.

Technology is having an impact on this approach. 64row multi-detector array chest CT with reconstruction is under evaluation in our center as an alternative to angiography. Preliminary results in more than 60 patients suggests that this technique is at least equivalent to pulmonary angiography (Fig. 84-6).

COMPLICATIONS Pulmonary Complications Significant hemoptysis occurs in fewer than 10 percent of patients; in our most recent series, it occurred in 5 of 142 (less than 4 percent). Two of five occurred during pregnancy. It may be massive and life threatening. Bronchial telangiectasias

may be the cause, but all cases in untreated patients in our experience have been due to PAVMs. An increasingly frequent problem in recent years is hemoptysis following extensive embolotherapy after a delay of months to years. This has generally been due to post-embolization bronchial collateral formation. Hemothorax has been reported in up to 9 percent of patients, but is usually less than 2 percent. Pregnancy may cause PAVMs to enlarge, and has been associated with hemothorax on several occasions. Hemothorax may also occur without any other predisposing factors, presumably caused by rupture of large subpleural PAVMs into the pleural space. Pulmonary hypertension is uncommon. Patients with PPH in HHT have ALK-1 mutations rather than mutations in the bone morphogenetic protein receptor type II (BMPR2) gene.

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Central Nervous System Complications The pulmonary capillary vascular bed appears to be an important filter for otherwise asymptomatic small emboli, and may also have a significant role in cleansing the bloodstream during transient bacteremias. Most neurologic complications, which occur in 8 to 12 percent of patients with HHT, are complications of PAVMs. In one series, 60 percent were due to PAVM, including brain abscess, paradoxical embolus, and hypoxemia. Transient ischemic attacks occur in approximately 37 percent of patients with PAVMs. PAVMs can cause symptomatic cerebrovascular accidents (Fig. 84-7); the frequency of this complication ranges from 6 to 27 percent. In our clinic, 28 of 132 patients screened by MRI had evidence of prior paradoxical embolic stroke. Unfortunately, paradoxical embolization to the brain may be the first manifestation of an occult pulmonary venous malformation. This has been a particularly regrettable repetitive problem in young women taking oral contraceptives while smoking. Brain abscess occurs in 3 to 10 percent of patients with PAVMs. In a series in our clinic, 5/132 (4 percent) had prior brain abscess. Up to 1 percent of HHT patients may have brain abscesses (1000 times the incidence in the general population). In one series, 5 of 31 patients had recurrent abscess;

Figure 84-8 PAVM detected in patient with HHT after initial presentation with brain abscess: The pulmonary angiogram and lateral chest radiographs were read as normal on several examinations. Right pulmonary angiogram with inferomedial PAVM (arrows).

Figure 84-7 Right-sided pulmonary angiogram showing multiple PAVMs in a middle-aged man with clubbing, polycythemia, and CT evidence of several prior strokes.

in another, 6 of 128. Up to 8 percent of brain abscesses in the general population may be due to PAVMs. Unfortunately, brain abscess may also be the first symptom of an occult PAVM (Fig. 84-8), and many years may elapse before diagnosis of PAVM (Fig. 84-9). Most occur following dental work. For that reason, antibiotic prophylaxis following the standard American Heart Association protocol for prevention of endocarditis is recommended. Migraine is more common in HHT than in the general population, and appears to be more common in those with PAVM. In one series, migraine occurred in 88 patients with HHT, a prevalence of 16.4 percent. The prevalence of migraine in patients with PAVM was 21.2 percent, which was significantly higher than in patients without PAVM (13.3 percent). In our experience, migraines occurred in 74/292 (25 percent) with HHT. Cerebral AVMs occur in up to 5 percent of patients. Cerebral arteriovenous malformations (CAVMs) occur in 4 to 8 percent of patients with HHT and tend to run in families.

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AVMs may also occur in the liver. The most common manifestation is high-output heart failure. This may result in pulmonary hypertension associated with elevated leftventricular end-diastolic pressure; this must be differentiated from primary pulmonary hypertension. During a 9-year period between 1997 and 2006, 346 patients with HHT were evaluated at the Washington University HHT center. Of these patients, 17 (4.9 percent) were found to have high output cardiac state: 13 due to hepatic AVMs. Other presentations include manifestations of portal hypertension, such as ascites or variceal bleeding, and manifestations of biliary disease, such as an elevated alkaline phosphatase level and abnormalities on bile duct imaging. Ischemia related to shunting may result in noncirrhotic fibrous nodules (telangiectasia-associated hepatic fibrosis or pseudocirrhosis). On rare occasions, this may result in liver failure. In one series, hepatic AVM occurred in 17 percent of patients with ALK-1 mutations. Liver transplantation may be lifesaving.

TREATMENT Figure 84-9 MRI showing brain abscess residua in patient whose brain abscess preceded diagnosis of pulmonary arteriovenous fistula by 17 years.

Although CAVMs are not complications of PAVMs, they occur more frequently in patients with endoglin mutations, as do PAVMs. In our series of 149 patients screened by MRI, 11 had CAVM (7 percent). An additional 16 (11 percent) had telangiectasia or venous angioma (11 percent). Although some have argued that the complication rate does not warrant routine screening, the hemorrhage rate in individuals with cerebral AV malformations appears to be 1.4 to 2.0 percent annually, comparable to figures in the non-HHT population with cerebral AV malformations. Cerebral MRI is currently the most sensitive non-invasive test, although it will fail to detect a significant proportion of AVMs. Some authors believe MRI should not be performed in patients with pulmonary AVMs embolized with non-MRI compatible coils; however, we have performed many cerebral MRI examinations in such individuals without complications, with the caveat that the MRI is not done for a minimum of 6 weeks after embolotherapy.

Miscellaneous Complications The other complications that may be associated with PAVMs are those connected with HHT. Epistaxis is the most common bleeding manifestation. It occurs in up to 85 percent of patients, with 10 percent having little or no bleeding and approximately 30 percent each suffering from mild, moderate, or heavy bleeding. GI bleeding, which tends to occur later in life, occurs in approximately 20 to 25 percent of patients. Genitourinary and intracerebral bleeding occurs in less than 10 percent each.

Early treatment of PAVMs consisted of thoracotomy and resection. The first successful surgical approach was pneumonectomy, reported in 1942. As thoracic surgery improved, the extent of surgery diminished; by 1959, local excision was the procedure of choice. Surgical removal of a PAVM inevitably results in loss of viable lung tissue, a problem for patients with multiple PAVMs; the record is probably held by a patient who underwent staged bilateral thoracotomies with removal of 23 PAVMs, with substantial symptomatic improvement. Thorascopic resection has recently been described. Although surgical mortality can be as low as 0 percent, the general anesthesia, morbidity of thoracotomy, and loss of viable lung tissue made a new approach desirable. Embolization of PAVMs has proved to be an excellent alternative. This procedure was first performed using homemade coils. The procedure was refined and perfected at Johns Hopkins by Terry, White, and colleagues. The original procedure used silicone balloons unless the feeding vessel was larger than 9 mm in diameter, in which case embolization coils with thrombogenic Dacron tails were used (Fig. 84-10A,B,C). Currently, the choice of coil vs. balloon generally reflects PAVM size, operator preference and center experience. Generally, all PAVMs with feeding vessel diameter of 3 mm or larger are embolized. Results have been very good, with success rates greater than 93 percent, and embolization therapy is now the procedure of choice, with an apparent mortality of 0 percent, few serious complications, no loss of pulmonary parenchyma, and no exposure to anesthesia or thoracotomy. Pregnant women requiring urgent embolotherapy because of hemoptysis or hemothorax may safely undergo embolization, with radiation exposure to the fetus acceptable after 16 weeks of gestational age, with successful pregnancy outcome. Embolotherapy may also be performed safely and effectively in children.

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There are some limitations. The feeding vessel must be 2 to 3 mm in diameter or larger. It is technically feasible to embolize most PAVMs, but occasionally this is not possible. All but three patients in our 18-year experience have been able to be treated with embolotherapy (2/132 in the most recent series). A majority have persistent intrapulmonary shunt and should receive pre-dental antibiotic prophylaxis. Recanalization of the embolized vessel may occur. Rates of 2 to 8 percent have been reported. This may require repeated embolotherapy, and it has been suggested that followup by CT occur at 1 month and 1 year. Although observations documenting serial growth of small PAVMs are somewhat limited, there is published evidence to support their growth with time. Progression of PAVMs appears more likely in those with multiple PAVMs. It has been suggested that patients with treated PAVM need follow-up every 5 years to detect growth of small PAVMs that could become large enough to cause paradoxical embolization and stroke. In general, successful embolization of most or all visible PAVMs results in abatement of hypoxemia and its complications, but a small number of patients have diffuse small PAVMs not amenable to embolization. Occlusion of all PAVMs with feeding vessels 3 mm or larger greatly reduces the risk of embolic stroke. Complex

Figure 84-10 Embolotherapy devices: A. Detachable balloon mechanism from catheter. B. Fluoroscopic image of balloon in vivo. C. Embolization coils of two sizes.

PAVMs must have all feeding vessels embolized for success. Embolotherapy may reduce the risk of brain abscess, but abscess may recur even after successful therapy. Although no data regarding efficacy exist, standard American Heart Association endocarditis guidelines for antibiotic prophylaxis before embolotherapy seem recommended. Because of the frequent observation of small persistent left-to-right shunt demonstrated by echocardiography even after successful embolotherapy, antibiotic prophylaxis is recommended for dental and other surgical procedures. Serious complications of embolotherapy are rare. Because of the potential for systemic air and particulate embolism, all intravenous tubing is equipped with micropore filters and embolization precautions are taken. Air embolism during the procedure is rare, occurring in less than 5 percent in one series. It is generally manifested by perioral paresthesias or angina without permanent effect. The most common postembolization symptom is pleurisy, and has been reported at rates ranging from 10 to 31 percent. The onset may be delayed for up to 17 days in our experience, and severity may range from mild pain to a level of discomfort requiring hospitalization. These episodes are sometimes accompanied by large pleural effusions. The effusions and resulting hypoxemia always resolve within several weeks. Other complications have included migration of an embolic device, PAVM perforation,

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transient ischemic attack (TIA), early cerebral infarction after embolization. and paradoxical embolization of a device during deployment (4 percent). Diffuse PAVMs resulting in hypoxemia whch are not amenable to embolotherapy represent a difficult problem. A few such cases have been successfully treated with lung transplantation.

PROGNOSIS Early reports suggested a high mortality for patients who did not undergo treatment of PAVMs. Examination of family trees in older reports impresses one with the frequency of death from meningitis, brain abscess, and stroke. Some of this apparently high mortality may have been due to selection bias. More recent studies suggest that the prognosis may be more benign, and complications may be non-existent when PAVMs are discovered by screening. In one series, mortality was approximately 10 percent. Two-thirds of deaths were due to cerebrovascular accident, and all of these patients were cyanotic and polycythemic. In summary, patients with PAVM can be successfully treated, with resolution of essentially all symptoms and substantial reduction in risk of complications. Embolotherapy is the treatment of choice for most patients. The relatives of patients with PAVMs or HHT should be screened with contrast echocardiography to prevent central nervous system complications as the first manifestation of disease. Patients with PAVMs should be fully educated about their diagnosis, potential clinical complications, and the often hereditary nature of the problem. Educational materials for patients with HHT, and the location of specialized centers for managing HHT and PAVM, are available from the HHT Foundation International at www.hht.org. Caregivers are also urged to consult the website for updated recommendations.

SUGGESTED READING Abdalla SA, Gallione CJ, Barst RJ, et al: Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J 23:373–377, 2004. Aller R, Moya JL, Moreira V, et al: Diagnosis of hepatopulmonary syndrome with contrast transesophageal echocardiography: Advantages over contrast transthoracic echocardiography. Dig Dis Sci 44:1243–1248, 1999. Anabtawi IN, Ellison RG, Ellison LT: Pulmonary arteriovenous aneurysms and fistulas: Anatomical variations, embryology, and classification. Ann Thorac Surg 1:277–285, 1965. Andersen PE, Kjeldsen AD, Oxhoj H, et al: Embolotherapy for pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia (Rendu-OslerWeber syndrome). Acta Radiol 39:723–726, 1998.

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Assar OS, Friedman CM, White RI: The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope 101:977–980, 1991. Babbington BG: Hereditary epistaxis. Lancet 2:362–363, 1865. Barzilai B, Waggoner A, Spessert C, et al: Two-dimensional contrast echocardiography in the detection and followup of congenital pulmonary arteriovenous malformations. Am J Cardiol 68:1507–1510, 1991. Bayrak-Toydemir P, McDonald J, Markewitz B, et al: Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: Mutations and manifestations. Am J Med Genet Part A 140:463–470, 2006. Bayrak-Toydemir P, McDonald J, Akarsu N, et al: A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7. Am J Med Genet Part A 140:2155–2162, 2006. Berg JN, Gallione CJ, Stenzel TT, et al: The activin receptorlike kinase 1 gene: Genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Am J Hum Genet 61:60–67, 1997. Boillot O, Bianco F, Viale JP, et al: Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement. Gastroenterology 116:187–192, 1999. Bourdeau A. Faughnan ME, Letarte M: Endoglin-deficient mice, a unique model to study hereditary hemorrhagic telangiectasia. Trends Cardiovasc Med 10:279–285, 2000. Brown SE, Wright PW, Renner JW, et al: Staged bilateral thoracotomies for multiple pulmonary arteriovenous malformations complicating hereditary hemorrhagic telangiectasia. J Thorac Cardiovasc Surg 83:285–289, 1982. Burke CM, Safai C, Nelson DP, et al: Pulmonary arteriovenous malformations: A critical update. Am Rev Respir Dis 134:334–339, 1986. Chiari O: Enfahrungen auf dem Gebiete der Hals und Nasenkrankheiten. Vienna, 1887. Chilvers ER, Whyte MK, Jackson JE, et al: Effect of percutaneous transcatheter embolization on pulmonary function, right-to-left shunt, and arterial oxygenation in patients with pulmonary arteriovenous malformations. Amer Rev Respir Dis 142:420–425, 1990. Churton T: Multiple aneurysm of pulmonary artery. Br Med J 1:1223, 1897. Cole SG, Begbie ME, Wallace GM, et al: A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5. J Med Genet 42:577–582, 2005. Cooney T, Sweeney EC, Coll R, et al: “Pseudocirrhosis” in hereditary hemorrhagic telangiectasia. J Clin Pathol 30:1134–1141, 1977. Cottin V, Plauchu H, Bayle JY, et al: Pulmonary arteriovenous malformations in patients with hereditary hemorrhagic telangiectasia. Am J Respir Crit Care Med 169:994–1000, 2004. Dakeishi M, Shioya T, Wada Y, et al: Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat 19:140–148, 2002.

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Dalton ML, Goodwin FC, Bronwell AW, et al: Intrapleural rupture of pulmonary arteriovenous aneurysm: Report of a case. Dis Chest 52:97–100, 1967. Dines DE, Arms RA, Bernatz PE, et al: Pulmonary arteriovenous fistulas. Mayo Clin Proc 49:460–465, 1974. Dines DE, Seward JB, Bernatz PE: Pulmonary arteriovenous fistulas. Mayo Clin Proc 58:176–181, 1983. Dinsmore BJ, Gefter WB, Hatabu H, et al: Pulmonary arteriovenous malformations: Diagnosis by gradient refocused MR imaging. J Comput Assist Tomogr 14:918–923, 1990. Dyer NH: Cerebral abscess in hereditary hemorrhagic telangiectasia: Report of two cases in a family. J Neurol Neurosurg Psychiatry 30:563–567, 1967. Easey AJ, Wallace GMF, Hughes JMB, et al: Should asymptomatic patients with hereditary haemorrhagic telangiectasia (HHT) be screened for cerebral vascular malformations. Data from 22,061 years of HHT patient life. J Neurol Neurosurg Psychiat 74:743–748, 2003. El-Harith El-HA, Kuhnau W, Schmidtke J, et al: Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: Support of homozygous lethality. Eur J Med Genet 49:323–330, 2006. Faughnan ME, Lui YW, Wirth JA, et al: Diffuse pulmonary arteriovenous malformations: Characteristics and prognosis. Chest 117:31–38, 2000. Faughnan ME, Thabet A, Mei-Zahav M, et al: Pulmonary arteriovenous malformations in children: Outcomes of transcatheter embolotherapy. J Pediatr 145:826–831, 2004. Ference BA, Shannon TM, White RI Jr, et al: Life-threatening pulmonary hemorrhage with pulmonary arteriovenous malformations and hereditary hemorrhagic telangiectasia. Chest 106:1387–1390, 1994. Fernandez A, Sanz-Rodriguez F, Zarrabeitia R, et al: Mutation study of Spanish patients with hereditary hemorrhagic telangiectasia and expression analysis of Endoglin and ALK1. Hum Mutat 27:295, 2006. Fulbright RK, Chaloupka JC, Putman CM, et al: MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. Am J Neuroradiol 19:477–484, 1998. Garcia-Tsao G, Korzenik JR, Young L, et al: Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 343:931–936, 2000. Gallione CJ, Repetto GM, Legius E, et al: A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363:852–859, 2004. Gallione CJ, Richards JA, Letteboer TGW, et al: SMAD4 mutations found in unselected HHT patients. J Med Genet 43:793–797, 2006. Gallitelli M, Guastamacchia E, Resta F, et al: Pulmonary arteriovenous malformations, hereditary hemorrhagic telangiectasia, and brain abscess. Respiration 73:553–557, 2006. Gammon RB, Miksa AK, Keller FS: Osler-Weber-Rendu disease and pulmonary arteriovenous fistulas: Deterioration and embolotherapy during pregnancy. Chest 98:1522– 1524, 1990.

Gelfand MS, Stephens DS, Howell EI, et al: Brain abscess: Association with pulmonary arteriovenous fistula and hereditary hemorrhagic telangiectasia: Report of three cases. Am J Med 85:718–720, 1988. Gershon AS, Faughnan ME, Chon KS, et al: Transcatheter embolotherapy of maternal pulmonary arteriovenous malformations during pregnancy. Chest 119:470–477, 2001. Gomes MR, Bernatz PE, Dines DE: Pulmonary arteriovenous fistulas. Ann Thorac Surg 7:582–593, 1969. Goodenberger DM: Unpublished data. Goodenberger D, Barzilai B, Picus D: Incidence and timing of pleuritic chest pain after therapeutic pulmonary embolization (abstract). Chest 103:159S, 1993. Goodenberger D, Barzilai B, Waggoner A, et al: Frequency of intrapulmonary shunt in relatives of patients with OslerWeber-Rendu and pulmonary arteriovenous malformation (abstract). Chest 98:59S, 1990. Goodenberger D, Picus D: Pulmonary Arteriovenous Malformation Frequency in Hereditary Hemorrhagic Telangiectasia: Impact of Screening Procedure. Sixth International HHT Scientific Conference, Lyon, France, April 24, 2005. Goodenberger D, Spessert C, Waggoner A, et al: Size and location of occult pulmonary arteriovenous malformations (PAVMs) in individuals with Osler-Weber-Rendu (OWR) (abstract). Am Rev Respir Dis 143:A663, 1991. Goodman J, Fallah M, Goodenberger D, et al: Liver transplantation for hereditary hemorrhagic telangiectasia. J Gastrointest Surg 7:313, 2003. Gossage JR, Kanj G: Pulmonary arteriovenous malformations. A state of the art review. Am J Respir Crit Care Med 158:643–661, 1998. Guttmacher AE, Marchuk DA, White RI Jr: Hereditary hemorrhagic telangiectasia. N Engl J Med 333:918–924, 1995. Haitjema T, Disch F, Overtoom TT, et al: Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 99:519–524, 1995. Hales MR: Multiple small arteriovenous fistulae of the lungs. Am J Pathol 32:927–943, 1956. Hanes FM: Multiple hereditary telangiectases causing hemorrhage (hereditary hemorrhagic telangiectasia). Bull Johns Hopkins Hosp 20:63, 1909. Hartnell GG, Jackson JE, Allison DJ: Coil embolization of pulmonary arteriovenous malformations. Cardiovasc Intervent Radiol 13:347–350, 1990. Hepburn J, Dauphinee JA: Successful removal of hemangioma of the lung followed by the disappearance of polycythemia. Am J Med Sci 204:681–685, 1942. Hernandez A, Strauss AW, McKnight R, et al: Diagnosis of pulmonary arteriovenous fistula by contrast echocardiography. J Pediatr 93:258–261, 1978. Heutink P, Haitjema T, Breedveld GJ, et al: Linkage of hereditary haemorrhagic telangiectasia to chromosome 9q34 and evidence for locus heterogeneity. J Med Genet 31:933–936, 1994. Higgins CB, Wexler L: Clinical and angiographic features of pulmonary arteriovenous fistulas in children. Radiology 119:171–175, 1976.

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Hoffman R, Rabens R: Evolving pulmonary nodules: Multiple pulmonary arteriovenous fistulas. Am J Roentgenol Radium Ther Nucl Med 120:861–864, 1974. Huseby JS, Culver BH, Butler J: Pulmonary arteriovenous fistulas: Increase in shunt at high lung volume. Am Rev Respir Dis 115:229–232, 1977. Jessurun GA, Kamphuis DJ, van der Zande FH, et al: Cerebral arteriovenous malformations in the Netherlands Antilles: High prevalence of hereditary hemorrhagic telangiectasiarelated single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg 95:193–198, 1993. Johnson DW, Berg JN, Baldwin MA, et al: Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 13:189–195, 1996. Khalil A, Farres MT, Mangiapan G, et al: Pulmonary arteriovenous malformations. Chest 117:1399–1403, 2000. Kjeldsen AD, Vase P, Green A: Hereditary haemorrhagic telangiectasia: A population-based study of prevalence and mortality in Danish patients. J Intern Med 245:31–39, 1999. Kjeldsen AD, Oxhoj H, Andersen PE, et al: Pulmonary arteriovenous malformations: screening procedures and pulmonary angiography in patients with hereditary hemorrhagic telangiectasia. Chest 116:432–439, 1999. Langiulli M, Aronow WS, Das M, et al: Prevalence and prognosis of intrapulmonary shunts in patients with hepatic cirrhosis. Cardiol Rev 14:53–54, 2006. LaRoche CM, Wells F, Shneerson J: Massive hemothorax due to enlarging arteriovenous fistula in pregnancy. Chest 101:1452–1454, 1992. Lee WL, Graham AF, Pugash RA, et al: Contrast echocardiography remains positive after treatment of pulmonary arteriovenous malformations. Chest 123:351–358, 2003. Lee DW, White RI Jr, Egglin TK, et al: Embolotherapy of large pulmonary arteriovenous malformations: Long-term results. Ann Thorac Surg 64:930–939, 1997. Legg W: A case of haemophilia complicated with multiple naevi. Lancet ii:856, 1876. Lesca G, Burnichon N, Raux G, et al: Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Hum Mutat 27:598, 2006. Letteboer TGW, Zewald RA, Kamping EJ, et al: Letteboer TGW, Zewald RA, Kamping EJ et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet 116:8–16, 2005. Lundell M, Finck E: Arteriovenous fistulas originating from Rasmussen aneurysms. Am J Roentgenol 140:687–688, 1983. Mager JJ, Overtoom TT, Blauw H, et al: Embolotherapy of pulmonary arteriovenous malformations: Long-term results in 112 patients. J Vasc Intervent Radiol 15:451–456, 2004. Maher CO, Piepgras DG, Brown RD Jr, et al: Cerebrovascular manifestations in 321 cases of hereditary hemorrhagic telangiectasia. Stroke 32:877–882, 2001. McAllister KA, Grogg KM, Johnson DW, et al: Endoglin, a TGF-beta binding protein of endothelial cells, is the gene

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for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351, 1994. McAllister KA, Lennon F, Bowles-Biesecker B, et al: Genetic heterogeneity in hereditary haemorrhagic telangiectasia: Possible correlation with clinical phenotype. J Med Genet 31:927–932, 1994. McCue CM, Hartenberg M, Nance WE: Pulmonary arteriovenous malformations related to Rendu-Osler-Weber syndrome. Am J Med Genet 19:19–27, 1984. McDonald JE, Miller FJ, Hallam SE, et al: Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. J Med Genet 93:320–327, 2000. McDonald MT, Papenberg KA, Ghosh S, et al: A disease locus for hereditary haemorrhagic telangiectasia maps to chromosome 9q33-34. Nat Genet 6:197–204, 1994. Milic A, Chan RP, Cohen JH, et al: Reperfusion of pulmonary arteriovenous malformations after embolotherapy. J Vasc Intervent Radiol 16:1675–1683, 2005. Nanthakumar K, Graham AT, Robinson TI, et al: Contrast echocardiography for detection of pulmonary arteriovenous malformations. Am Heart J 141:243–246, 2001. Oliveira GH, Seward JB, Cortese DA, et al: Contrast transesophageal echocardiography in the diagnosis and localization of diffuse pulmonary telangiectasias. Chest 118:557–559, 2000. Osler W: On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Bull Johns Hopkins Hosp 12:333–337, 1901. Oxhoj H, Kjeldsen AD, Nielsen G: Screening for pulmonary arteriovenous malformations: contrast echocardiography versus pulse oximetry. Scand Cardiovasc J 34:281–285, 2000. Peery WH: Clinical spectrum of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease). Am J Med 82:989–997, 1987. Pierce JA, Reagan WP, Kimball RW: Unusual cases of pulmonary arteriovenous fistulas, with a note on thyroid carcinoma as a cause. N Engl J Med 260:901–907, 1959. Pollak JS, Saluja S, Thabet A, et al: Clinical and anatomic outcomes after embolotherapy of pulmonary arteriovenous malformations. J Vascular Int Radiol 17:35–44, 2006. Porteous ME, Curtis A, Williams O, et al: Genetic heterogeneity in hereditary hemorrhagic telangiectasia. J Med Genet 31:925–926, 1994. Post MC, Letteboer TG, Mager JJ, et al: A pulmonary right-toleft shunt in patients with hereditary hemorrhagic telangiectasia is associated with an increased prevalence of migraine. Chest 128:2485–2489, 2005. Prasad V, Chan RP, Faughnan ME: Embolotherapy of pulmonary arteriovenous malformations: Efficacy of platinum versus stainless steel coils. J Vasc Intervent Radiol 15:153–160, 2004. Press OW, Ramsey PG: Central nervous system infections associated with hereditary hemorrhagic telangiectasia. Am J Med 77:86–92, 1984.

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Prigoda NL, Savas S, Abdalla SA, et al: Hereditary haemorrhagic telangiectasia: Mutation detection, test sensitivity and novel mutations. J Med Genet 43:722–728, 2006. Przybojewski JZ, Maritz F: Pulmonary arteriovenous fistulas: A case presentation and review of the literature. South Afr Med J 57:366–373, 1980. Rankin S, Faling LJ, Pugatch RD: CT diagnosis of pulmonary arteriovenous malformation. J Comput Assist Tomogr 6:746–749, 1982. Reading B: Case of congenital telangiectasia of lung, complicated by brain abscess. Tex St J Med 28:462–464, 1932. Reilly PJ, Nostrant TT: Clinical manifestations of hereditary hemorrhagic telangiectasia. Am J Gastroenterol 79:363– 367, 1984. Remy J, Remy-Jardin M, Giraud F, et al: Angioarchitecture of pulmonary arteriovenous malformations: Clinical utility of three-dimensional helical CT. Radiology 191:657–664, 1994. Remy J, Remy-Jardin M, Wattinne L, et al: Pulmonary arteriovenous malformations: Evaluation with CT of the chest before and after treatment. Radiology 182:809–816, 1992. Remy-Jardin M, Dumont P, Brillet PY, et al: Pulmonary arteriovenous malformations treated with embolotherapy: Helical CT evaluation of long-term effectiveness after 2–21-year follow-up. Radiology 239:576–585, 2006. Remy-Jardin M, Wattinne L, Remy J: Transcatheter occlusion of pulmonary arterial circulation and collateral supply: Failures, incidents, and complications. Radiology 180:699– 705, 1991. ´ Rendu M: Epistaxis répétées chez un sujet porteur de petits angiomes cutanés et muqueux. Bull Mém Soc Méd Hôp Par 13:731–733, 1896. Reynaud-Gaubert M, Thomas P, Gaubert JY et al.‘Pulmonary arteriovenous malformations: Lung transplantation as a therapeutic option. Eur Respir J 14:1425–1428, 1999. Rodes CB: Cavernous hemangiomas of the lung with secondary polycythemia. JAMA 110:1914–1915, 1938. Roman G, Fisher M, Perl DP, et al: Neurological manifestations of hereditary hemorrhagic telangiectasia (RenduOsler-Weber disease): Report of two cases and review of the literature. Ann Neurol 4:130–144, 1978. Sanjay S, White RI: Hereditary hemorrhagic telangiectasia of the liver: Hyperperfusion with relative ischemia—poverty amidst plenty. Radiology 230:25–27, 2004. Schulte C, Geisthoff U, Lux A, et al: High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat 25:595, 2005. Shovlin CL, Guttmacher AE, Buscarini E, et al: Diagnostic criteria for hereditary hemorrhagic telangiectasia (RenduOsler-Weber syndrome). Am J Med Genet 91:66–67, 2000. Shovlin CL, Hughes JM, Tuddenham EG, et al: A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 6:205–209, 1994. Shovlin CL, Letarte M: Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: Issues in clinical management and review of pathogenic mechanisms. Thorax 54:714–729, 1999.

Shub C, Tajik AJ, Seward JB, et al: Detecting intrapulmonary right-to-left shunt with contrast echocardiography: Observations in a patient with diffuse pulmonary arteriovenous fistulas. Mayo Clin Proc 51:81–84, 1976. Shumacker HB, Waldhausen JA: Pulmonary arteriovenous fistulas in children. Ann Surg 158:713–720, 1963. Sluiter-Eringa H, Orie NGM, Sluiter HJ: Pulmonary arteriovenous fistula: Diagnosis and prognosis in noncomplainant patients. Am Rev Respir Dis 100:177–188, 1969. Smith HL, Horton BT: Arteriovenous fistula of the lung associated with polycythemia vera: Report of a case in which the diagnosis was made clinically. Am Heart J 18:589–592, 1939. Srinivasan S, Hanes MA, Dickens T, et al: A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Hum Mol Genet 12:473–482, 2003. Sutton HG: Epistaxis as an indication of impaired nutrition and of degeneration of the vascular system. Med Mirror 1:769, 1864. Svetliza G, De la Canal A, Beveraggi E, et al: Lung transplantation in a patient with arteriovenous malformations. J Heart Lung Transplant 21:506–508, 2002. Swanson KL, Prakash UB, Stanson AW: Pulmonary arteriovenous fistulas: Mayo Clinic experience, 1982–1997. Mayo Clin Proc 74:671–680, 1999. Terry PB, White RI, Barth KH, et al: Pulmonary arteriovenous malformations: Physiologic observations and results of therapeutic balloon embolization. N Engl J Med 308:1197– 1200, 1983. Thompson RD, Jackson J, Peters AM, et al: Sensitivity and specificity of radioisotope right-left shunt measurements and pulse oximetry for the early detection of pulmonary arteriovenous malformations. Chest 115:109–113, 1999. Trell E, Johansson BW, Linell F, et al: Familial pulmonary hypertension and multiple abnormalities of large systemic arteries in Osler’s disease. Am J Med 53:50–63, 1972. Vase P, Holm M, Arendrup H: Pulmonary arteriovenous fistulas in hereditary hemorrhagic telangiectasia. Acta Med Scand 218:105–109, 1985. Watanabe N, Munakata Y, Ogiwara M, et al: A case of pulmonary arteriovenous malformation in a patient with brain abscess successfully treated with video-assisted thoracoscopic resection. Chest 108:1724–1727, 1995. Weber FP: Multiple hereditary developmental angiomata (telangiectases) of the skin and mucous membranes associated with recurring hemorrhages. Lancet 2:160–162, 1907. Westermann CJ, Rosina AF, De Vries V, et al: The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: A family screening. Am J Med Genet Part A 116:324–328, 2003. White RI Jr: Pulmonary arteriovenous malformations: How do we diagnose them and why is it important to do so? Radiology 182:633–635, 1992.

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White RI Jr, Lynch-Nyhana A, Terry P, et al: Pulmonary arteriovenous malformations: Techniques and long-term outcome of embolotherapy. Radiology 169:663–669, 1988. White RI Jr, Mitchell SE, Barth KH, et al: Angioarchitecture of pulmonary arteriovenous malformations: An important consideration before embolotherapy. Am J Roentgenol 140:681–686, 1983.

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White RI Jr, Pollak JS, Wirth JA: Pulmonary arteriovenous malformations: Diagnosis and transcatheter embolotherapy. J Vasc Interv Radiol 7:787–804, 1996. Whyte MK, Peters AM, Hughes JM, et al: Quantification of right to left shunt at rest and during exercise in patients with pulmonary arteriovenous malformations. Thorax 47:790–796, 1992.

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PART

X Disorders of the Pleural Space

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85 Non-Malignant Pleural Effusions Martin L. Mayse

I. PARAPNEUMONIC EFFUSIONS AND/OR EMPYEMA Parapneumonic Effusions Empyema II. TUBERCULOUS PLEURAL EFFUSIONS III. FUNGAL PLEURAL EFFUSIONS IV. VIRAL PLEURAL EFFUSIONS V. PARASITIC INFECTIONS OF THE PLEURAL SPACE VI. PULMONARY EMBOLI VII. PANCREATITIS VIII. ESOPHAGEAL PERFORATION IX. INTRA-ABDOMINAL ABSCESS X. COLLAGEN VASCULAR DISEASES Rheumatoid Arthritis Systemic Lupus Erythematosus Churg-Strauss Syndrome

Pleural effusion is the abnormal accumulation of fluid in the pleural space. A pleural effusion is always abnormal and indicates the presence of an underlying disease. Approximately 1.4 million people in the United States develop a pleural effusion each year. Despite the fact that there are many causes of pleural effusion (Table 85-1), it is estimated that 90 percent of all pleural effusions are the result of only 5 disease processes; congestive heart failure, pneumonia, malignancy, pulmonary embolism, and viral infection. The diagnostic approach to patients with a pleural effusion is detailed elsewhere in this volume. This chapter outlines the importance of descriminating transudative effusions from exudative effusions and details the major causes of exudative pleural effusions; including signs and symptoms, characteristics of pleural fluid analysis, treatment options, and prognosis.

XI. PLEURAL EFFUSION FROM DRUG REACTIONS XII. PLEURAL EFFUSION SECONDARY TO ASBESTOS EXPOSURE XIII. CHYLOTHORAX XIV. HEMOTHORAX XV. POSTSURGICAL PLEURAL EFFUSIONS XVI. SARCOIDOSIS XVII. POST-CARDIAC INJURY (DRESSLER’S) SYNDROME XVIII. UREMIC PLEURITIS XIX. YELLOW NAIL SYNDROME XX. PLEURAL EFFUSIONS IN PATIENTS WITH AIDS

The first step in the evaluation of a pleural effusion is a detailed history and physical examination; the importance of the history and physical arises from the fact that a significant percentage of pleural effusions have no definitive diagnostic features on pleural fluid analysis or pleural biopsy. Diagnosis of the cause of many pleural effusions is based on the clinical setting and exclusion of other alternative causes. The next step is sampling of the pleural fluid and categorization as a transudate or exudate. Transudative pleural effusions result from systemic diseases that do not directly involve the pleura but instead produce an imbalance of Starling’s forces, resulting in movement of fluid into the pleural space. The diagnostic focus for transudates call for recognition of the systemic disease. Such systemic diseses include congestive heart failure, cirrhosis with ascites, and the nephrotic syndrome. Treatment of transudative effusions

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Table 85-1 Differential Diagnosis of Non-Malignant Pleural Effusions Transudative Pleural Effusions

Exudative Pleural Effusions

Congestive heart failure Cirrhosis Peritoneal dialysis Nephrotic syndrome Superior vena cava obstruction Myxedema Pulmonary thromboemboli

Infectious diseases Bacterial infections Tuberculosis Fungal infections Viral infections Parasitic infections Pulmonary thromboembolization Gastrointestinal disease Pancreatitis Esophageal perforation Intra-abdominal abscesses Collagen vascular diseases Rheumatoid arthritis Lupus erythematosus Churg-Strauss syndrome Drug-induced pleural disease Nitrofurantoin Dantrolene Methysergide Bromocriptine Interleukin-2 Procarbazine Amiodarone Asbestos exposure Chylothorax Hemothorax Postsurgical Abdominal surgery Coronary artery bypass Sarcoidosis Post-cardiac-injury (Dresslerâ&#x20AC;&#x2122;s) syndrome Uremic pleuritis Yellow nail syndrome

Source: Modified from Light RW: Pleural Diseases. DISEASE-A-MONTH 28:263â&#x20AC;&#x201C;331, 1992.

should focus on treatment of the underlying disease. Exudative pleural effusions result from local or systemic diseases that directly injure the pleural surface. The diagnostic focus for exudative effusions is to recognize the responsible intrapleural disease. Exudative pleural effusions have any one or more of the following characteristics: (1) the pleural total fluid protein divided by the serum total protein is greater than 0.5; (2) the pleural fluid lactic dehydrogenase (LDH) divided by the

serum LDH is greater than 0.6; and (3) the absolute level of LDH in the pleural fluid is greater than two-thirds of the upper normal limit for serum. Transudative pleural effusions meet none of the above three criteria. In addition to the measurement of pleural fluid protein and LDH to differentiate transudate from exudate, other tests that can be helpful include: white blood cell count and differential; glucose; amylase; cytologic examination; and cultures for aerobic and anaerobic bacteria, mycobacteria, and fungi. For example, a pleural fluid cell population with a high percentage of small lymphocytes suggests that the patient has pleural tuberculosis or pleural malignancy and serves as an indication for a needle or thoracoscopic biopsy of the pleura. Most patients who have more than 10 percent of eosinophils in their pleural fluid have had either blood or air in their pleural spaces. If this is not the case, one should consider a drug reaction, paragonimiasis, or the Churg-Strauss syndrome. A pleural fluid glucose below 60 mg/dl narrows the diagnostic possibilities to seven: parapneumonic effusion, malignant effusion, tuberculous effusion, rheumatoid effusion, hemothorax, paragonimiasis, or the Churg-Strauss syndrome. An elevated pleural amylase limits the diagnostic possibilities to three: esophageal rupture, pancreatic disease, or malignant pleural effusion. With esophageal rupture and malignant pleural effusion, the amylase present in the pleural fluid is a salivary type. Depending on the patient, other tests are sometimes useful in determining the cause of a pleural effusion. For example, if a chylothorax is suspected, one should measure the level of triglycerides in the pleural fluid, and measurement of the adenosine deaminase (ADA) is useful in establishing the diagnosis of tuberculous pleuritis.

PARAPNEUMONIC EFFUSIONS AND/OR EMPYEMA Parapneumonic Effusions A parapneumonic effusion is any pleural effusion associated with bacterial pneumonia or lung abscess. Parapneumonic effusions occur in approximately 40 percent of the more than 1 million patients in the United States who have bacterial pneumonia each year, making pneumonia the most common cause of exudative pleural effusions. The possibility of a parapneumonic effusion should be considered each time a patient with acute pneumonia is evaluated. Parapneumonic effusions are often small, but if the depth of the effusion is greater than 10 mm on the decubitus chest radiograph, a diagnostic thoracentesis should be strongly considered. Pleural effusions secondary to pneumonia arise from an inflammatory process contiguous to the visceral pleura. The effusion derives from fluid entering the lung interstices, transversing the visceral pleura, and accumulating in the pleural space when the rate of accrual exceeds the capacity of the parietal pleural lymphatics to remove fluid. The fluid initially has a low white blood cell count, low concentration of lactic

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Figure 85-1 Compartmentalization of pleural fluid in empyema resulting from inflammation and the formation of semipermeable fibrin membranes. In compartment B of the schematic, bacteria and polymorphonuclear leukocytes abound; pleural fluid sampled from this area will be culture-positive and have an elevated white cell count, low pH, and decreased glucose level. The fibrin membrane prevents migration of bacteria and polymorphonuclear leukocytes to the adjacent compartment A. However, the semipermeable membrane permits diffusion of carbon dioxide from compartment B to compartment A, and glucose diffusion from A to B. Thus, fluid taken from compartment A, although sterile and with a low polymorphonuclear leukocyte count, will have a low pH and glucose, indicating the presence of neighboring infection.

dehydrogenase (LDH), normal concentration of glucose, pH greater than 7.3, and no demonstrable bacteria. This is an “uncomplicated parapneumonic effusion.” If appropriate antibiotic therapy for the pulmonary infection is initiated at this stage, the effusion usually does not progress, pleural drainage is frequently unnecessary, and the pleural process resolves with antibiotic therapy alone. However, if the infection in the pulmonary parenchyma is unchecked, the infectious agent invades the pleural space to create an empyema. Once bacterial infection has involved the pleural space, the effusion increases in size with a concomitant increase in the number of polymorphonuclear leukocytes and fall in pleural fluid pH and glucose. At this point, fibrin frequently is deposited in the pleural space forming semipermeable barriers that envelop or loculate the infected area and lead to regional variation in the composition of pleural fluid (Fig. 85-1). In the region of bacterial proliferation, white blood cells are actively phagocytosing bacteria, and the resultant oxidative burst results in an increased consumption of glucose with increased production of CO2 and lowering of the pH. Neighboring compartments equilibrate glucose and CO2 across the semipermeable loculations producing a low pH and glucose; the loculations, however, are impervious to white cells and bacteria (Fig. 85-1). Sampling the infected loculation demonstrates

Non-Malignant Pleural Effusions

pus and/or bacteria and establishes a diagnosis of empyema thoracis. Fluid from neighboring loculations demonstrates a low pH and low glucose but no bacteria. The latter identifies a “complicated parapneumonic effusion” and strongly suggests infection in nearby loculations and the need for pleural space drainage. The incidence of parapneumonic effusions depends, in part, on the infecting organism. For example, a parapneumonic effusion occurs in 50 percent of Streptococcus pneumoniae infections of the lung, but the organism can be demonstrated in pleural fluid in fewer than 5 percent of patients. In contrast, culture of the pleural fluid is positive in 20 percent of adults and 80 percent of children with pleural effusions secondary to Staphylococcus aureus infections. Pleural effusions also develop in 40 to 50 percent of gram-negative aerobic pneumonias, and the majority of these are culture-positive. Pseudomonas species and Escherichia coli account for more than two-thirds of all infections of the pleural space caused by aerobic gram-negative organisms. Pleural effusions occur in 30 to 50 percent of patients with pneumonia due to Legionella species. Although the morbidity and mortality rates in patients with pneumonia and effusion are higher than those with pneumonia alone, most uncomplicated parapneumonic effusions resolve with antibiotics alone. Less than ten percent ultimately require pleural drainage for resolution. Decortication and/or open drainage are rarely needed in the management of an uncomplicated parapneumonic effusion. Uncomplicated parapneumonic effusion that enlarges in the face of antibiotic therapy should undergo repeat thoracentesis to assess if the effusion has become complicated. Complicated parapneumonic effusions require tube thoracostomy for drainage and adequate treatment (Table 85-2). The tube should be positioned in the dependent portion of the effusion and connected to an underwater seal drainage system. If the patient fails to improve clinically and radiographically within 48 hours, ultrasonic examination of the pleural space is performed to detect undrained loculated fluid; if a pocket is identified, additional chest tubes should be inserted. Decortication and/or open drainage are sometimes needed in the management of complicated parapneumonic effusions.

Empyema Empyema is defined by the presence of pus in the pleural space. Direct extension of a pulmonary parenchymal infection into the pleural space causes more than half the cases of empyema; postsurgical infection accounts for an additional 20 percent. Empyema also occurs after penetrating or blunt trauma to the thorax. Sometimes bacteria from abdominal infection, such as a subdiaphragmatic abscess, cross the diaphragm and enter the pleural space. Rarely does empyema complicate thoracentesis or pleural biopsy. Sixty to seventy percent of patients with empyema have an underlying serious disease. Chronic obstructive pulmonary disease and pulmonary neoplasm are each found in approximately one-third

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Table 85-2 Criteria for Tube Thoracostomy in Parapneumonic Effusions and Empyema Radiographic criteria Pleural fluid loculations Effusion filling more than half the hemithorax Air-fluid level Microbiologic criteria Pus in the pleural space Positive stain for microorganisms Positive pleural fluid cultures Chemical criteria Pleural fluid pH < 7.2 Pleural fluid glucose < 60 mg/dl Source: Modified from Colice GL, Curtis A, Deslauriers J, et al: Medical and surgical treatment of parapneumonic effusions. An evidence-based Guideline. Chest 118:1158â&#x20AC;&#x201C;71, 2001.

of patients with empyema. Other associated illnesses include alcoholism, diabetes, esophageal disease, and disorders of the central nervous system that lead to aspiration of oropharyngeal contents. The symptoms of empyema are usually non-specific. Eighty percent of patients have dyspnea and fever, and 70 percent complain of cough or chest pain. However, some patients with empyema present with only constitutional complaints, such as weight loss, fatigue, and malaise. Evidence of fluid in the pleural space is the principal radiographic finding; most empyema patients also have a recognizable parenchymal infiltrate. The bacteriology of empyema has changed considerably in the past 50 years. Prior to the availability of antibiotics, S. pneumoniae and S. pyogenes accounted for most pleural infections. After the use of penicillin became widespread in the 1940s, S. aureus succeeded S. pneumoniae and S. pyogenes as the major cause of empyema. Since the advent of Î˛-lactamaseresistant semisynthetic penicillins in the early 1960s, the incidence of staphylococcal empyema has decreased, and infections caused by anaerobic bacteria and aerobic gram-negative rods have increased markedly. Anaerobic organisms are now isolated from up to 75 percent of patients with empyema; about half of the isolates consist of only anaerobic organisms and the other half of mixed anaerobic and aerobic organisms. Approximately 75 percent of patients with empyema have multiple infecting organisms, averaging three bacterial species per patient. Anaerobic bacteria in the pleural space may originate in the mouth or from a subphrenic source via transdiaphragmatic spread or, less commonly, reach the pleura via the bloodstream. Carious teeth or advanced periodontal disease should alert the clinician to the possibility of anaerobic infection. Despite careful sampling and meticulous culturing, pleural

fluids are culture-negative in up to 20 percent of patients with empyema. The mortality from empyema is ranges from 11 to 50 percent, depending on the patient population. Contributing to a poor prognosis in patients with empyema are underlying pulmonary disease, underlying malignancy, persistent systemic symptoms, gram-negative bacterial infection, and advanced age. A good outcome demands prompt recognition, appropriate antibiotic therapy, and adequate pleural drainage. Apart from reducing the risk of sepsis, early antibiotic therapy also decreases the degree of residual pleural fibrosis. The initial choice of antibiotics depends on the clinical setting and should be guided by the results of the gram stain of pleural fluid and sputum. Antibiotics should be modified when culture results become available and the in vitro sensitivity patterns of the infecting bacteria are determined. In patients in whom empyema is suspected, empiric antibiotic therapy is started immediately. Until proved otherwise, anaerobic involvement is presumed, and an antibiotic that is effective against this group of organisms is started. For patients with empyema thoracis from community-acquired infection, the second-generation cephalosporins provide coverage against most aerobic gram-positive cocci, anaerobic bacteria including bacteroides species, and some gram-negative rods (Haemophilus spp., Klebsiella spp., E. coli and Enterobacter spp.). In the absence of a positive gram stain, coverage for Legionella species and Chlamydia pneumoniae should be added.For nosocomial infections, broader antibiotic coverage for gram-negative organisms is recommended. Initially, the antibiotics are administered parenterally. However, should the infection prove to be caused by highly susceptible organisms, oral antibiotics are often substituted after the empyema is adequately drained and signs of sepsis have resolved. The duration of antibiotic therapy depends on the individual response. As a rule, antibiotics are continued until: (1) the patient is afebrile and the white blood cell count is normal; (2) the tube thoracostomy drainage yields less than 50 ml of fluid daily; and (3) the radiograph shows considerable clearing. Typically, 3 to 6 weeks of antibiotic therapy is required to achieve these results. Prompt external drainage of infected pleural fluid collections is a mainstay of treatment (Fig. 85-2) and indicated for all patients with empyema thoracis. Several therapeutic options are available and include: (1) thoracentesis; (2) nonâ&#x20AC;&#x201C;image-guided chest tube placement; (3) imageguided catheter drainage; (4) thoracoscopy with lysis of adhesions and directed chest tube placement; (5) thoracotomy with debridement and directed chest tube placement; and (6) thoracotomy with pleural decortication. Percutaneous drainage is most effective in patients with a short duration of symptoms, free-flowing or unilocular parapneumonic effusions, absence of a thick pleural peel on sonography or computed tomography (CT) scans, and fluid that can be aspirated easily by needle. Chest tube placement with or without image guidance is usually the initial procedure. Sonography or CT can accurately guide drainage

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Figure 85-2 A. Chest radiograph of a 63-year-old woman with left lower lobe pneumonitis. B. The patient developed a large leftsided pleural effusion despite 5 days of oral antibiotic therapy. C. Sonographic study of the pleural space showed marked septation throughout the fluid collection. D. Adequate drainage was established with thoracotomy, digital lysis of adhesions, and operative placement of a chest tube.

catheter placement, with sonography the procedure of choice. Radiologically guided pleural drainage procedures have success rates that are slightly increased over that of nonâ&#x20AC;&#x201C;imageguided chest tube drainage. Close radiographic or sonographic follow-up is indicated to ensure adequate drainage. Successful percutaneous tube drainage of an empyema or complicated parapneumonic effusion should see clinical and radiologic improvement in 48 hours. If the patient fails to improve, the drainage is either inadequate or antibiotic selection is incorrect. In pa-

tients with inadequate drainage, the choices are: (1) percutaneous insertion of additional chest tubes; (2) intrapleural injection of a fibrinolytic agent; (3) thoracoscopy with lysis of adhesions; or (4) thoracotomy with digital lysis of adhesions, operative placement of chest tubes with or without decortication. Intraplerual fibrinolytics can dissolve fibrin membranes and potentially facilitate drainage of the pleural space, although long-term outcomes with this therapy have been mixed. Streptokinase, urokinase, and more recently tissue

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Figure 85-3 The course of pneumococcal empyema in a 16-year-old immunocompetent patient. A. When first seen, the patient has a large volume of loculated pleural fluid with distinct anterior and posterior margins and a meniscus high up on the lateral chest wall forming an obtuse angle between the pleural density and the adjacent parenchyma. B. Five days after tube thoracostomy the volume of pleural fluid is reduced by over 50 percent. C. One month after chest tube removal the patient remains free of symptoms of infection, but significant loculated pleural density remains. D. Three months later the pleural abnormality has totally resolved, and the chest radiograph is normal.

plasminogen activator have been used in this setting. Diluted in 50 to 100 ml of normal saline solution, these fibrinolytics can be injected directly through a chest tube into the pleural space. The chest tube is then clamped for 4 hours and returned to low level suction when the tube is unclamped. This form of therapy can be repeated daily up to 14 days, depending on the rapidity of improvement. Successful response is indicated by an increase in the amount of chest tube drainage, radiographic improvement, and decrease in the systemic signs of infection.

Once the patientâ&#x20AC;&#x2122;s condition has improved, a decision has to be made about when to remove the chest tube. Criteria for tube removal are: (1) system signs of infection are controlledâ&#x20AC;&#x201D;usually after 7 to 10 days of therapy; (2) less than 50 ml of fluid is being drained per day; (3) the lung has expanded as fully as possible; and (4) if a bronchopleural fistula was present, it has sealed. Should the lung not completely reexpand and the volume of unfilled pleural space exceed 100 ml, reexpansion of the lung should be attempted before removing the chest tube. To do so sometimes requires the

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placement of an additional chest tube or surgical decortication of the lung. In 20 to 30 percent of patients with thoracic empyema, antibiotics and drainage with percutaneous chest tubes fail to control the infection. In these patients, thoracotomy with digital lysis of adhesions and operative placement of chest tubes should be strongly considered. Procrastination in moving to thoracotomy is a common error. Thoracotomy frequently returns the patient to good health most quickly. Decortication is used only for control of pleural infection. It is not used in patients in whom the infection is controlled, but the pleura remains persistently thickened; this type of thickening usually resolves spontaneously over several months (Fig. 85-3). Adequate pleural drainage is particularly crucial in an empyema that is accompanied by a bronchopleural fistula. Undrained pleural fluid can spill through the fistula into the lung and cause a diffuse pneumonitis. A bronchopleural fistula is suspected when the chest radiographs show pleural air-fluid levels and when a patient raises more sputum than anticipated, especially when the production of sputum is position dependent.

TUBERCULOUS PLEURAL EFFUSIONS In the United States, tuberculosis is responsible for approximately 2 percent of all pleural effusions. Although usually considered a chronic illness, one-third of patients with tuberculous pleuritis have an acute illness of less than 1 weekâ&#x20AC;&#x2122;s duration, and two-thirds seek medical attention within 1 month of the time of onset of symptoms. Nonproductive cough, pleuritic chest pain, and fever occur in most patients; however, as many as 15 percent of patients may be afebrile. Patients with chronic infection frequently present with weight loss, malaise, and dyspnea. Tuberculous effusions are usually unilateral and moderate in size. In approximately one-third of patients with tuberculous pleural effusions, coexisting parenchymal disease is evident radiographically. If there is no radiographic evidence of parenchymal disease, the infection usually signifies primary tuberculosis. In 65 percent of patients with tuberculous pleuritis in whom the effusion resolves spontaneously, symptomatic parenchymal disease will occur within 12 months. In 30 percent of patients with tuberculous pleural effusion, the initial tuberculin skin test is negative. However, a repeat test, within 8 weeks of the development of symptoms, is likely to be positive. A tuberculous effusion is usually serous, may be serosanguineous, but is almost never frankly bloody. Examination of pleural fluid is diagnostic of tuberculosis only if mycobacteria are demonstrated by smear or culture. Unfortunately this is an uncommon occurrence as mycobacteria are demonstrable on smear in less than 10 percent of patients and on culture in only 25 percent of patients. Decisions regarding treatment are usually made without confir-

Non-Malignant Pleural Effusions

matory stains and well before the culture results are available. Certain features of tuberculous pleural fluid are helpful in either supporting or discounting the diagnosis of tuberculosis. Typically, more than 50 percent of all white blood cells in a tuberculous pleural effusion are mature lymphocytes, and a differential count that reveals more than 80 percent mature lymphocytes strongly suggests either tuberculosis or malignancy. The eosinophil count rarely exceeds 10 percent in tuberculous pleural fluid. Mesothelial cells are rare; indeed, more than 5 percent mesothelial cells in the differential count argues strongly against a tuberculous etiology. A pleural effusion ADA greater than 70 IU/l has been shown to be highly sensitive and specific for the diagnosis of pleural tuberculosis in patients suspected of having tuberculosis. Increased ADA levels have also been found in patients with malignancy or empyema, and histologic or bacteriologic confirmation of tuberculosis remains a necessity. The total protein content of the tuberculous effusion tends to be quite high; values above 5 g/dl suggest a tuberculous effusion. The concentration of glucose in pleural fluid is usually greater than 60 mg/dl; the pH varies widely and is of little diagnostic help. Biopsy of the pleura demonstrates granuloma in approximately 80 percent of patients. Pleural tuberculosis is the only non-neoplastic pleural exudate readily diagnosed by a pleural biopsy. Culture of the pleural biopsy is helpful as well since Mycobacterium tuberculosis can be isolated from over 85 percent of biopsies. Although other diseases, including fungal infection, sarcoidosis, and rheumatoid arthritis, may produce granulomatous pleuritis, more than 95 percent of patients with demonstrable pleural granuloma have tuberculosis. Even though pleural biopsy and pleural fluid examination fail to substantiate the diagnosis of tuberculosis, empiric antituberculous therapy is appropriate in certain patients. A positive tuberculin skin test in a patient less than 40 years old, in combination with a pleural fluid analysis that is compatible with tuberculosis, is an indication for empiric antituberculous therapy. In contrast, the patient with a suspected tuberculous pleural effusion who is more than 40 years old and who has risk factors for bronchogenic carcinoma should be subjected to thoracoscopy or open pleural biopsy rather than to empiric therapy. The absence of granulomatous inflammation in the open pleural biopsy of a tuberculin-positive patient virtually excludes the diagnosis of tuberculosis and obviates the need for antituberculous therapy. With antituberculous therapy, the average patient becomes afebrile within 2 weeks and radiographic clearing usually occurs in 6 to 12 weeks. The addition of corticosteroids may lead to more rapid resolution of symptoms and pleural fluid on chest radiograph. Tuberculous effusions may be accompanied by pleural thickening, but the thickening usually undergoes striking resolution in response to antituberculous therapy. Fibrothorax is rare. Therefore, consideration of decortication for pleural thickening should be delayed until the patient has had at least 6 months of antituberculous therapy.

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Tuberculosis in the form of pleural disease sometimes becomes manifest in a patient in whom long-dormant tuberculous disease reactivates and forms a bronchopleural fistula. The patient then usually produces sputum and develops fever, sometimes in conjunction with chest pain; most have bacterial superinfections of the pleural space. Empyema thoracis in a patient with previous tuberculosis, particularly one who has never received chemotherapy, should rouse the strong suspicion of reactivation of tuberculous infection. The diagnosis is suggested by the development of an air-fluid level in the pleural cavity. A tuberculous bronchopleural fistula requires antituberculous chemotherapy and chest tube drainage of the infected pleural cavity. In some individuals in whom antituberculous therapy has succeeded in eliminating mycobacteria from the sputum, a persistent bronchopleural fistula requires decortication for relief.

when the disease is not disseminated. Most patients with primary coccidioidomycosis and pleural effusion do not require systemic antifungal therapy. Cryptococcosis is another rare cause of pleural effusion. Pleural cryptococcosis appears to result from extension of a primary subpleural cryptococcal infection into the pleural space. More than half of the patients have serious underlying disease, most often leukemia, lymphoma, or the acquired immunodeficiency syndrome (AIDS). The pleural effusion is usually unilateral; cultures are positive for the organism in approximately 50 percent of patients. Cryptococcal pleural effusions have high titers of cryptococcal antigen. Patients with serious coexisting disease should receive amphotericin B and 5-fluorocytosine. However, immunocompetent patients may recover without specific therapy. Histoplasmosis rarely produces pleural effusions, i.e., less than 1 percent of patients with histoplasmosis manifest pleural fluid radiographically. Treatment is unnecessary, since the effusion usually resolves spontaneously in several weeks.

FUNGAL PLEURAL EFFUSIONS Fungal diseases account for only 1 percent of all pleural effusions. The most common cause is Aspergillus infection (usually A. fumigatus), which invades the pleural cavity via a bronchopleural fistula complicating lung resection or reactivation tuberculosis. The signs and symptoms mimic chronic bacterial infection of the pleura. In pleural fluid, clumps of hyphae appear as brown suspended particles, and their gross appearance raises a suspicion of aspergillosis. In patients with pleural aspergillosis, precipitating antibodies in the serum and the wheal and flare cutaneous reaction are almost always positive. Optimal therapy consists of surgical evacuation of the pleural cavity, closure or excision of the bronchopleural fistula, and administration of amphotericin B systemically. An entirely different expression of Aspergillus infection is localized pleural thickening developing in the vicinity of an Aspergillus mycetoma. This is considered in detail elsewhere in this volume. However, it is worth emphasizing that occasionally in patients with chronic cavitary or cystic parenchymal disease the initial radiographic feature of Aspergillus infection is focal pleural fibrosis followed, months later, by a mycetoma in the abnormal adjacent parenchyma. Approximately 20 percent of patients with acute Coccidioides immitis infection show evidence of pleural disease on the chest radiograph, and 70 percent complain of pleuritic chest pain. Free fluid in the pleural cavity is demonstrable in approximately 7 percent of patients. The patients are almost always febrile, and about one-half have either erythema nodosum or erythema multiforme. In about 50 percent of patients, parenchymal infiltrates accompany the pleural effusion. The effusions are usually unilateral. Examination of the pleural fluid reveals a predominance of lymphocytes on the white cell count, a glucose concentration greater than 60 mg/dl, and, rarely, eosinophilia. Pleural fluid cultures are positive for C. immitis in 20 percent of patients; culture of the pleural biopsy specimen has a much higher yield. Complement fixation titers higher than 1:16 are common even

VIRAL PLEURAL EFFUSIONS The true incidence of viral pleural effusions is unknown. It is also believed that many self-limited effusions represent undiagnosed viral infections; these would account for approximately 10 to 15 percent of the total of all effusions. Rarely is a particular viral agent identified, so the diagnosis of viral pleural effusion is almost invariably one of exclusion. Pleural effusions occur in approximately 10 percent of patients with adenovirus infections. In addition to adenovirus infections, pleural effusions also occur with influenza virus, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, and infectious hepatitis. A pleural fluid cell count usually reveals a predominance of mononuclear cells.

PARASITIC INFECTIONS OF THE PLEURAL SPACE Amebic liver abscess is the most common extraintestinal site of infection by E. histolytica. In turn, pleural pulmonary amebiasis is the most common complication of amebic liver abscess and is usually due to the erosion of the abscess through the diaphragm to involve the pleural space or lung parenchyma. Sympathetic pleural effusions and atelectasis are common accompaniments of liver abscesses and do not indicate extension of infection into the pleural space. Patients with pleural pulmonary complications present with cough, pleuritic pain, and dyspnea. Empyema due to rupture of the abscess into the pleural cavity presents with sudden respiratory distress and pain and has a substantial mortality. In some instances, a hepatobronchial fistula forms and has been associated with spontaneous drainage of the hepatic abscess. The diagnosis of amebic abscess is suggested by the discovery of

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“anchovy paste” or “chocolate sauce” pleural fluid. E. histolytica is usually demonstrable in the pleural collection. Treatment consists of metronidazole 750 mg PO tid for 5 to 10 days plus diloxanide furoate 500 mg 3 times a day for 10 days. Human infection by the lung fluke Paragonimus westermani is widely distributed in Africa, Asia, and South America. The cercariae are ingested orally, transit the intestinal wall, and migrate through the peritoneal cavity across the diaphragm into the pleural cavities and then into the lungs, where they ultimately lodge. The clinical manifestations of paragonimiasis are eosinophilia and chest complaints, including a cough productive of brown sputum with intermittent hemoptysis. Up to half of patients will have pleural effusions, and in some they may be quite large. The characteristics of the pleural fluid with paragonimiasis are glucose less than 10 mg/dl, LDH level above 1000 IU/l, the pH below 7.1, and differential count with a high percentage of eosinophils. The diagnosis is established by demonstrating the presence of operculated eggs in sputum or feces. A serum complement fixation test is also available and helpful. The hydatid cysts of E. granulosus form in the liver in 50 to 70 percent of patients and in the lung of 20 to 30 percent of patients. Pleural disease develops when either a hepatic or parenchymal lung cyst ruptures into the pleural space. The patient develops an acute illness with severe chest pain, dyspnea, and sometimes shock, secondary to severe allergic reactions to parasitic antigens suddenly released. The diagnosis is established by recognition of daughter cysts in the pleural fluid. Optimal treatment is surgical resection to drain the pleural space and removal of the original cyst.

PULMONARY EMBOLI Pulmonary emboli likely represent a very common and underapprecieated cause of pleural effusion. In fact, pleural effusions occur in 30 to 50 percent of patients with pulmonary emboli. Different mechanisms have been postulated to account for the pathogenesis of pleural effusion in these patients and to account for the fact that about 25 percent of the effusions are transudates and about 75 percent are exudates. In patients with pleural effuions and any level of suspicion for pulmonary embolism exists, it is prudent to evaluate this patient. Computed tomography with contrast enhancement per pulmonary embolism protocol is the modality of choice in this situation because it can provide additional diagnositic information about the pulmonary parenchyma and pleural space. This topic is covered in detail elsewhere in this volume.

PANCREATITIS Approximately 20 percent of patients with acute pancreatitis develop pleural effusions. Although most of the effusions are unilateral and left-sided, the effusion is some-

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times bilateral and occasionally only right-sided. The effusion results from contact of the pleura with enzyme-rich peripancreatic fluid that gains access to the pleural space, most commonly via transdiaphragmatic lymphatics, and less often, through a sinus tract between a pancreatic pseudocyst and the pleural space. Rarely, pancreatic fluid can transverse the aortic and esophageal hiatuses into the mediastinum, where an inflammatory response may evoke a mediastinal pseudocyst. Usually the symptoms of pancreatitis (abdominal pain, nausea, and vomiting) dominate the clinical picture. At times, however, pleuritic chest pain and dyspnea may be the presenting complaint. The diagnosis is established by demonstrating abnormally high levels of amylase in the pleural fluid. The pleural fluid amylase is invariably higher than the serum amylase in pancreatitis-induced pleural effusions, often with a ratio of 6:1 or more. High levels of amylase in pleural fluid are not necessarily diagnostic of pancreatic disease; similar increments also occur after esophageal rupture into the pleura and occasionally with a malignant pleural effusion. About 10 percent of patients with malignant pleural effusions have high levels of amylase in their pleural fluids. However, the degree of increase is only slight to moderate in malignant effusions, and isoenzyme analysis will show the amylase to be salivary in type. The pleural fluid associated with pancreatitis is frequently serosanguineous and sometimes bloody. The concentration of glucose in the pleural fluid is normal, and the white blood cell count may vary from 1000 to 50,000 cells per cubic millimeter; as a rule, polymorphonuclear leukocytes predominate. Pleural effusions secondary to pancreatitis usually resolve promptly as the pancreatic inflammation subsides. If resolution has not occurred within 2 weeks, the possibility of a pancreatic pseudocyst or abscess is likely. Should a sizable effusion remain after 2 to 3 weeks of nasogastric suction, no oral intake, and repeated thoracenteses, the abdomen should be reimaged or even surgically explored, looking for abscess, pseudocyst, and pancreaticopleural sinus. At the time of operation, a pancreatogram is performed to search for the sinus tract that can be ligated or excised. If no sinus is identified, careful dissection of the retroperitoneum in the region of the aortic and esophageal hiatus is undertaken in search of the tract.

ESOPHAGEAL PERFORATION Approximately two-thirds of esophageal perforations occur as a complication of esophagoscopy. This is particularly true when the procedure is performed in an attempt to remove a foreign body or dilate an esophageal stricture. Other potential causes include esophageal carcinoma, gastric intubation, chest trauma, and finally, spontaneous rupture as a complication of vomiting (Boerhaave syndrome). Perforation of the esophagus introduces oropharyngeal contents into the mediastinum, thereby evoking an acute

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mediastinitis. The inflammatory reaction, in turn, often ruptures through the mediastinal pleura to produce a pleural effusion that is frequently complicated by a pneumothorax. Pleural effusions occur in approximately 60 percent of patients with esophageal perforation; 25 percent have a pneumothorax. The pleural effusion is usually left-sided but is sometimes right-sided or bilateral. Radiographic findings include widening of the mediastinum and pneumomediastinum. Most of the morbidity from esophageal perforation is due to the infection of the mediastinum and the pleural space by oropharyngeal bacterial flora. Clinical symptoms are dominated by chest pain that is usually quite severe. Hematemesis occurs in about half of the patients. Subcutaneous emphysema as a late manifestation occurs in about 10 percent of patients with esophageal rupture. Examination of the pleural fluid reveals an exudative reaction: the amylase level is high, the pH is very low (frequently less than 6.0), squamous epithelial cells are present, and rarely, there may be ingested food particles. The amylase that has entered the pleural space through the esophageal defect is salivary rather than pancreatic. The treatment of choice for esophageal rupture is exploration of the mediastinum, primary repair of the esophageal tear, and drainage of the pleural space and mediastinum.

INTRA-ABDOMINAL ABSCESS Pleural effusion occurs in about 80 percent of patients with a subphrenic abscess. The infection usually follows an intraabdominal surgical procedure; splenectomy and exploratory laparotomy for trauma are the more common antecedents. A surgically related subphrenic abscess usually becomes clinically evident 1 to 3 weeks postoperatively. Other predisposing illnesses include gastric, duodenal, or appendiceal perforation, diverticulitis, cholecystitis, pancreatitis, or trauma. The pleural fluid is an exudate in which polymorphonuclear leukocytes predominate. The pleural fluid white blood count may be as high as 50,000 per cubic millimeter, but the pH is higher than 7.2, and the glucose concentration exceeds 60 mg/dl. It is uncommon for the pleural fluid to become infected. The diagnosis of a subphrenic abscess is often first made on the basis of a routine chest or abdominal radiograph. An air-fluid level, below the diaphragm and outside the gastrointestinal tract, is demonstrable in about 70 percent of these patients. Abdominal CT scans and ultrasound studies are very effective in diagnosing subphrenic abscesses. A CTguided percutaneous aspiration of the subphrenic abscess is frequently helpful in finalizing the diagnosis and in identifying the responsible organisms. Treatment should be directed at the abdominal abscess with appropriate antibiotics and percutaneous or surgical drainage. About 20 percent of patients with a hepatic abscess develop a pleural effusion; the effusion is usually, though not invariably, right-sided (Fig. 85-4). Most of the patients mani-

Figure 85-4 A. Chest radiograph of a 62-year-old man with insulin dependent diabetes mellitus and bilateral pleural effusions. B. The CT scan revealed a large abscess in the right lobe of the liver complicating chronic pancreatitis. The pleural fluid was an exudate and sterile. Aspirate of the hepatic abscess yielded Enterococcal spp. and Clostridium spp.

fest fever, abdominal pain, and abnormal liver function tests, especially an increase in the concentration of alkaline phosphatase in the blood. CT scanning of the abdomen is currently the most sensitive means of detection; definitive diagnosis can be made using CT scanning as a guide to percutaneous aspiration.

COLLAGEN VASCULAR DISEASES Rheumatoid Arthritis Pleural thickening and effusions are the most common pulmonary manifestations of rheumatoid arthritis. They are frequently symptomatic and occur in 8 percent of men and

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2 percent of women with rheumatoid arthritis in whom chest radiographs are made serially. Autopsy studies have revealed that 40 to 50 percent of patients with rheumatoid arthritis have histologic evidence of pleural disease. Although in most patients pleural disease develops a few weeks to months after the onset of joint symptoms, in about 5 percent the pleural disease precedes the arthritis; in another 15 percent, the onset of the pleural disease is simultaneous with the initial episode of synovitis. The severity of arthritis, in terms of the number of joints involved or destruction on joint radiographs, does not correlate with the presence of pleural disease. However, the incidence of pleural effusions increases in those patients who have high titers of rheumatoid factor and subcutaneous nodules. In some patients, pericardial effusion occurs concurrently. About one-third of patients with rheumatoid pleural effusions have no respiratory symptoms. However, most notice some combination of pleuritic chest pain, cough, dyspnea, or fever. Sometimes the joint symptoms flare coincident with the onset of the pleural syndrome. The pleural effusions are usually small in volume but occasionally become large enough to produce respiratory compromise. Eighty percent of patients have a unilateral pleural effusion; in 20 percent, the effusions are bilateral. Both intrapulmonary nodules and diffuse fibrosis sometimes accompany rheumatoid pleural disease. The nodules are often subpleural; at times, they undergo necrosis to produce a pyopneumothorax. The pleural fluid in rheumatoid arthritis is usually an exudate; the concentration of total protein ranges from 3.5 to 6.0 g/dl and the LDH concentration is greater than 700 units. In 80 percent of the patients, the concentration of glucose in the pleural fluid is less than 30 mg. The pH is usually less than 7.2. The predominant cell is either the polymorphonuclear leukocyte or, less often, the lymphocyte; a mixture of both cell types is not uncommon. In many patients, the ratio of pleural fluid complement to serum complement is less than 0.4. Pleural biopsy is usually nonspecific but can rarely demonstrate pleural rheumatoid nodules that are diagnostic. For the most part, the etiologic diagnosis of the pleural effusion is one of exclusion. Most patients can be treated with a nonsteroidal anti-inflammatory/analgesic medication such as aspirin, indomethacin, or ibuprofen. Only one-third of patients require systemic corticosteroids for pleural disease. The response to steroids is good, with symptomatic relief and control of pleural fluid volume occurring in more than 75 percent of those treated. The duration of active pleural inflammation is limited in most patients. Fifty percent of patients (both treated and untreated) undergo resolution of the pleural disease within 4 months of onset. Many are left with an asymptomatic, pleural density on chest radiograph. If the patient is asymptomatic and the pleural fluid has not recurred while off therapy for 6 months, the chance of recurrence of the pleural syndrome is small; fewer than 10 percent of patients develop a late recurrence. The postinflammatory pleural residuum is rarely clinically significant, but a few patients show a modest reduction in vital capacity. An overt fibrothorax that produces symp-

Non-Malignant Pleural Effusions

tomatic restrictive ventilatory disease and requires decortication is rare. However, about 20 percent of the patients develop a chronic, persistent pleural syndrome that tends to flare when therapy is stopped. The therapeutic goal for these patients should be symptomatic relief. The frequency of residual pleural fibrosis and restrictive ventilatory defects is higher in this group than in patients who undergo rapid spontaneous remission. There is little evidence to suggest that either nonsteroidal or corticosteroid therapy reduces the degree of longterm respiratory dysfunction. The majority of patients who experience chronic rheumatoid activity undergo remission of the pleural syndrome in 1 to 5 years.

Systemic Lupus Erythematosus Pleural effusions occur in up to 40 percent of patients with SLE (Fig. 85-5). Even more have pleuritic chest pain without effusion at some time during the course of their illness. A comparable incidence of pleural effusions has been reported in drug-induced SLE. In most patients with lupus pleuritis, arthritis or other symptoms precede the pleuritis; however, the pleural disease occasionally presents first. The pleural effusions are small in volume and bilateral in about 50 percent of the patients; in the remainder, the incidence is about equally divided between the right and left sides. In 20 percent of the patients, the effusions flit from side to side. Chest radiographs often show lesions other than the pleural effusionsâ&#x20AC;&#x201D;parenchymal infiltrates, platelike atelectasis, and cardiomegaly due to myocardiopathy, pericardial effusion, or both. The pleural fluid is usually clear and yellow; the white cell count reveals a preponderance of polymorphonuclear leukocytes or lymphocytes. The concentration of complement in the pleural fluid of most patients with lupus pleuritis is subnormal, and the ratio of pleural fluid to serum complement is less than 0.4. In contrast to rheumatoid arthritis, the pH of the SLE effusion is usually higher than 7.20, the concentration of glucose is greater than 60 mg/dl, and the LDH is less than 500 units. A pleural fluid ANA titer greater than or equal to 1:160 and a pleural fluid to serum ANA ratio greater than or equal to 1 is strongly suggestive of lupus pleuritis. The demonstration of LE cells in pleural fluid is diagnostic of lupus pleuritis. The pleural effusion associated with lupus usually responds well to corticosteroids.

Churg-Strauss Syndrome This syndrome is a disorder characterized by hypereosinophilia and systemic vasculitis occurring in individuals with asthma and allergic rhinitis. Approximately 30 percent of patients with this syndrome have a pleural effusion. The pleural fluid is characterized by a very high LDH, low glucose and pH levels, and a high percentage of eosinophils. The only other disease with comparable findings is paragonimiasis. This syndrome responds well to treatment with corticosteroids.

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and there are no readily available laboratory tests which accurately link the medication to the adverse event. The diagnosis is important, as discontinuation of the drug is frequently followed by a spontaneous reversal of the pleural disease. Most drug-induced pleural reactions are associated with a parenchymal abnormality. The symptoms sometimes are acute, i.e., chills, fever, cough, and dyspnea develop within hours to days after taking the offending drug. An acute reaction of this type usually develops when prior use has sensitized the patient to the medication. Nitrofurantoin and procarbazine are identified with this pattern of acute illness. Acute pleuropulmonary reactions are often accompanied by eosinophilia in both blood and pleural fluid. If the offending medication is continued, a chronic syndrome developing over weeks to months can occur. Methysergide, dantrolene, and practolol tend to produce a chronic pleural syndrome with effusion and/or fibrosis. Pleural disease is occasionally not evident clinically until 2 to 3 years after the initial administration of the drug. The pleural changes are either unilateral or bilateral. After stopping the medication, the pleural reaction improves in most patients over a period of 6 months; however, some are left with a fibrothorax.

PLEURAL EFFUSION SECONDARY TO ASBESTOS EXPOSURE

Figure 85-5 A. Chest radiograph of a 60-year-old woman with bilateral pleural effusions from systemic lupus erythematosus. The pleural fluid was an exudate with a pleural fluid to serum C4 ratio of 0:11, pleural fluid ANA titer 1:320, and pleural fluid/serum ANA ratio of 2:1. B. The pleural effusions ultimately required pleurodesis for control; talc slurry on the left and surgical parietal pleurectomy on the right.

PLEURAL EFFUSION FROM DRUG REACTIONS Few pleural effusions are induced by drugs. It is very difficult to make an accurate diagnosis of a drug reaction on clinical grounds. Rechallenge is seldom feasible in clinical practice,

Three percent of asbestos workers develop pleural effusions related to their asbestos exposure. There is a direct relationship between the level of asbestos exposure and the development of the pleural effusion. In patients with heavy, moderate, and mild asbestos exposure, the incidence of pleural effusion was 9.2, 3.9, and 0.7 effusions per 10,000 personyears of observation, respectively. The pleural effusion frequently develops within 10 years of the initial exposure, in contrast to the occurrence of pleural plaques and calcification, which usually do not occur until more than 10 years have passed since the initial exposure. It is hypothesized that an asbestos fiber is inhaled, passes to the periphery of the lung, ultimately pierces the visceral pleura, and there rubs against and irritates the parietal pleura creating an inflammatory reaction that will lead to effusion and/or plaque. Microscopic examination of the parietal pleura reveals chronic fibrosing pleuritis with varying degrees of inflammation, but asbestos bodies and fibers are conspicuous for their absence in both the pleural plaque and effusion. There is, however, a heavy burden of asbestos fibers and ferruginous bodies in the lymphatic plexus beneath the visceral pleura, and a lung biopsy can demonstrate the causative agent. Almost two-thirds of patients with asbestos-related pleural effusions are asymptomatic. Pleuritic chest pain and dyspnea are seen in the other third. Pleural friction rubs are rare. The chest radiograph usually reveals a small or moderate unilateral pleural effusion. In 10 percent of patients, the effusions are bilateral. Approximately 20 percent have associated pleural plaques, fewer than 5 percent have pleural

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calcification, and fewer than 10 percent develop pulmonary fibrosis. The pleural fluid is either serous or serosanguineous. The total white blood count in the pleural fluid may be as high as 20,000 per cubic millimeter, and either polymorphonuclear leukocytes or mononuclear cells predominate. Pleural fluid eosinophilia is common. The diagnosis of asbestos pleural effusion is one of exclusion. Patients should be carefully evaluated for mesothelioma or bronchogenic carcinoma. An extensive evaluation, including direct visualization of the pleural space by thoracoscopy, or an open pleural biopsy is necessary to feel confident that all other possibilities have been excluded. In most patients, asbestos pleural effusion resolves in 1 to 2 years. Approximately 20 percent will progress to massive pleural fibrosis; another 5 percent develop mesotheliomas. In 30 percent of patients, the volume of the effusion waxes and wanes over a long period. Rounded atelectasis, or folded lung, is an unusual form of asbestos-associated pleural disease that results in a subpleural focus of airless lung. Radiographically such patients present with a subpleural, rounded mass usually at the lung base. Specific for the syndrome is a curvilinear shadow extending from the lower border of the mass toward the hilus, the â&#x20AC;&#x153;comet tailâ&#x20AC;? sign. In most instances, the pleura immediately adjacent to the mass is thickened, often in conjunction with thickening of the lobar fissures. The initial event in the pathogenesis of rounded atelectasis is believed to be thickening of the parietal and visceral pleurae incident to the asbestos exposure; the adjacent pulmonary parenchyma then undergoes atelectasis. Fusion of the parietal and visceral pleurae immobilizes the lung at its periphery, and further atelectasis causes the airless lung to curl, thereby drawing blood vessels and bronchi to the inferior pole of the mass and creating the comet tail. Once radiographically visible, the rounded atelectasis usually does not progress either in size or contour over many years.

CHYLOTHORAX Most absorbed fat is conveyed to the blood by the thoracic duct in the form of chylomicrons. Fat enters the intestinal lacteal vessels and then travels to the cisterna chyli, a lymphatic structure located on the body of the second lumbar vertebra. From the cisterna chyli, the thoracic duct traverses the esophageal hiatus of the diaphragm to enter the thoracic cavity. The thoracic duct then ascends extrapleurally in the posterior mediastinum along the right side of the anterior surface of the vertebral column in proximity to the esophagus and the pericardium. At the level of the fourth to sixth thoracic vertebra, the duct crosses to the left of the vertebral column and continues cephalad to terminate in the left subclavian vein. A chylothorax is formed when the thoracic duct is disrupted and chyle enters the pleural space. Chyle is a milky, opalescent fluid that contains chylomicrons, triglycerides,

Non-Malignant Pleural Effusions

and lymphocytes; it is bacteriostatic and non-irritating and has little propensity to form fibrothorax. Fifteen hundred to twenty-five hundred milliliters of chyle normally empty into the venous system daily. As a result, pleural effusions resulting from disruption of the thoracic duct can be quite large and tend to reaccumulate rapidly following drainage. The flow of lymph through the thoracic duct can be increased 2 to 10 times the resting level by ingesting fat, whereas ingestion of protein or carbohydrates has little effect on lymph flow. The protein content of chyle is usually above 3 g/dl, and the electrolyte composition is similar to that of serum. More than 50 percent of chylothoraxes are related to tumor invading the thoracic lymph duct; lymphoma being responsible for 75 percent of the malignancy-associated chylothoraxes. Therefore, nontraumatic chylothorax is an indication for a diligent search for malignancy. Trauma is the second leading cause of chylothorax, responsible for 25 percent of cases. Surgery is the most common cause of traumatic chylothorax, especially in operations that mobilize the left subclavian artery. Chylothorax also may be a result of left subclavian lines complicated by clot that obstructs the thoracic duct ostium. Penetrating trauma to the chest, such as gunshot or knife wounds, occasionally sever the thoracic duct, but nonpenetrating trauma can also produce the syndrome. A chylothorax secondary to closed trauma is usually on the right side, and the site of rupture is in the region of the ninth and tenth thoracic vertebra. Falls, motor vehicle accidents, and compressive injuries to the trunk and abdomen are common causes. However, everyday stresses such as coughing, sneezing, vomiting, and lifting heavy objects may produce a chylothorax. Approximately 25 percent of chylothoraxes have no identifiable cause; they are presumed to be secondary to minor trauma. Pulmonary lymphangiomyomatosis, which is a rare interstitial parenchymal disease, has been associated with chylothorax. The symptoms of chylothorax are almost exclusively related to the volume of fluid in the thoracic cavity. Fever and chest pain are virtually absent. After trauma, the chylothorax usually develops in 2 to 10 days. Lymph collects extrapleurally in the mediastinum after the thoracic duct is disrupted to form a chyloma, a posterior mediastinal mass. In time, the mediastinal pleura ruptures, and chyle enters the pleural space. A pleural fluid that is white, odorless, and milky in appearance suggests the diagnosis of chylothorax. Effusions of this appearance are chylothorax, a pseudochylothorax caused by high lipid levels (cholesterol or lecithin-globulin complexes) in chronic pleural effusions, or an empyema. The first step in differentiation is to centrifuge the fluid. If the supernatant clears, the white color is due to large numbers of white blood cells, and the patient probably has an empyema; the supernatant of a chylous or pseudochylous effusion remains opalescent after centrifugation. Cholesterol crystals are usually easily recognized as rhomboid structures on smears of the sediment. A second way to identify cholesterol is to add 1 to 2 ml of ethyl ether to the pleural fluid, which clears if a high concentration of cholesterol is responsible for the

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Disorders of the Pleural Space

opalescence. Pseudochylothorax accounts for approximately 10 percent of effusions rich in lipids; rheumatoid pleuritis and tuberculosis are the most common underlying diseases for pseudochylothorax. The best way to establish the diagnosis of chylothorax is to determine the concentrations of the triglyceride in the pleural fluid. Triglyceride concentrations greater than 110 mg/dl usually indicate a chylothorax. Levels below 50 mg/dl virtually exclude a chylothorax. In patients with the intermediate values (50â&#x20AC;&#x201C;110 mg/dl), a lipoprotein analysis of the pleural fluid is performed. The demonstration of chylomicrons by lipoprotein analysis establishes the diagnosis of chylothorax. Remember that not all chylous fluids have a classic milky appearance. Indeed, almost half are either bloody or turbid in appearance. Therefore, determination of the triglyceride content of an exudative fluid of unknown etiology, particulary in patients with mediastinal malignancy, thoracic trauma, or recent thoracic surgery, is a must. For patients with chylothorax resulting from traumatic or surgical disruption of the thoracic duct, therapeutic efforts should be directed toward correction of the leak rather than simply removing the fluid. The defect in the thoracic duct often closes spontaneously if caused by trauma. In the dyspneic patient, management begins with placement of either a pleuroperitoneal shunt or chest tube. Efforts are then made to reduce chyle formation; these include placing the patient on constant gastric suction and keeping the patient at bed rest; fluid and nutrition are best supplied by parenteral hyperalimentation. Medium-chain triglycerides have been proposed as a means of providing an oral source of calories to these patients. The rationale is that the medium-chain triglycerides are absorbed into the portal vein directly and thus enter the circulatory system rather than travel through the thoracic duct. In most instances, the drainage of chyle will slow or stop within the first 7 days following chest tube insertion. Malnutrition and lymphopenia are likely to occur in a patient with chylothorax if large amounts of lymph are drained. If lymph drainage has not stopped spontaneously within 7 days, surgical ligation of the thoracic duct is in order. At the time of surgery, an attempt is made to find the leak in the duct and ligate on both sides of the leak. In many instances, the leak will not be found, and the thoracic duct is ligated both high and low in the thorax. Pleurodesis is a therapeutic alternative that is reserved for poor-risk patients who are not surgical candidates. The management of a nontraumatic chylothorax poses a challenge to the clinician to identify the cause of the leak and treat it successfully. Lymphoma is a key candidate. Often the patient with lymphoma and chylothorax has no evidence of lymphoma outside the thorax. A CT study of the mediastinum should be done on all such patients. The initial management of the patient with chylothorax suspected of occult intrathoracic lymphoma is as described above: inserting a chest tube, placing the gastrointestinal tract at rest, and preserving the patientâ&#x20AC;&#x2122;s nutritional status by using parenteral hyperalimentation. If the CT scan and/or chest radiograph show evidence

of intrathoracic tumor, the patient should undergo biopsy of this tumor to establish diagnosis. In a patient known to have lymphoma or metastatic carcinoma, chylothorax may be treated by chemotherapy and mediastinal irradiation in anticipation that the leak will stop. Surgical ligation of the thoracic duct is less successful in chylothorax resulting from malignancy. Pleurodesis may still be effective and for chylothorax secondary to lymphoma has been shown to be highly effective.

HEMOTHORAX Hemothorax is the presence of significant amounts of blood in the pleural space (Fig. 85-6). The most common causes

Figure 85-6 A. Admission chest radiograph of a 56-year-old man with a 1-week history of left-sided chest pain showed total opacification of the left hemithorax. Thoracentesis demonstrated a hemothorax. B. A CT scan of the thorax showed a dissecting aneurysm of the ascending thoracic aorta with hemorrhage into the left pleural space.

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are penetrating and non-penetrating chest trauma. Occasionally iatrogenic procedures, such as percutaneous placement of central venous catheters in the subclavian or internal jugular veins, or translumbar aortography, produce a hemothorax. Hemothorax should be considered to be present when the hematocrit of the pleural fluid is more than half that of the peripheral blood. The diagnosis should be entertained in any individual with thoracic trauma and a pleural effusion on the chest radiograph. A number of bleeding sites may be responsible for the hemothorax, complicating either blunt or penetrating trauma. These sites include pulmonary parenchymal laceration, intercostal vessel laceration, and rupture of pleural adhesions. Much less common is mediastinal injury that causes damage of a major blood vessel or decompression of abdominal hemorrhage through a traumatic diaphragmatic injury. The vast majority of hemothoraxes are due to bleeding from the low-pressure, pulmonary parenchymal vessels; they stop bleeding spontaneously when the hemothorax is evacuated and the pleural surfaces are reapposed. In 60 to 80 percent of these patients, an associated pneumothorax is found, after both nonpenetrating and penetrating trauma. The treatment of choice is the immediate insertion of a chest tube. The chest tube is useful to: (1) evacuate blood from the pleural space, thereby decreasing the incidence of empyema and/or fibrothorax; (2) stop bleeding from pulmonary parenchyma or pleural lacerations by apposing the pleural surfaces to create a tamponade; and (3) provide a quantitative measure of continued bleeding. Immediate thoracotomy is rarely indicated, since tube thoracostomy controls bleeding in about 85 percent of cases. But cardiac tamponade, continued bleeding, evidence of a major bronchial rupture, or sucking chest wounds require immediate thoracotomy. If bleeding is more than 200 ml/hour and shows no signs of slowing over 4 to 6 hour, thoracotomy should be seriously considered to control bleeding. Thoracotomy is not indicated for removal of retained blood in patients without active bleeding. The incidence of empyema thoracis is the same in patients undergoing surgical evacuation as in those who are allowed to undergo spontaneous lysis of the pleural clot. Approximately 85 percent of patients with hemothorax and retained blood are left with no pleural abnormalities on follow-up examination. Empyema occurs in approximately 5 percent of patients with hemothorax. Those with gross contamination of the pleural space at the time of their original injury are most susceptible. Empyema is also more common in patients who are in shock on admission, in those with associated abdominal injuries, and in patients who require prolonged pleural drainage. An exudative pleural effusion occasionally follows a hemothorax after removal of the chest tubes. This occurs in 15 to 30 percent of patients and is more common in those with residual hemothorax when the tube is removed. When such an effusion does occur, a diagnostic thoracentesis is per-

Non-Malignant Pleural Effusions

formed to rule out the possibility of pleural infection. If a pleural infection is not present, the pleural effusion usually clears spontaneously without residual disease. Fewer than 1 percent of patients with hemothorax develop a fibrothorax. Nontraumatic hemothorax is uncommon. But when it does occur, it usually indicates pleural malignancy. It can also occur during anticoagulant therapy for pulmonary embolus. Other causes include bleeding disorders such as hemophilia or thrombocytopenia, complication of spontaneous pneumothorax, ruptured thoracic aorta, and pancreatic pseudocyst.

POSTSURGICAL PLEURAL EFFUSIONS Two to three days after an upper abdominal surgical procedure, pleural effusions can be identified on the decubitus chest radiograph in up to 70 percent of patients. The effusions are usually small with only 20 percent measuring more than 10 mm in thickness on the decubitus films. Postoperative pleural effusions are more common in patients undergoing upper abdominal surgical procedures, in patients with postoperative atelectasis, and in those with free abdominal fluid at the time of operation. Large effusions are particularly apt to occur after splenectomy. The effusions resolve spontaneously. The incidence of pleural effusion following coronary artery bypass surgery is as high as 40 percent. The mechanism is unknown but probably involves trauma to the pleura and pericardium during surgery. Effusions are frequently bilateral or unilateral on the left but rarely unilateral on the right. Proper management is usually observation, and a diagnostic tap is not warranted.

SARCOIDOSIS Pleural sarcoidosis has typically been identified at thoracotomy or autopsy. Small pleural effusions and pleural thickening from sarcoidosis are rarely extensive enough to produce clinical or physiological consequences and often are not readily apparent on chest radiographs. CT scanning, however, has demonstrated a high incidence of minor pleural abnormalities. Pleural thickening is often seen in association with extensive parenchymal disease. Pleural abnormalities are often located in the lower lung fields. A pleural effusion can occur in up to 7 percent of patients with sarcoidosis. One-third of cases are bilateral. Pleural biopsy often reveals multiple non-caseating granuloma. Effusions are free-flowing, rarely loculate, and generally small to moderate in size. The fluid is usually an exudate and invariably shows a predominance of lymphocytes. The pleural effusion is rarely associated with acute symptoms such as pleuritic pain, fever, or dyspnea. In some, the effusion may clear spontaneously or with corticosteroid therapy in 1 to 2 months; in others, the effusion can progress to chronic pleural

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Disorders of the Pleural Space

thickening. Because of its relatively rare occurrence, the presence of a pleural effusion in association with pulmonary sarcoidosis should raise a possibility of other causes, including tuberculosis, pneumonia, or heart failure.

With dialysis, the effusion gradually disappears within 4 to 6 weeks in the majority of patients.

YELLOW NAIL SYNDROME POST-CARDIAC INJURY (DRESSLER’S) SYNDROME The post-cardiac injury syndrome consists of fever and pleuropericarditis developing after injury to the pericardium or myocardium. The syndrome has been described following myocardial infarction, cardiac surgery, and blunt chest trauma and occurs in approximately 1 percent of patients with acute myocardial infarction and up to 30 percent of patients undergoing surgical procedures involving the pericardium. Dressler’s syndrome is thought to be an immunologic response to damage of the pericardium, and antibodies to cardiac antigens can be demonstrated in many patients. Affected individuals develop fever, chest pain, pericarditis, pleuritis, and sometimes air space disease after the cardiac injury. Symptoms usually occur in the second or third week following myocardial injury. Almost all patients have a pericardial friction rub, and many have a pericardial effusion. Most patients have a peripheral leukocytosis and an elevated erythrocyte sedimentation rate. The pleural effusion may be either unilateral or bilateral and is usually small. Pericarditis is the dominant clinical feature. The pleural fluid is an exudate with a normal pH and a normal glucose level. Almost a third of patients will have bloody pleural fluid. The pleural fluid cell population will vary from polymorphonuclear predominance to lymphocyte predominance in the more chronic syndromes. The diagnosis is one of exclusion. Non-steroidal anti-inflammatory treatment is typically quite effective at relieving symptoms and hastening resolution of the effusion. For those who fail non-steroidal antiinflammatory treatment, oral corticosteroids are typically effective.

UREMIC PLEURITIS Fibrinous pleuritis is found at autopsy in approximately 20 percent of patients dying of uremia. The pleuritis frequently is asymptomatic but sometimes produces pleuritic chest pain, pleural friction rubs, and pleural effusions. The incidence of pleural effusions with uremia is approximately 3 percent; half of the patients are symptomatic. Sometimes, the effusions are quite large and may occupy more than 50 percent of the hemithorax. The fluid is an exudate that is frequently serosanguineous or hemorrhagic. The glucose level is normal, and the differential white blood count reveals a predominance of lymphocytes in most patients. Pleural biopsy results are nonspecific and reveal chronic fibrinous pleuritis. The diagnosis of uremic pleuritis is again one of exclusion in the patient with chronic renal failure. Dialysis is the treatment of choice.

The yellow nail syndrome refers to thickening, yellowing, and curvature of all the nails in association with lymph edema. It may be associated with pleural effusions, chronic pulmonary infections, and bronchiectasis. The basic abnormality is hypoplasia of the lymphatic vessels. It is conjectured that pleural effusions may develop when a lower respiratory tract infection or pleural inflammation further damages already compromised lymphatic vessels. Pleural effusion occurs in approximately one-third of patients with the yellow nail syndrome. The pleural effusions are bilateral half the time and vary in size from small to massive. The pleural fluid is a clear yellow exudate with normal glucose and predominant lymphocytes in the pleural fluid differential. No specific treatment is available. Spontaneous remission is very unlikely. If the effusion is large, and produces dyspnea, pleurodesis should be considered.

PLEURAL EFFUSIONS IN PATIENTS WITH AIDS Pleural effusions occur in up to 27 percent of hospitalized patients with AIDS. A series of 59 AIDS patients with pleural effusions revealed the cause to be infectious in 39 (66 percent), noninfectious in 18 (31 percent), and unknown in 2 (3 percent). Pleural effusions were caused by bacterial pneumonia in 18 (31 percent) patients, Pneumocystis carinii pneumonia in 9 (15 percent), Mycobacterium tuberculosis in 5 (8 percent), septic embolization in 2 (3 percent), Nocardia asteroides in 2 (3 percent), Cryptococcus neoformans in 2 (3 percent), and Mycobacterium avium intracellulare in 1 (2 percent). Among noninfectious causes (18 patients), hyperalbuminemia was the cause in 11 patients (19 percent), cardiac failure in 3 (5 percent), and atelectasis, Kaposi’s sarcoma (KS), uremic pleurisy, and adult respiratory syndrome in 1 (2 percent) each. Patients with AIDS who had pleural effusions have significantly lower serum albumin levels and lower CD4 counts than those without pleural effusions. In some patients with Pneumocystis carinii–associated pleural effusion, the diagnosis can be established by demonstrating the organism in pleural fluid stained with Gomori’s methenamine-silver. The pleural fluid is an exudate with normal pleural fluid glucose and pH.

ACKNOWLEDGMENT The author offers great appreciation to Dr. Richard H. Winterbauer for allowing him to build on his outstanding previous work.

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SUGGESTED READING Banales JL, Pineda PR, Fitzgerald JM, et al: Adenosine deaminase in the diagnosis of tuberculous pleural effusions. A report of 218 patients and review of the literature. Chest 99:355–357, 1991. Barbas CSV, Cukier A, de Varvalho CRR, et al: The relationship between pleural fluid findings and the development of pleural thickening in patients with pleural tuberculosis. Chest 100:1264–1267, 1991. Berger HA, Morganroth ML: Immediate drainage is not required for all patients with complicated parapneumonic effusions. Chest 97:731–735, 1990. Brook I, Frazier EH: Aerobic and anaerobic microbiology of empyema. A retrospective review in two military hospitals. Chest 103:1502–1507, 1993. Burgess LJ, Maritz FJ, Med M, et al: Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates. Chest 107:1604–1609, 1995. Colice GL, Curtis A, Deslauriers J, et al: Medical and surgical treatment of parapneumonic effusions. An evidencebased guideline. Chest 118:1158–1171, 2001. Connell TR, Stephens DH, Carlson HC, et al: Upper abdominal abscess: continuing and deadly problem. Am J Roentgenol 134:759–765, 1980. Cordasco EM Jr, Beder S, Coltro A, et al: Clinical features of the yellow nail syndrome. Cleve Clin J Med 57:472–476, 1990. Craighead JB, Mossman BT: Medical progress. The pathogenesis of asbestos-associated diseases. N Engl J Med 306:1446– 1455, 1982. Epler GR, McLoud TC, Gaensler EA: Prevalence and incidence of benign asbestos pleural effusion in a working population. JAMA 247:617–622, 1982. Epstein DM, Kline LR, Albelda SM, et al: Tuberculous pleural effusions. Chest 91:106–109, 1987. Fairfax AJ, McNabb WR, Spiro SG: Chylothorax: a review of 18 cases. Thorax 41:880–885, 1986. Halla JT, Schronhenloher RE, Volanakis JE: Immune complexes and other laboratory features of pleural effusions. A comparison of rheumatoid arthritis, systemic lupus erythematosus, and other disease. Ann Intern Med 92: 748–752, 1980. Heffner JE, Brown LK, Barbieri C, et al: Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med 151:1700–1708, 1995. Henke CA, Leatherman JW: Intrapleurally administered streptokinase in the treatment of acute loculated, nonpurulent parapneumonic effusions. Am Rev Respir Dis 145:680–684, 1992. Horowitz ML, Schiff M, Samuels J, et al: Pneumocystic carinii pleural effusion. Pathogenesis and pleural fluid analysis. Am Rev Respir Dis 148:232–234, 1993. Houston MC: Pleural fluid pH: Diagnostic, therapeutic, and prognostic value. Am J Surg 154:333–337, 1987.

Non-Malignant Pleural Effusions

Joseph J, Strange C, Sahn SA: Pleural effusions in hospitalized patients with AIDS. Ann Int Med 118:856–859, 1993. Joseph J, Viney S, Beck P, et al: A prospective study of amylaserich pleural effusions with special reference to amylase isoenzyme analysis. Chest 102:1455–1459, 1992. Keszler P, Buzna E: Surgical and conservative management of esophageal perforation. Chest 80:158–162, 1981. Khan AH: The postcardiac injury syndromes. Clin Cardiol 15:67–72, 1992. Khare V, Baethge B, Lang S, et al: Antinuclear antibodies in pleural fluid. Chest 106:866–871, 1994. Klein JS, Schultz S, Heffner JE: Interventional radiology of the chest: image-guided percutaneous drainage of pleural effusions, lung abscess and pneumothorax. Am J Roentgenol 164:581–588, 1995. Kuhn M, Fitting J, Lewenberger P: Probability of malignancy in pleural fluid eosinophilia. Chest 96:992–994, 1989. Kumar S, Seshadri MS, Koshi G, et al: Diagnosing tuberculous pleural effusion: Comparative sensitivity of mycobacterial culture and histopathology. Br Med J 283:20, 1981. Lanham JG, Elkon KB, Pusey CD, et al: Systemic vasculitis with asthma and eosinophilia: A clinical approach to the Churg-Strauss syndrome. Medicine 63:65–81, 1984. Lee CH, Wang WJ, Lan RS, et al: Corticosteroids in the treatment of tuberculous pleurisy. A double-blind, placebocontrolled, randomized study. Chest 94:1256–1259, 1988. Light RW: Pleural diseases. Disease-a-Month 28:263–331, 1992. Light RW: Pleural Diseases. Philadelphia, Lippincott Williams & Wilkins, 2001. Light RW, Girard WM, Jenkinson SG, et al: Parapneumonic effusions. Am J Med 69:507–511, 1980. Maskell NA, Davies CWH, Nunn AJ: U.K. Controlled trial of intrapleural streptokinase for pleural infection: N Engl J Med 352:865–874, 2005. Mathur PN, Mares DC: Medical thoracoscopic talc pleurodesis for chylothorax due to lymphoma: A case series. Chest 114:731–735, 1998. Meisel S, Shamiss A, Thaler M, et al: Pleural fluid to serum bilirubin concentration ratio for the separation of transudates from exudates. Chest 98:141–144, 1990. Michel L, Grillo HC, Malt RA: Operative and nonoperative management of esophageal perforation. Ann Surg 194:57– 63, 1981. Mintzer RA, Gore RM, Vogelzang RL, et al: Rounded atelectasis and its association with asbestos-induced pleural disease. Radiology 139:567–570, 1981. Nielsen PH, Jepsen SB, Olsen AD: Postoperative pleural effusion following upper abdominal surgery. Chest 96:1133– 1135, 1989. Nordkild P, Kromann-Andersen H, Struve-Christensen E: Yellow nail syndrome, the triad of yellow nails, lymphedema, and pleural effusions. Acta Med Scand 219:221– 227, 1986. Peng M-J, Vargas FS, Cukier A, et al: Postoperative pleural changes after coronary revascularization. Chest 10:327– 330, 1992.

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Pfalzer B, Hamm H, Beisiegel U, et al: Lipoproteins and apolipoproteins in human pleural effusions. J Lab Clin Med 120:483–493, 1992. Poe RH, Marin MG, Israel RH, et al: Utility of pleural fluid analysis in predicting tube thoracostomy/decortication in para-pneumonic effusions. Chest 100:963–967, 1991. Pollak JS, Passik CS: Intrapleural urokinase in the treatment of loculated pleural effusions. Chest 105:868–873, 1994. Raasch BN, Carsky EW, Lane EJ, et al: Pleural effusion: Explanation of some typical appearances. Am J Roentgenol 139:899–904, 1982. Rasmussen OV, Brynitz S, Struve-Christensen E: Thoracic injuries. A review of 93 cases. Scand J Thorac Cardiovasc Surg 20:71–74, 1986. Romero S, Candela A, Martin C, et al: Evaluation of different criteria for the separation of pleural transudates from exudates. Chest 104:399–404, 1993. Roth BJ, O’Meara TF, Cragun WH: The serum-effusion albumen gradient in the evaluation of pleural effusions. Chest 98:546–549, 1990.

Ruskin JA, Gurney JW, Thorsen MK, et al: Detection of pleural effusions on supine chest radiographs. Am J Roentgenol 148:681–683, 1987. Staats BA, Ellefson RD, Budahn LL, et al: The lipoprotein profile of chylous and nonchylous pleural effusions. Mayo Clin Proc 55:700–704, 1980. Stelzner TJ, King TE Jr, Antony VB, et al: The pleural pulmonary manifestations of the postcardiac injury syndrome. Chest 84:383–387, 1983. Strausser JL, Flye MW: Management of nontraumatic chylothorax. Ann Thoracic Surg 31:520–526, 1981. Valdes L, Pose A, Suarez J, et al: Cholesterol: a useful parameter for distinguishing between pleural exudates and transudates. Chest 99:1097–1102, 1991. Varkey B, Rose HD, Cutty CPK, et al: Empyema thoracis during a 10 year period: analysis of 72 cases in comparison to a previous study (1952–1967). Arch Intern Med 141:1771– 1776, 1981. Yang P, Luh K, Chang D, et al: The value of sonography in determining the nature of pleural effusion: Analysis of 320 cases. Am J Roentgenol 159:29–33, 1992.

86 Malignant Pleural Effusions Steven A. Sahn

I. MALIGNANCIES ASSOCIATED WITH PLEURAL EFFUSIONS II. PATHOGENESIS III. CLINICAL PRESENTATION

V. PLEURAL FLUID CHARACTERISTICS VI. DIAGNOSIS VII. PROGNOSIS VIII. TREATMENT

IV. CHEST RADIOGRAPHY

A malignant pleural effusion is diagnosed by detecting exfoliated malignant cells in pleural fluid or demonstrating these cells in pleural tissue obtained by percutaneous pleural biopsy, thoracoscopy, or thoracotomy, or at autopsy. In a number of patients, even though the pleural effusion is caused by the malignancy, neoplastic cells cannot be demonstrated in pleural fluid or pleural tissue and, in fact, probably are not present in these tissues. It makes sense to categorize these pleural effusions associated with malignancy, in which there is no direct pleural involvement with tumor and no other cause for the effusion is found, as paramalignant effusions (Table 86-1). Lymphatic obstruction appears to be the most common mechanism for the development of a paramalignant effusion, for the accumulation of large volumes of fluid. Other local effects of the tumor causing a paramalignant effusion are bronchial obstruction resulting in pneumonia or atelectasis. Furthermore, it is important for the clinician to recognize that effusions can result from systemic effects of the tumor and adverse effects of therapy. Establishing the diagnosis of a malignant pleural effusion secondary to lung cancer signals incurability. A malignant effusion secondary to a non-lung primary is a manifestation of far advanced disease and is associated with limited survival.

MALIGNANCIES ASSOCIATED WITH PLEURAL EFFUSIONS Carcinoma of any organ can metastasize to the pleura. However, carcinoma of the lung is the most common malignancy to invade the pleura and produce malignant and paramalignant effusions (Table 86-2). Carcinoma of the breast is second in incidence and, in some populations, exceeds lung cancer as a cause of malignant effusions. After lung and breast cancer, the frequency declines markedly, with ovarian and gastric cancer representing up to 5 percent of malignant pleural effusions. Lymphoma accounts for approximately 10 percent of all malignant pleural effusions and is a common cause of chylothorax. Carcinomas of the lung, breast, ovary, and stomach and lymphomas account for about 80 percent of all malignant pleural effusions. In approximately 7 percent of patients with malignant pleural effusions, the primary site is unknown when the diagnosis of a malignant pleural effusion is first established. A less common cause of a malignant pleural effusion, other than metastatic carcinoma and lymphoma, is a primary tumor of the pleura, malignant mesothelioma. The association of asbestos exposure and malignant mesothelioma was

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Disorders of the Pleural Space

Table 86-1

Table 86-2

Causes of Paramalignant Pleural Effusions

Causes of Malignant Pleural Effusion∗

Cause

Tumor

Percent

Lung

641

Breast

449

Lymphoma

187

Ovary

Stomach

Unknown primary

129

All other malignancies

257

Local effects of tumor Lymphatic obstruction Bronchial obstruction with pneumonia Bronchial obstruction with atelectasis Chylothorax

Comment Predominant mechanism for pleural fluid accumulation Parapneumonic effusion; does not exclude operability in lung cancer Transudate; does not exclude operability in lung cancer Disruption of thoracic duct or its major tributaries; lymphoma a common cause

Systemic effects of tumor Pulmonary embolism Hypercoagulable state; adenocarcinomas Hypoalbuminemia Serum albumin <1.5 g/dl; anasarca typically present Complications of therapy Radiation therapy Early Pleuritis 6 weeks to 6 months following completion of radiation Late Mediastinal fibrosis Constrictive pericarditis Vena caval obstruction Chemotherapy Methotrexate Procarbazine Cyclophosphamide Mitomycin Bleomycin

Pleuritis or effusion ± blood eosinophilia Blood eosinophilia; fever and chills Pleuropericarditis In association with interstitial disease In association with interstitial disease

documented in the 1960s following an initial report from the North Western Cape Province of South Africa and a subsequent study of insulation workers in this country. Owing to the long latency period of 20 to 40 years between exposure and onset of disease, death due to mesothelioma is expected to reach 9000 in 2020 in Europe and 2200 annually in the United States.

PATHOGENESIS Lymphatics are situated beneath the parietal pleura over the intercostal spaces. An important feature of the parietal

∗

n = 1793. Combined data from nine series.

pleura is lymphatic stomata, 2- to 12-µm openings between parietal pleural mesothelial cells. The stomata and their associated lymphatic channels form lymphatic lacunae immediately beneath the mesothelial layer. These lacunae coalesce into collecting lymphatics, which join the intercostal trunk vessels with flow directed mainly toward the mediastinal lymph nodes. The lymphatic system of the parietal pleura plays a major role in the resorption of pleural liquid and protein. Interference with the integrity of the lymphatic system between the parietal pleura and mediastinal lymph nodes can result in a pleural effusion. Autopsy series have indicated that impaired lymphatic drainage from the pleural space is the predominant mechanism for the accumulation of fluid associated with malignancy: A strong relationship was found between carcinomatous infiltration of the mediastinal lymph nodes and the occurrence of pleural effusion; in contrast, no relationship was found between the extent of direct pleural involvement by metastasis and the occurrence of pleural effusion. Further support for this mechanism is provided by the observation that pleural effusions generally do not develop when the pleura is involved by sarcoma because of the characteristic absence of lymphatic metastases. When pleural metastases occur, tumor cells either “seed” the mesothelial surface or invade the subserous layer: When the mesothelial surface is involved, abundant tumor cells can be found in pleural fluid; with subserous involvement, a paucity of malignant cells are exfoliated into the pleural space. Tumor involvement of the pleura causes reactive changes in the mesothelium that may lead to mesothelial shedding, mesothelial thickening, and, on occasion, marked pleural fibrosis. Pleural fibrosis, usually observed in the more advanced stage of tumor involvement of the pleura, is at least partially responsible for the low concentrations of glucose and

1507 Chapter 86

the low pH seen in some malignant pleural effusions and for the failure to achieve pleurodesis after instillation of chemical agents. A bloody, malignant pleural effusion usually results from direct invasion of blood vessels, occlusion of venules, tumor-induced angiogenesis, or possibly increased capillary permeability due to vasoactive cytokines and chemokines. Malignant pleural effusions usually contain a large number of morphologically normal lymphocytes, usually in the 50 to 70 percent range, but typically less than occurs with tuberculous pleurisy (usually greater than or equal to 80 percent). Although the reason for the lymphocytosis is not clear, these lymphocytes are predominantly T lymphocytes that appear to play a role in the local defense against tumor invasion of the pleural cavity. The percentage of mesothelial cells in malignant effusions is variable, ranging from few to a large percentage of the total cells. An abundance of mesothelial cells occurs early in the course of pleural infiltration, before pleural fibrosis and marked infiltration with tumor; in more advanced stages of pleural metastasis, fewer mesothelial cells are generally seen because of pleural fibrosis. Autopsy data in patients with malignant effusions have provided valuable information about the pathogenesis of pleural metastases. When carcinoma of the lung metastasizes to the pleura, both the visceral and parietal pleural surfaces tend to be involved. The visceral pleural surface is rarely, and the parietal pleural surface almost never, the sole site of involvement. Parietal pleural involvement in lung cancer probably results from neoplastic spread across the pleural cavity from visceral pleural sites along pleural adhesions that are either preformed or secondary to the malignant process. The pathogenesis of visceral pleural metastasis in lung cancer appears to be through pulmonary artery invasion and embolization. The histological type of lung cancer does not seem to determine the propensity for pulmonary arterial invasion. Adenocarcinoma of the lung is the most common cell type to involve the pleura because of its peripheral location and spread by contiguity. Bilateral pleural metastases in lung cancer are almost always associated with evidence of hepatic involvement and parenchymal invasion of the contralateral lung. Pleural metastases from primary sites below the diaphragm generally are a manifestation of a tertiary spread from established liver metastases. The data with breast cancer are conflicting; some studies show a high incidence of ipsilateral pleural effusion, while others show no such predilection. Probably two mechanisms are operative, chest wall lymphatic invasion resulting in an ipsilateral effusion and hepatic spread with bilateral or contralateral disease. At diagnosis, pleural effusions are rare in Hodgkin’s disease but not infrequent in non-Hodgkin’s lymphoma. Pleural effusions can be found in previously untreated patients with non-Hodgkin’s lymphoma, even in the absence of detectable intrathoracic lymphadenopathy; however, the pleural effusion is usually not an isolated manifestation of the disease. At autopsy in Hodgkin’s disease, lymphomatous infiltration of the lung rather than direct pleural invasion or mediastinal

Malignant Pleural Effusions

adenopathy has been found in association with the pleural effusion. Lymphomatous invasion of the pleura appears to be an uncommon and late finding in Hodgkin’s disease but is seen with increased frequency in non-Hodgkin’s lymphoma. As Hodgkin’s disease progresses, the incidence of pleural effusion increases and approaches 30 percent. At autopsy, a 30 to 60 percent incidence of pleural effusions and a 7 to 30 percent incidence of pleural nodular infiltrative lesions have been noted. While pleural effusion in lymphoma can be due to impaired lymphatic drainage secondary to mediastinal adenopathy, pleural or pulmonary infiltration, or thoracic duct obstruction, impaired lymphatic drainage appears to be the primary mechanism in Hodgkin’s disease and direct pleural infiltration the predominant cause in non-Hodgkin’s lymphoma. Malignant mesothelioma (see Chapter 88) is usually a unilateral disease (Fig. 86-1); bilateral tumors are present in less than 10 percent of patients. An early manifestation of the tumor is pleural effusion that is reabsorbed or organized and then largely replaced by tumor and fibrosis. At autopsy, the lung is often encased in tumor that involves both visceral and parietal pleural surfaces. The pleural space is often obliterated, and the amount of pleural fluid is variable. The tumor seldom penetrates deeply into the lung parenchyma; instead, it extends into interlobar fissures. Hilar lymph nodes are involved by tumor in less than 50 percent of patients. Distant hematogenous metastases are unusual but have been described in liver, bone, adrenals, thyroid, and kidneys. The two distinct histological types of malignant mesothelioma (epithelial and sarcomatous) generally behave differently. Some patients have mixed tumors with both epithelioid and sarcomatous features. The clinical features of epithelial mesothelioma are similar to those of metastatic carcinoma of the pleura associated with tumor spread by direct extension, i.e., a large pleural effusion and metastases to regional lymph nodes. In contrast, patients with sarcomatous mesotheliomas tend to have features characteristic of sarcomas, i.e., distant metastases are common, whereas there is little or no pleural effusion. These data are consistent with the pathogenesis of pleural effusions in carcinoma of the pleura, i.e., the pleural effusion is due primarily to invasion of the lymphatic system. Moreover, the large bulk of tumor on the pleural surface would be expected to interfere with the removal of pleural fluid by the parietal pleural lymphatics even if the lymphatics were not directly involved with tumor. Benign asbestos pleural effusions (BAPE) probably develop as a result of the pleural inflammation that occurs during the passage of asbestos fibers across the pleural space to the parietal pleural lymphatics.

CLINICAL PRESENTATION Patients with carcinoma involving the pleura most often present with symptoms attributable to a large pleural

1508 Part X

Disorders of the Pleural Space

A B

effusion, dyspnea on exertion and cough. The presence and degree of dyspnea depends on the size of the effusion and the patient’s underlying pulmonary function. A therapeutic thoracentesis results in relief of dyspnea in most patients. However, the volume of pleural fluid removed at thoracentesis does not correlate with the change in lung volume. The increase in total lung capacity (TLC) approximates one-third of the volume of fluid removed, while the forced vital capacity (FVC) increases to about one-half of the TLC. Indeed, the mechanism of dyspnea caused by a large pleural effusion appears to be multifactorial in origin, probably entailing a decrease in the compliance of the chest wall, a contralateral shift of the mediastinum, inversion of the ipsilateral diaphragm, and a decrease in ipsilateral lung volume modulated by neurogenic reflexes from the lungs and

Figure 86-1 Malignant mesothelioma in a 64-year-old man. A,B. Diffuse, right-sided involvement. C. Computed tomography scan shows peripheral disposition of mesothelioma along right pleura. The radiodensity in the right hemithorax is a consequence primarily of pleural tumor with little pleural effusion, subsequently treated by right extrapleural pneumonectomy. (Courtesy of Dr. David Murphy.)

chest wall. An obstructive pneumonitis, endobronchial lesion that causes atelectasis, or infiltrative malignant disease of the pulmonary parenchyma may also contribute to dyspnea and cough. Since malignant involvement of the pleura signifies far advanced disease, these patients commonly have substantial weight loss and appear chronically ill. Chest pain may be present because of involvement of the parietal pleura, ribs, or chest wall. However, in a large series of patients with metastatic carcinoma of the pleura, almost 25 percent were “asymptomatic” at the time of presentation. In these patients, the malignant pleural effusion was first suspected on physical examination or diagnosed on routine chest radiograph; in almost 50 percent of patients, the pleural effusion was the first indication of cancer.

1509 Chapter 86

The respiratory symptoms of patients with pleural effusion due to lymphoma are indistinguishable in nature and frequency from those due to carcinoma. About 20 percent of patients with lymphoma have no respiratory symptoms when the malignant pleural effusion is diagnosed. Most patients with carcinoma of the pleura have evidence of a pleural effusion on physical examination when first seen by the physician; physical signs of pleural effusion are to be expected, since the volume of pleural fluid in most malignant effusions is greater than 500 mL. Cachexia and lymphadenopathy are present in about one-third of patients on initial presentation; ipsilateral chest wall tenderness and pleural friction rub are rare. In contrast to patients with carcinomatous involvement of the pleura, virtually all patients with malignant mesotheliomas are symptomatic when first seen by the physician: In six series of patients encompassing 160 cases of malignant mesothelioma, only one patient was asymptomatic at presentation. Chest pain is the most common presenting symptom and occurs in 60 to 70 percent of patients. Dyspnea and cough are next in frequency and are present in about 25 and 20 percent of patients, respectively. Pleural effusion due to asbestos exposure is a diagnosis of exclusion. Its frequency of occurrence in exposed workers is estimated to be up to 7 percent. BAPE is the most common manifestation of asbestos-related pleuropulmonary disease in the first 20 years after initial asbestos exposure. Two-thirds of patients with BAPE are asymptomatic at presentation, with the effusion diagnosed on a routine chest radiograph. Approximately 20 percent of patients present with pleuritic pain and 10 percent with dyspnea. The effusion generally persists for several months and resolves within a year. Recurrent effusions, either on the ipsilateral or contralateral side, occur in approximately 25 percent of patients. The differential diagnosis centers around distinguishing BAPE from mesothelioma. Since BAPE occurs sooner after initial exposure than does mesothelioma, i.e., 20 years being the rough dividing line, the pleural effusion in a young asbestos-exposed individual is more likely to represent BAPE than is an effusion that occurs 20 to 40 years after initial exposure. Also, an asymptomatic pleural effusion is more apt to be benign. The absence of other radiographic manifestations of asbestos exposure is not helpful in distinguishing between benign effusion and mesothelioma. Preoccupation with asbestos-related disease occasionally leads to overlooking treatable disorders, such as tuberculosis.

Malignant Pleural Effusions

Figure 86-2 Carcinoma of the cervix metastatic to the left pleura and mediastinum. The massive pleural effusion is associated with a contralateral shift of the mediastinum.

In three of four patients who present with carcinomatous involvement of the pleura, the pleural effusion is moderate to large, i.e., with volumes ranging from 500 to 2000 ml of fluid. Approximately 10 percent present with effusions of less than 500 ml; another 10 percent present with massive pleural effusions (complete opacification of the hemithorax) (Fig. 86-2). Some 70 percent of patients with a massive pleural effusion have a malignancy. The finding of bilateral effusions and a normal heart size also suggests a malignant etiology (Fig. 86-3). Approximately 50 percent of patients who present with this radiographic

CHEST RADIOGRAPHY A pleural effusion ipsilateral to the primary lesion is the rule in carcinoma of the lung. When the primary site of the cancer is elsewhere than the lung, with the possible exception of breast cancer, there seems to be no ipsilateral predilection and bilateral effusions are common.

Figure 86-3 Carcinoma of the lung involving right lower lobe, with metastasis to right pleura and mediastinal lymph nodes. The pleural effusions are bilateral and the heart size is normal.

1510 Part X

Disorders of the Pleural Space

Figure 86-4 Carcinoma of the left mainstem bronchus resulting in complete atelectasis of the left lung. The left hemithorax is completely opacified, and the mediastinum has shifted to the side of the bronchial occlusion. The radiographic opacity represents a combination of collapsed lung and pleural fluid.

finding have a malignant effusion; however, lupus pleuritis, hypoalbuminemia, constrictive pericarditis, rheumatoid pleurisy, BAPE, and cirrhosis must also be considered in the differential diagnosis. If the mediastinum does not shift contralaterally in the face of a large pleural effusion (greater than 1500 ml), malignancy is highly likely. The following diagnoses are then considered: (1) carcinoma of the ipsilateral mainstem bronchus resulting in atelectasis (Fig. 86-4); (2) a fixed mediastinum due to malignant lymph nodes; (3) malignant mesothelioma (the radiodensity represents predominantly tumor with only a small effusion); and (4) extensive tumor infiltration of the ipsilateral lung radiographically mimicking a large effusion. Interstitial infiltrates with effusions (lymphangitic carcinomatosis) and multiple nodules with effusions also suggest malignant disease. Depending on the stage of the mesothelioma at the time of presentation, the chest radiograph may show a moderate to large pleural effusion (early) or a nodular, thickened pleura with extension to the apex of the hemithorax (late). Contralateral mediastinal shift often occurs early, i.e., when the pleural effusion is large; but, as fluid resorbs and is replaced by tumor, the ipsilateral hemithorax shrinks in size and the mediastinal structures either remain in the midline or shift ipsilaterally (Fig. 86-1). Contralateral manifestations of asbestos-induced pleuropulmonary disease, such as pleural plaques with or without calcification and interstitial lung disease, often reinforce the diagnosis. In the more advanced stages of malignant mesothelioma, other radiographic find-

Figure 86-5 Bilateral pleural thickening in a 44-year-old man exposed to asbestos for 18 months 20 years ago. Bilateral pleural effusions were succeeded by progressive pleural thickening.

ings are mediastinal widening due to lymph node involvement, an enlarged cardiac silhouette due to pericardial involvement with effusion, and extrapleural lesions such as soft tissue masses or rib destruction. Benign asbestos pleural effusions are small to moderate (less than 1000 ml) unilateral effusions with evidence of pleural plaques or asbestosis identifiable in less than 20 percent of patients. Calcified pleural plaques are rare, since calcifications require 25 to 40 years from the time of initial asbestos exposure, whereas BAPE tends to be the earliest manifestation of asbestos pleuropulmonary disease. Some patients are left with normal chest radiographs, but most have residual abnormalities. These include a blunted costophrenic angle (most common), crowâ&#x20AC;&#x2122;s feet (converging fibrous strands creating a likeness of a birdâ&#x20AC;&#x2122;s foot), rounded atelectasis (in which a portion of the lung periphery has become atelectatic due to pleural adhesions that collapse small bronchi), and diffuse pleural thickening that is sometimes progressive (Fig. 86-5).

PLEURAL FLUID CHARACTERISTICS Malignant pleural fluid may be serous, serosanguinous, or grossly bloody. The number of nucleated cells in the pleural fluid is modest (1500 to 4000/Âľl) and consists of lymphocytes, macrophages, and mesothelial cells. In about one-half of malignant pleural effusions, lymphocytes predominate (50 to 70 percent of nucleated cells). Malignant cells in pleural fluid are rare in some patients; in others they constitute virtually the complete population. Polymorphonuclear

1511 Chapter 86

leukocytes usually represent less than 25 percent of the cell population; but, rarely, when pleural inflammation is active, they predominate. The reported prevalence of pleural eosinophilia in malignant effusions ranges from 8 to 12 percent. However, malignancy was as frequent in eosinophilic as noneosinophilic pleural effusions. Therefore, the finding of pleural fluid eosinophilia should not be considered a predictor of benign disease. The pleural fluid in patients with carcinoma of the pleura is usually an exudate with a protein concentration of about 4 g/dl. However, protein concentrations have been reported in the range of 1.5 to 8.0 g/dl. Often unappreciated is the fact that less than 5 percent of malignant pleural effusions can be transudates. These transudates are due either to concomitant congestive heart failure, atelectasis from tumor obstructing a major bronchus, or the early stages of lymphatic obstruction. Since protein can exit from the pleural space only by parietal pleural lymphatics, a few weeks are necessary for protein to accumulate (from the 1.5 g/dl of normal pleural liquid) to a level of greater than 50 percent of the serum concentration. Chronic pleural effusions and those with a low pleural fluid pH and glucose tend to have a higher total protein concentration and are virtually never transudates. Sometimes, the total protein pleural fluid to serum ratio may be low (less than 0.50), but the fluid would qualify as an exudate by lactic dehydrogenase (LDH) criterion alone. In about one-third of patients with malignant pleural effusions at the time of diagnosis, the pleural fluid pH is low (less than 7.30), ranging from 6.95 to 7.29. In these lowpH effusions, the glucose concentration is also low (less than 60 mg/dL, or the ratio of pleural fluid to serum glucose is below 0.5), the lactate concentration is high, the PcO2 is high, and the PO2 is low. On rare occasions, the glucose is as low as 5 mg/dl; but as a rule the concentrations are in the range of 30 to 55 mg/dl. These low-pH, low-glucose effusions have usually been present for several months and are associated with a large tumor burden and fibrosis of the pleura. The markedly abnormal pleura interferes with glucose transport from blood to pleural fluid; the glucose that does enter is metabolized by normal and malignant pleural cells to form CO2 and lactate. The abnormal pleura impairs the efflux of these end products of glucose metabolism from the pleural space, resulting in pleural fluid acidosis. About 10 percent of malignant pleural effusions have high amylase concentrations. The finding of a high level of salivary-like isoamylase in a patient without esophageal rupture essentially establishes the diagnosis of malignancy, most likely adenocarcinoma of the lung. Early in the course of malignant mesothelioma, the pleural fluid may be serous; later, it tends to be hemorrhagic. The effusion associated with malignant mesothelioma is an exudate with a protein concentration in the range of 4 to 5 g/dl and a modest number of nucleated cells (less than 5000/Âľl), predominantly mononuclear. The LDH concentration tends to be higher than in the patient with carcinoma of the pleura; frequently the concentration exceeds 600 IU/L. In 60 percent of patients with malignant mesothelioma, at the time that

Malignant Pleural Effusions

the diagnosis is established, the pleural fluid pH is low (below 7.30) and the glucose concentration is also low (pleural fluid/serum ratio below 0.5); in contrast, the incidence of low pH and low glucose concentration in carcinoma of the pleura is about 30 percent. The natural progression of malignant mesothelioma resulting in large tumor masses and concomitant fibrosis that obliterate the pleural membrane provides a reasonable explanation for these biochemical findings. In some instances of malignant mesothelioma, the viscosity of pleural fluid is greatly increased because of a high concentration of hyaluronic acid. Although a high concentration of hyaluronic acid in pleural fluid does raise the question of malignant mesothelioma as the cause, this test is not specific and only moderately sensitive; thus, it is of no diagnostic value. The pleural fluid in BAPE is a sanguineous, lymphocyte-predominant exudate with pleural fluid eosinophilia in 30 percent of cases. During the acute stage, there may be a moderate number of polymorphonuclear leukocytes. The pH and glucose are in the normal range (above 7.30 and 60 mg/dl, respectively).

DIAGNOSIS Malignant pleural effusion can be diagnosed only by demonstrating malignant cells in pleural fluid or pleural tissue. Cytology is a more sensitive test for the diagnosis than percutaneous pleural biopsy, because pleural metastases tend to be focal and the latter is a blind sampling procedure. The yield on either procedure increases as the disease becomes more advanced. However, the yield from pleural biopsy with a proven malignant effusion averages 50 to 60 percent. It appears, based on thoracoscopy, that initial pleural metastases originate near the mediastinum and diaphragm; as the disease progresses, tumor spreads cephalad and costally. With improved techniques, the yield from exfoliative cytology now approaches 90 to 95 percent. If the clinician suspects a malignant effusion, several hundred milliliters of fluid should be removed at the initial diagnostic thoracentesis. This maneuver will not improve the yield on the initial study but, if it is negative, a repeat procedure several days later may provide fluid with fewer degenerative mesothelial cells and freshly exfoliated malignant cells. Percutaneous pleural biopsy should be reserved for the second thoracentesis if the initial pleural fluid cytological examination is negative. If the second cytological examination and initial pleural biopsy are negative, a third cytological examination and second pleural biopsy soon after usually is not diagnostic. There are several options for the patient with suspected malignancy and negative pleural fluid and pleural tissue examination. These include observation for a few weeks with repeat studies, thoracoscopy, or open pleural biopsy. Before proceeding to more invasive procedures, other causes of an exudative pleural effusion must be excluded. Tuberculous pleurisy should always be considered in the patient

1512 Part X

Disorders of the Pleural Space

with a lymphocyte-predominant exudate with or without a positive tuberculin skin test. The yield from pleural biopsy culture and histology, in conjunction with pleural fluid culture, should provide a bacteriological diagnosis of tuberculous pleurisy in 90 to 95 percent of cases. Even if diagnostic studies are negative, patients with a positive purified protein derivative skin test and a lymphocyte-predominant exudate should be treated for tuberculous pleurisy because of the high risk (43 to 65 percent) of developing active pulmonary or extrapulmonary tuberculosis within 5 years if untreated. Bronchoscopy has a low diagnostic yield for an idiopathic pleural effusion without parenchymal lesions on chest radiograph, ipsilateral mediastinal shift, or hemoptysis. The value of computed tomographic examination of the chest in an undiagnosed exudative effusion is unknown and probably not cost effective. If observation is the course undertaken, the clinician would expect a malignant pleural effusion to be stable or progress and an effusion not due to malignancy to be stable or regress over time. Failure to identify a malignant pleural effusion for several weeks is rarely a disservice to the patient, who has incurable disease. Exceptions are those malignancies that tend to be responsive to therapy, such as breast cancer, prostate cancer, thyroid cancer, small-cell lung carcinoma, germ-cell neoplasms, and lymphomas. The diagnostic utility of immunohistochemistry in the diagnosis of malignant pleural effusions secondary to adenocarcinoma, mesothelioma, and lymphoma has been established. Carcinoembryonic antigen (CEA), Leu-M1, B 72.3, Ber-EP4, and BG-8 are the best markers for the diagnosis of adenocarcinoma. Calretinin and cytokeratin 5/6 are the best markers for mesothelioma. Flow cytometry, a technique used to quantitate nuclear DNA levels, is useful in the evaluation of lymphocytic pleural effusions in which lymphoma is a possible diagnosis. The ability of tumor markers to discriminate between benign and malignant pleural effusions is poor. Markers such as CEA, vascular endothelial growth factor (VEGF), carbohydrate antigens (e.g., CA 15-3, 19-9, and 72.4), cytokeratin 19, and enolase have significant overlap between benign and malignant pleural effusions. Hyaluronan does not appear to discriminate between pleural effusions from adenocarcinoma and mesothelioma. Inflammatory processes involving the pleura may mimic mesothelioma, and patients are often subjected to a battery of tests and consultations before the diagnosis is established. An accurate diagnosis is imperative for proper epidemiological records, appropriate therapeutic intervention, and litigation. Early in the course of the mesothelioma, establishing a definitive diagnosis may be problematic. Pleural fluid cytology and pleural biopsy may allow the diagnosis of malignancy but usually cannot distinguish between mesothelioma and adenocarcinoma. Sarcomatous type mesothelioma can be confused with rare tumors such as fibrosarcomas or hemangiopericytomas. Thoracoscopic biopsy or open thoracotomy is usually necessary to obtain adequate tissue to confirm the diagnosis. Thoracoscopic biopsy has a high diagnostic

yield for mesothelioma, approaching 100 percent in some series, while the yield for pleural fluid cytology alone is 25 percent and that for combined pleural fluid cytology and closed pleural biopsy is 40 percent. Histochemical and immunochemical studies in conjunction with electron microscopy have improved the accuracy of the diagnosis of malignant mesothelioma.

PROGNOSIS The diagnosis of a malignant pleural effusion signals a poor prognosis. Patients with carcinoma of the lung, stomach, and ovary tend to have a survival time of only a few months from the time that the malignant effusion is diagnosed; patients with breast cancer may survive longer, several months to years, depending on the response to chemotherapy. Patients with lymphomatous pleural effusions tend to have survival times intermediate between those of breast cancer and other carcinomas. When pH and glucose concentrations in the malignant pleural effusion are low (below 7.30 and 60 mg/dl, respectively), the survival time is less (average 2 months) than in those with a normal pH and glucose (average 10 months). Thus, the pH and glucose in the pleural fluid may provide helpful information with respect to a rational plan of palliative treatment. A pleural effusion in the setting of lung cancer usually excludes operability; however, approximately 5 percent of these patients have a paramalignant effusion or effusion from another cause and may be operable and curable. Thus, it is essential to establish the cause of the pleural effusion before deciding that the patient is no longer a candidate for curative surgery. Survival following the diagnosis of malignant mesothelioma is related to the stage of the disease at the time of presentation. Those patients with only ipsilateral involvement of the pleura and lung survive the longest, whereas those with distant hematogenous metastases have the shortest survival. Chest pain portends a worse prognosis than dyspnea, reflecting a more advanced stage of disease. Overall, the median survival in malignant mesothelioma is about 9 months. The epithelial type has a median survival approximately twice that of the sarcomatous type; long-term survivors of more than 3 years are seen almost exclusively with the epithelial type. As in metastatic carcinoma of the pleura, a low pH effusion in malignant mesothelioma is also predictive of a short survival. Benign asbestos pleural effusions tend to resolve within 3 to 4 months, leaving some residual on the chest radiograph. Although malignant mesothelioma occasionally develops in patients with BAPE, it does not appear to be a harbinger of mesothelioma. Obviously, the risk of developing mesothelioma is greater in these asbestos-exposed individuals than in the general population.

1513 Chapter 86

Malignant Pleural Effusions

Table 86-3 Management of Malignant and Paramalignant Pleural Effusions Option

Comment

Observation

Small asymptomatic effusion; most will progress and require therapy

Therapeutic thoracentesis

Prompt relief of dyspnea; recurrence rate variable

Chemotherapy

May be effective in lymphoma, small-cell lung cancer, breast cancer

Radiotherapy

Mediastinal radiation may be effective in lymphoma and lymphomatous chylothorax

Indwelling catheter

Patient controlled symptom relief; spontaneous pleurodesis in 50% by 2 months. Effective for symptomatic relief with lung entrapment.

Chest tube drainage with talc slurry

Control of effusion in >90 percent of cases if lung entrapment not present

Thoracoscopy with talc poudrage

Control of effusion in >90 percent of cases if lung entrapment not present

Pleuroperitoneal shunt

When other options have failed or not indicated; may be useful for chylothorax

Pleural abrasion and partial pleurectomy

Virtually 100 percent effective; requires VATS or thoracotomy

TREATMENT When the pleural effusion has been proved to be malignant or paramalignant and the patient is not a surgical candidate, the type of palliative therapy is weighed, taking into account the patientâ&#x20AC;&#x2122;s general condition, symptoms, and expected survival. Several management options are available (Table 86-3). Asymptomatic patients need not be treated; however, most will develop progressive pleural effusions that will evoke symptoms and require therapy, but some will reach a steady state of pleural fluid formation and removal and not progress to a symptomatic stage. In the debilitated patient in whom a short survival is expected based upon the general health, extent of disease, and biochemical characteristics of the pleural fluid, periodic therapeutic thoracentesis as an outpatient is often preferable to hospitalization for tube thoracostomy and intrapleural instillation of a chemical agent. However, outpatient pleurodesis using small-bore catheters can be accomplished successfully with decreased cost and morbidity. The use of indwelling catheters (PleurX, Denver Biomaterials, Golden, Colorado) has gained popularity; because it is an outpatient procedure, and the patient and family can manage the pleural effusion in a timely fashion at home. Approximately 50 percent of patients develop spontaneous pleurodesis by 2 months. The infection rate appears to be low. However, the expense of the drainage bottles can be prohibitive for

some patients. An option with the indwelling catheter is to perform chemical pleurodesis through the catheter 1 or 2 weeks following insertion depending upon the clinical situation. Because the patient with a malignant pleural effusion frequently has lung entrapment signifying that there are two mechanisms responsible for the volume of fluid, the patient is instructed to remove fluid when dyspnea occurs and stop drainage immediately when chest pain develops. The onset of substernal chest pain signals the point when the â&#x20AC;&#x153;malignant fluidâ&#x20AC;? has been evacuated, leaving the unexpandable lung from tumor involvement of the visceral pleural surface. The remaining fluid simply represents hydrostatic equilibrium. Pleural abrasion with or without pleurectomy is almost always effective in obliterating the pleural space and controlling a malignant pleural effusion. However, pleurectomy is a major surgical procedure associated with considerable morbidity and some mortality. Accordingly, this procedure is reserved for patients who are in good general condition and have a reasonably long expected survival or who have failed a sclerosing agent procedure. In general, systemic chemotherapy is disappointing for the control of malignant pleural effusions. However, some patients with lymphoma, breast cancer, or small-cell carcinoma of the lung manifest a good response to chemotherapy. In patients with carcinoma of the breast, procurement of quantitative data about steroid receptors from the malignant pleural fluid can provide valuable information relating to the potential response to hormonal manipulation.

1514 Part X

Disorders of the Pleural Space

As a rule, radiation of the hemithorax is contraindicated in malignant pleural effusions from lung cancer, since the adverse effects from radiation pneumonitis outweigh possible benefits of therapy. However, when involvement of mediastinal nodes predominates, radiotherapy may be helpful in patients with lymphoma and lymphomatous chylothorax. Until recently, the most common method of controlling a malignant pleural effusion was chest tube drainage and intrapleural instillation of a chemical agent. A number of antineoplastic and nonantineoplastic chemical agents have been used for pleurodesis with variable success. Currently, the most widely used agents are talc, doxycycline, and bleomycin. Talc pleurodesis by either poudrage or slurry has been shown by numerous investigators to have a success rate of about 90 percent. In head-to-head comparisons with tetracycline and bleomycin, talc has been shown to be more effective. Talc is available to administer as a slurry or an aerosol. When used as a slurry through a chest tube, talc is less expensive than doxycycline and substantially less expensive than bleomycin. The use of VATS to administer talc significantly increases the cost and usually requires a few days of hospitalization. The degree of pain associated with talc has been variously reported from nonexistent to severe. Fever following talc poudrage and slurry is common, occurring 16 to 69 percent of the time. Fever, occasionally as high as 102◦ F, characteristically occurs 4 to 12 hours after talc instillation and may last for 72 hours. Other complications that have been reported with talc include empyema, arrhythmia, and respiratory failure, including adult respiratory distress syndrome (ARDS) and pneumonitis. The method of administration (poudrage or slurry) does not appear to be associated with the development of respiratory failure, and both high (10 g) and low (2 g) doses have been implicated. The size of the talc particles may be the major risk factor for respiratory failure, with fewer episodes reported with large particle size. Patients with severe pulmonary impairment appear to be at greatest risk of developing acute respiratory failure. Before instituting chest tube drainage for intrapleural instillation of a chemical agent, it is necessary to demonstrate that fluid removal improves dyspnea. Determination of the FVC and PO2 during the first 12 hours after therapeutic thoracentesis can be misleading. Some patients experience a transient decrease in PO2 and minimal improvement in pulmonary function despite relief of dyspnea, as dyspnea is largely related to decreased chest wall compliance and stimulation of the neurogenic receptors of the chest wall and lung. Following the initial therapeutic thoracentesis, the recurrence rate and the interval for return of symptoms should be noted. If recurrence is rapid, with return of dyspnea, pleurodesis should be considered. If the expected survival is at least several weeks, the patient is not debilitated, and the pleural fluid pH is above 7.30, the patient is a suitable candidate for pleurodesis. However, it is fruitless to attempt pleurodesis if the lung cannot be expanded fully, as with bronchial occlusion or lung entrapment. Furthermore, demonstrating a low

pleural fluid pH not only suggests a shorter survival but also predicts a poorer response to chemical pleurodesis. A large tumor bulk involving the pleural surfaces, seen with low-pH, low-glucose pleural effusions is associated with diminished effectiveness of the chemical agent. Ideally, when contemplating chemical pleurodesis the patient should undergo pleural manometry with therapeutic thoracentesis. A simple water manometer connected to a digital analog system can determine whether the patient has lung entrapment. If lung entrapment is present, the pleurodesis procedure will not be completely successful. Pleural manometry measures elastance of the pleural space by evaluating the pressure change in relationship to the volume of fluid removed. Individuals with lung entrapment have a significant drop in pleural pressure with removal of fluid. When the patient’s pleural elastance is normal (less than 14.5 cm H2 O/L of fluid removed) there is a high likelihood of successful pleurodesis with proper technique. The pleural space should be drained as completely as possible so that the pleural surfaces remain in close contact during the time of the initial inflammatory insult. This is best accomplished by tube thoracostomy. A small-bore chest tube, 14 to 16◦ F, is as effective as a standard large-bore chest tube and causes less morbidity for the patient. When the follow-up chest radiograph demonstrates that the effusion has been drained and the lung is fully expanded, 5 g of talc slurry should be instilled into the pleural space. Following instillation, the tube should be clamped for 1 to 2 hours. It has been demonstrated that the instillation of radiolabeled tetracycline through a chest tube disperses rapidly and completely in the pleural space without patient repositioning. However, with talc slurry it is currently recommended that the patient be rotated frequently during the period when the chest tube is clamped, including Trendelenburg and sitting upright. The chest tube should be removed when drainage is less than 150 ml in 24 hours. If a large volume of drainage persists, a repeat dose of talc should be instilled. With the properly selected candidate and rigorously applied technique, the malignant effusion is controlled with talc slurry in about 90 percent of cases. A further option available for the patient with an intractable, symptomatic, malignant effusion who cannot undergo pleurodesis is a pleuroperitoneal shunt. These shunts have been found to be safe and effective. The shunt may be particularly beneficial in refractory chylothorax, as it allows recirculation of chyle. Few complications have been associated with shunt placement, and it can be inserted in patients who are poor surgical candidates. With experienced operators, palliation is obtained in 80 to 90 percent of properly selected patients. The major problem has been shunt failure, which is most commonly due to clotting of the catheter. It is unknown whether patients who have experienced shunt occlusion are at greater risk for occlusion after a new shunt is placed. In general, there is a nihilistic attitude regarding the management of patients with malignant mesothelioma because of the tumor’s poor response to chemotherapy and radiation therapy. Early in the course of some patients with

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a mesothelioma, a large unilateral pleural effusion can cause substantial dyspnea. Pleurodesis may be successful in some patients; however, in others, the procedure is unhelpful because of lung entrapment from the tumor burden in the pleural space.

SUGGESTED READING Antman KH: Natural history and epidemiology of malignant mesothelioma. Chest 103:373S–376S, 1993. Brown RW, Clark JM, Tandon AK: Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma. Hum Pathol 24:347–354, 1993. Doelken P, Huggins JT, Pastis NJ, et al.: Pleural manometry: Technique and clinical implications. Chest 126:1767–1769, 2004. Ferrer J, Villarino MA, Tura JM, et al.: Talc preparations used for pleurodesis vary markedly from one preparation to another. Chest 119:1901–1905, 2001. Gottehrer A, Taryle DA, Reed CE, et al.: Pleural fluid analysis in malignant mesothelioma: Prognostic implications. Chest 100:1003–1006, 1991. Guzman J, Bross KJ, Costabel U: Malignant lymphoma in pleural effusions: An immunocytochemmical cell surface analysis. Diagn Cytopathol 7:113–118, 1991. Heffner JR, Nietart PJ, Barbieri C: Pleural fluid pH as a prediction of survival for patients with malignant pleural effusions. Chest 117:79–86, 2000. Heffner JR, Nietart PJ, Barbieri C: Pleural fluid pH as a prediction of pleurodesis failure. Chest 117:87–95, 2000. Hillerdal G, Lindqvist U, Engstrom-Laurant A: Hyaluronan in pleural effusions and in serum. Cancer 67:2410–2414, 1991. Kennedy L, Sahn SA: Talc pleurodesis for the treatment of pneumothorax and pleural effusion. Chest 106:1215– 1222, 1994. Martinez-Garcia MA, Kasses-Viedma E, Cordero-Rodriguez PJ, et al.: Diagnostic utility of eosinophils in the pleural fluid. Eur Respir J 15:166–169, 1999.

Malignant Pleural Effusions

Momi H, Matsuyama W, Inoue K, et al.: Vascular endothelial growth factor and pro-inflammatory cytokines in pleural effusions. Respir Med 96:817–822, 2002. Peto J, Hodgson JT, Matthews FE, et al.: Continuing increase in mesothelioma mortality in Britain. Lancet 345:535–539, 1995. Putnam JB Jr, Light RW, Rodriguez RN, et al.: A randomized comparison of indwelling pleural catheter and doxycycline pleurodediss in the management of malignant pleural effusions. Cancer 86:1992–1999, 1999. Putnam JB Jr, Walsh GL, Swisher SG, et al.: Outpatient management of malignant pleural effusion by a chronic indwelling catheter. Ann Thorac Surg 69:369–375, 2000. Rijken A, Dekker A, Taylor S: Diagnostic value of DNA analysis in effusions by flow cytometry and image analysis. A perspective study on 102 patients as compared with cytological examination. Amer J Clin Pathol 95:6–12, 1991. Rubins JB, Rubins HB: Etiology of prognostic significance of eosinophilic pleural effusions. A prospective study. Chest 110:1271–1274, 1996. Sahn SA: Pleural effusion in lung cancer. Clin Chest Med 14:189–200, 1993. Sahn SA, Good JT Jr: Ann Intern Med 108:345–349, 1998. Sahn SA: Talc should be used for pleurodesis. Am J Resp Crit Care Med 62:2024–2025, 2001. Sahn SA, Good JT Jr.: Ann Intern Med 108:345–349, 1998. Sanchez-Armengol A, Rodriguez-Panadero F: Survival and talc pleurodesis in metastatic pleural carcinoma— Revisited. Chest 104:1482–1485, 1993. Sterman DH, Albelda SM: Advances in the diagnosis, evaluation, and management of malignant pleural mesothelioma. Respirology 10:266–283, 2000. Tremblay A, Michaud G: Single-center experience with 250 tunnelled catheter insertions for malignant pleural effusion. Chest 129:362–368, 2006. Villena V, Lopez-Encuentra A, Echave-Sustaeata J, et al.: Diagnostic value of CA 72-4, carcinoembryonic antigen, CA 15-3 and CA 19-9 assay in pleural fluid: A study of 207 patients. Cancer 78:736–740, 1996. Walker-Renard PB, Vaughan LM, Sahn SA: Chemical pleurodesis for the treatment of malignant pleural effusions. Ann Intern Med 120:56–64, 1994.

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87 Pneumothorax Deborah J. Levine Edward Y. Sako

Jay Peters

I. PATHOPHYSIOLOGY

VI. RADIOGRAPHIC APPEARANCE

II. REABSORPTION OF PLEURAL GASES

VII. THERAPY Observation Aspiration Pleurodesis Operative Therapy Th oracoscopy Suggested Guidelines for Therapy

III. SYNDROMES Primary Spontaneous Pneumoth orax IV. ETIOLOGY Secondary Spontaneous Pneumoth orax Cystic Fibrosis Traumatic Pneumoth orax Catamenial Pneumoth orax Pneumoth orax in Acquired Immunodeficiency Syndrome Tuberculosis

VIII. COMPLICATIONS Tension Pneumoth orax Bronch opleural Fistula Re-expansion Pulmonary Edema

V. CLINICAL FEATURES

A pneumothorax is defined as the accumulation of air in the pleural space with secondary collapse of the surrounding lung. Pneumothoraces can be divided into spontaneous pneumothorax and traumatic pneumothorax. Spontaneous pneumothorax is subclassified as either primary spontaneous pneumothorax or secondary spontaneous pneumothorax. Primary spontaneous pneumothorax occurs without a precipitating event in a person with no clinical evidence of lung disease. Many of these individuals have occult lung disease with subpleural blebs on computed tomography (CT) scans. In contrast, secondary spontaneous pneumothorax occurs as a complication of underlying lung disease, most often chronic obstructive lung disease (COPD). Traumatic (or nonspontaneous) pneumothorax occurs as the result of blunt (nonpenetrating) or penetrating trauma disrupting the lung, bronchus, or esophagus. A subcategory of traumatic pneumothorax is iatrogenic pneumothorax, which occurs as a consequence of diagnostic or therapeutic maneuvers (i.e., thoracentesis, insertion of a central venous catheter, surgery, or mechanical ventilation).

PATHOPHYSIOLOGY The pressure within the pleural space is negative with respect to the alveolar pressure during the entire respiratory cycle. This negative pressure results from the inherent tendency for the lung to collapse (elastic recoil) and the chest wall to expand. The negative intrapleural pressure is not uniform throughout the pleural space; a gradient of 0.25 cm of water per centimeter of vertical distance can be measured between the apex and base of the lung. At the apex, the pressure is more negative than at the base, and this pressure difference tends to favor a greater distention of the alveoli located in this region. When a communication develops between an alveolus and the pleural space, air will move from the alveolus into the pleural space until there is equalization of pressure or the communication is sealed. The same happens with a communication between the chest wall and pleural cavity. Although the mechanism responsible for spontaneous pneumothorax

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Figure 87-1 Proposed mechanism of alveolar rupture in spontaneous pneumothorax. A. Normal structures. B. Overdistention of marginal alveoli. Pressure in the adjacent bronchovascular sheath remains lower than in the overdistended alveoli. This pressure gradient may lead to rupture of the alveoli with dissection of air toward the pleura or mediastinum. (From Maunder: Arch Intern Med 144:1449, 1984.)

is not completely understood, experimental overdistention of normal lungs results in rupture of subpleural alveoli. Air can dissect along the bronchovascular sheath medially to produce pneumomediastinum, which may be accompanied by subcutaneous emphysema or pneumothorax (Fig. 87-1), or it can dissect to the peripheral portion of the lung. Peripheral dissection of air may result in an air-containing space within or immediately below the visceral pleura. Pathological studies of a resected lung from patients with spontaneous pneumothorax usually show one or both of these types of airspaces, a bleb or a bulla. A bulla is lined partly by thickened fibrotic pleura and partly by fibrous tissue within the lung itself, whereas a bleb is situated entirely within the pleura. A pneumothorax may occur when these peripheral bullae or blebs become distended and rupture into the pleural space. The main physiological consequences of a pneumothorax are a decrease in the vital capacity of the lung and a decrease in PaO2 . Total lung capacity, functional residual capacity, and diffusing capacity are also reduced, although less than vital capacity. Air in the pleural space eliminates the gravitational gradients of pleural pressure and regional lung volume so that regional ventilation is uniform. The reduction in arterial PaO2 appears to be caused by low ventilation˙ Q) ˙ ratios, anatomic shunts, and, occasionperfusion (Va/ ally, alveolar hypoventilation. Anthonisen reported that lungs demonstrate airway closure at low lung volumes and sug˙ Q) ˙ imgested that airway closure is the main cause of (Va/ balance in patients with pneumothorax. If perfusion to the collapsed lung is preserved, there is an increase in pulmonary shunt and substantial hypoxemia. If perfusion to the collapsed lung is reduced by hypoxic vasoconstriction, hypoxemia may be minimal. In general, pneumothoraces occupying less than 25 percent of the hemithorax are not usually associated with significant shunts. Under normal circumstances, despite the degree of pneumothorax; hypoxemia tends to abate within

24 hours, presumably because of redistribution of pulmonary blood flow. In the healthy person, the decrease in vital capacity and PaO2 is well tolerated. In patients with compromised pulmonary function before the pneumothorax, the decrease in vital capacity may result in significant hypoxemia, alveolar hypoventilation, and respiratory acidosis. When air is evacuated from the pleural space, the PaO2 usually improves. In animal studies, the PaO2 returns to baseline immediately after re-expansion of the lung. In humans, normalization of the PaO2 takes longer and may occur over hours to several days. The delay in improvement may be related to the duration of the pneumothorax.

REABSORPTION OF PLEURAL GASES Gas reabsorption from the pleural space is achieved by simple diffusion from the pleural space into the venous blood. The rate of gas reabsorption depends on four variables: (1) the pressure gradient for the gases between the pleural space in relation to the venous blood; (2) the diffusion properties for the gases present in the pleural space; (3) the area of contact between the pleural gas and pleura; and (4) the permeability of the pleural surface (i.e., a thickened, fibrotic pleura will absorb less than normal pleura). The solubility and diffusion properties of different gases vary considerably, and the speed of reabsorption depends on the type of gas. Oxygen is absorbed 62 times faster than nitrogen, the slowest gas to be reabsorbed. Carbon dioxide is absorbed 23 times faster than oxygen, and carbon dioxide and water vapor equilibrate almost instantaneously. If a patient develops a pneumothorax while receiving 100 percent oxygen, the pleural gas will be composed mostly of

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oxygen and contain no nitrogen. The pneumothorax reabsorbs much faster for two reasons: the pneumothorax is filled with the more soluble oxygen, and the pressure gradient between the pneumothorax and venous blood is larger, because 100 percent oxygen washes out nitrogen from the alveoli and, eventually, the venous blood. Under normal circumstances, the total gas pressure in the pneumothorax is within a few millimeters of mercury of that of the atmosphere, or 760 mmHg. Tissue gas tensions are close to those of systemic venous blood: typically PcO2 = 46 mmHg, PO2 = 40 mmHg, PH2 O = 47 mmHg, and pN2 = 569 mmHg, giving a total pressure of 702 mmHg. This positive-pressure gradient between the pneumothorax and venous blood constitutes the driving force responsible for gas reabsorption from a pneumothorax. If the gas in the pneumothorax equilibrates with tissue in terms of PO2 and PcO2 , the PN2 must be about 627 mmHg (atmospheric pressure less the sum of PO2 , PcO2 , and PH2 O), and N2 is reabsorbed. This reabsorption decreases the volume of the pneumothorax, but decreases its total pressure only slightly, so that PO2 and PcO2 increase. As they equilibrate with tissue, PN2 again rises and is reabsorbed in a continuing cycle (Fig. 87-2). The time required to absorb all gases in a pneumothorax is quite variable. It has been estimated that between 1 and 6 percent of a pneumothorax is absorbed in 24 hours.

Figure 87-2 Hypothetical representation of the resorption of a spontaneous pneumothorax. A. Closed pleural space after leak has stopped. The alveolar gas in the space contains 15 percent O2 , 5 percent CO2 , and 80 percent N2 . B. CO2 and O2 have quickly equilibrated with the surrounding tissues; the amount of N2 in the pneumothorax is unchanged. The pneumothorax is already decreased by about 10 percent. C . The number of N2 molecules is unchanged, but the total volume of the pneumothorax has decreased (see B). Therefore, the outward diffusion of N2 increases because pN2 in the pleural space is greater than PN2 in the tissues. As N2 diffuses out, the total volume of gas in the pleural space decreases and concentrations of O2 and CO2 increase. As a result, O2 and CO2 diffuse out of the pleural space. D. The high N2 concentration promotes the exit of N2 from the pleural space and continues the cycle by which the pneumothorax grows smaller. (From Farhi: JAMA 188:986, 1964.)

Pneumothorax

SYNDROMES Primary Spontaneous Pneumothorax Incidence and Patient Demographics Primary spontaneous pneumothorax (PSP) is an entity that occurs most commonly in young men between the ages of 20 and 40 years of age. Although women have a much lower incidence of PSP, they tend to develop PSP 2 to 5 years earlier than men. A patient rarely presents with a primary episode after the age of 40 years. Patients with primary spontaneous pneumothoraces tend to be taller and thinner than control populations. A study on military recruits who developed spontaneous pneumothorax found that they were, on average, 2 inches taller and 25 pounds lighter than the typical military recruit. In another study by Melton and colleges, primary spontaneous pneumothorax was found to be increased with increased height and reached an incidence of 200 per 100,000 person-years for subjects at least 76 in tall. A population-based study of residents of Olmsted County, Minnesota, between 1950 and 1974, there was 141 cases of spontaneous pneumothorax (77 primary, 64 secondary) reported among the countyâ&#x20AC;&#x2122;s population. The ageadjusted incidence of primary spontaneous pneumothorax was 7.4/100,000/year for males and 1.2/100,000/year for females. The male-to-female predominance for primary spontaneous pneumothorax ranges from 6-to-1 to 3-to-1. Tobacco smoking significantly increases the risk of spontaneous pneumothorax. In one study it was found that it was associated with a ninefold or greater risk of developing a first PSP. The relative risk of PSP has been shown to be dependent on the quantity of cigarettes per day and the length of exposure, with the relative risk increasing more than 20 times in men who smoke one-half pack per day and 100 times higher in men who smoke one pack per day compared to nonsmokers. The lifetime risk in healthy smoking men may be as much as 12 percent, as opposed to 0.1 percent in nonsmokers. One review of 402 patients with spontaneous primary pneumothorax reported that 92 percent of the patients were smokers or exsmokers. Another study showed that patients who had stopped smoking more than 1 year before their first spontaneous pneumothorax had no recurrence during a follow-up of 5.2 years.

ETIOLOGY Although the definition of PSP is a pneumothorax that occurs in patients without primary lung disease; it may be that these patients do have some underlying pathology. A more accurate definition may be that PSPs occur in patients with no obvious lung disease. This is because PSP is most often associated with the rupture of subpleural blebs or bullae on the apical portion of the upper lobes. Although these blebs

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are demonstrated on chest radiographs in only 20 percent of cases, their visualization may be facilitated radiographically in expiration or at the time of maximal pulmonary collapse. Computed tomography (CT) more often reveals blebs (often bilateral) that may not be visualized on plain radiographs. On CT exams, blebs and bullae are designated as emphysema-like changes (ELC). In two studies, ELCs were found in 89 percent on the ipsilateral side and up to 80 percent bilaterally, while only 20 percent of those without PSP had these changes. Another study showed that 81 percent of nonsmokers with healed PSP had ELCs, while those nonsmokers without PSP had none. Although there are multiple other studies showing an association between ELC and the risk of PSP, this theory remains controversial as there are also at least two large studies using CT scan changes that do not reveal this potential association between ELC and PSP. These changes are not only seen radiographically, but also at the time of thoracotomy. One series identified these blebs in 85 to 100 percent of surgical cases. There are multiple studies showing an association between ELC and the risk of PSP. A study by Bense found that on CT scan of the chest of patients with PSP, 81 percent of patients had ELC mainly in the upper lobes, while those without PSP had none. This theory remains controversial as there are also two large studies using CT scan changes that do not reveal this potential association between ELC and PSP. The pathogenesis of these subpleural blebs or bullae is unknown; however, it is thought to be related to airway inflammation. Airway inflammation secondary to cigarette smoking may be associated with or contribute to the development of these blebs. Respiratory bronchiolitis in smokers may either contribute to or be a leading factor in PSP. Pathologic evidence of respiratory bronchiolitis was found on more than 88 percent of smokers undergoing surgery for PSP. Other etiologies include abnormalities of connective tissue (e.g., Marfanâ&#x20AC;&#x2122;s syndrome), inflammation of the bronchioles, bronchial abnormalities, and overdistention of alveoli with poor collateral ventilation. Pleural pressure is most negative at the apices, and the degree of negativity relates to the height of the lungs. The alveoli of taller persons are subjected to greater mean distending pressures. Over a long period, this phenomenon could lead to the formation of subpleural blebs in a taller population genetically predisposed to bleb formation. There are multiple reports throughout the literature of genetic associations or patterns of PSP. Some reports suggest that PSP is inherited through an autosomal-dominant gene with variable penetrance, while others report an associated autosomal recessive or X-linked recessive inheritance pattern. Genetic risk factors that have been associated to PSP include the HLA haplotype A2 B40 , the Îą1 -antitrypsin phenotypes M1 M2 , and the FBN1 gene mutations. The rate of recurrence after a primary spontaneous pneumothorax is approximately 25 percent (range, 23 to 52 percent). Recurrence usually occurs within 1 to 2 years after the first episode.

The rate of recurrence may increase with each successive pneumothorax. Gobbel and coworkers found the risk of recurrence increased to more than 60 percent after the second pneumothorax and to 83 percent after the third. Although there is no predilection for the right or left hemithorax with the initial episode, more than 75 percent of recurrences occur on the same side as the first pneumothorax. Despite the documentation that pleural blebs occur bilaterally in many patients with primary spontaneous pneumothorax, the risk of contralateral pneumothorax is only 5 to 10 percent. The recurrence rates reported for both primary and secondary pneumothoraces vary widely in the literature. This difference may be secondary to treatment choices and duration of follow up. Recently, Guo and his group described risk factors for recurrence in a retrospective study in 182 patients. They found that greater height, lower weight, and the existence of pre-existing lung disease (secondary spontaneous pneumothorax) were associated with higher risk of recurrence. Death rarely occurs after primary spontaneous pneumothorax. In a study of spontaneous pneumothorax, in which patients ages ranged from 15 to 34 years (most likely representing patients with PSP) the mortality rate was reported to be 0.09 percent for men and 0.06 percent for women.

Secondary Spontaneous Pneumothorax Incidence and Demographics Secondary spontaneous pneumothorax (SSP) is more serious than primary spontaneous pneumothorax because, by definition, the patient already has underlying lung disease. A pneumothorax in these patients with already diminished pulmonary reserve, can be life threatening. The incidence of secondary spontaneous pneumothorax is similar to that of primary spontaneous pneumothorax. In Olmsted County, Minnesota, the incidence of secondary spontaneous pneumothorax was 6.3/100,000/year for males and 2.0/100,000/year for females. On average, patients with secondary spontaneous pneumothorax are 15 to 20 years older than patients with primary spontaneous pneumothorax. The risks of recurrence for SSP are somewhat higher than those for PSP and vary from 40 to 80 percent in the literature. Etiology Multiple pulmonary diseases have been associated with spontaneous pneumothorax, but chronic obstructive pulmonary disease (COPD) is the most common. The Veterans Administration Cooperative Study on Pneumothorax noted that pneumothorax tended to occur in patients with moderately severe COPD, with a quarter of the participants having an FEV1 below 1 L and a mean FEV1 /FVC ratio of 57 percent. Persistent bronchopleural fistula was also noted to be common in patients with obstructive lung disease, and 35 percent of patients had an air leak for more than 5 days.

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Table 87-1 Etiology of Secondary Spontaneous Pneumothorax Obstructive lung disease Chronic obstructive lung disease (COPD) Asthma Interstitial lung disease Idiopathic pulmonary fibrosis (usual interstitial pneumonitis [UIP]) Non-specific interstitial pneumonitis Eosinophillic granuloma Lymphangioleiomyomatosis Sarcoidosis Langerhans cell granulomatosis Radiation pneumonitis or fibrosis Histocytosis X Infection P. jerovici pneumonia Tuberculosis Coccidioidomycosis Acute bacterial pneumonia (i.e.: staphylococcus) Malignancy Primary lung carcinoma Pulmonary metastasis (especially sarcomas) Complications of chemotherapy Connective tissue disease Rheumatoid arthritis Ankylosing spondylitis Marfan’s syndrome Ehlers-Danlos syndrome Polymyositis/dermatomyositis Scleroderma Other Catamenial pneumothorax Pulmonary infarction Pulmonary hemorrhage Pulmonary alveolar proteinosis Tuberous sclerosis von Recklinghausen’s disease Wegener’s granulomatosis

Although airway diseases (COPD, CF, and severe asthma) are the most common, virtually every other pulmonary disease process has been associated with secondary spontaneous pneumothorax. The spectrum of diseases associated with secondary spontaneous pneumothorax is extensive (Table 87-1).

Pneumothorax

In contrast to the low mortality rate in PSP, in patients with SSP, there is a much higher risk of mortality. Although the mortality for recurrent pneumothorax was only 1.5 percent in the VA Cooperative Study, previous studies with secondary pneumothorax in patients with COPD have a combined mortality of 16 percent. In the VA cooperative study, the mortality was up to 36 percent, but most of these deaths were secondary to the patient’s underlying COPD or cancer. Videm et al. showed that SSP increased the mortality of age-matched COPD patients by 3.5 times.

Cystic Fibrosis Pneumothorax is a serious complication in patients with cystic fibrosis (CF) and is far more common than in the general population. It occurs in patients with more advanced disease and results in a significant increase in both morbidity and mortality. The etiology of spontaneous pneumothorax in CF patients has not been clearly established, but likely is associated with the rupture of subpleural blebs or cysts, which are usually located in the apices of the lungs. Another etiology may be that there is significantly increased pressure and volume in the alveoli because of mucus plugging and inflammation of the proximal airways leading to rupture in the pleural space. Multiple studies have shown the high incidence in this population. One study found that spontaneous pneumothorax occurred in 12.5 percent of 144 patients with cystic fibrosis over 10 years of age. A multicenter study by Flume using data from the national CF Foundation Patient Registry showed that approximately 6 percent of all patients with cystic fibrosis and 16 to 20 percent of those who reach age 18 will have an episode of pneumothorax. Prior reports of pneumothorax in CF patients from single centers have suggested that the mean age of occurrence was between 15 and 17 years of age. These reports were between the years 1968 and 1990. A recent analysis of patients in the 1990s reveals that pneumothoraces generally occur later in life with the mean age of occurrence in the early twenties. This may be because the median survival of CF patients has increased over time because of advanced therapies. The risk of developing a pneumothorax increases as age increases and pulmonary function (FEV1 ) decreases. In one study, greater than 50 percent of patients with an FEV1 > 20 percent predicted had at least one pneumothorax. Additional risk factors include the presence of P. aeruginosa, B. cepacia, and Aspergillus in the airways. The presence of these pathogens may cause increased inflammation as well as significant airway secretions leading to obstruction of the distal airways with air trapping. Recurrence of pneumothorax is more frequent in this population as well. An older study revealed a recurrence rate of spontaneous pneumothorax treated with tube thoracostomy alone to be 50 percent. A more recent study confirmed that more than one in five of the patients experienced at least two events in separate years. Because the recurrence rate is so

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high, consideration should be given to preventative measures after pneumothorax even after the first episode occurs. In the past, pleurodesis was not easily offered, as it was thought that it would preclude patients from lung transplantation. However, recent studies have shown that pleurodesis did not add appreciably to complications during lung transplantation. Although center-dependent, pleurodesis is no longer considered a contraindication to transplantation. Pneumothorax in CF patients is associated with a high rate of mortality and is an indicator of a poor prognosis in patients with CF. In one study, the median survival after the first spontaneous pneumothorax was only 29.9 months.

Traumatic Pneumothorax Trauma is the most common cause of pneumothorax. Patients who have either multitrauma or trauma to the thorax are at risk for pneumothorax. Between 1950 and 1974, there were 318 cases of pneumothorax in Olmsted County, Minnesota. Trauma was responsible for 177 of these cases (56 percent), of which 102 were iatrogenic. Noniatrogenic traumatic pneumothorax can result from either penetrating or nonpenetrating chest injury. The diagnosis needs to be considered in any patient who is evaluated for significant trauma. Penetrating chest trauma produces a pneumothorax by allowing air to enter the pleural cavity directly through the chest wall. In addition, if the visceral pleural is penetrated; air may leak from the tracheobronchial tree. If the continuity of the chest wall is disrupted, an open pneumothorax is produced. If the opening in the chest wall is larger than the diameter of the trachea (1.2 to 1.5 cm in an adult), air movement occurs through the pathway of least resistance, and air is preferentially inspired into the thoracic cavity through the open chest wound. Any open chest wound must be occluded to assure adequate ventilation of the patient. Pneumothorax is also a frequent finding in patients with blunt trauma to the chest. The visceral pleura may be lacerated secondary to a rib fracture or dislocation; however, in almost one-half of patients with pneumothorax secondary to blunt trauma, there are no associated rib fractures. This is especially common with blunt trauma to the chest secondary to blast injuries and high-altitude falls into water. In such incidents, the abrupt increase in the pressure gradient between the alveolus and the adjacent bronchovesicular sheath causes disruption of the alveolar membrane. Dissection of air through the interstitial space results in either pneumothorax or pneumomediastinum. Occasionally, patients with traumatic pneumothorax have coexisting injuries of the tracheobronchial tree or of the esophagus. In a patient with a traumatic pneumothorax, fiberoptic bronchoscopy should be performed in the presence of hemoptysis or a persistent air leak. Eighty percent of injuries to the tracheobronchial tree are within 2.5 cm of the carina, most commonly on the right side at the membranouscartilaginous interface. The main lobar bronchi and cervical trachea are the next most common sites of injury.

Traumatic rupture of the esophagus usually produces a hydropneumothorax. Therefore, if a patient with a traumatic pneumothorax also has a pleural effusion, the possibility of esophageal rupture should be entertained. Almost all patients with perforation of the thoracic esophagus also have dysphagia and pneumomediastinum. An elevated pleural fluid amylase concentration is a reliable screening procedure for esophageal rupture. Once the diagnosis is suspected, contrast radiographic studies of the esophagus should be performed as soon as possible. Untreated, esophageal rupture results in mediastinitis and septic shock; therefore, a high index of suspicion is essential in making an early diagnosis. Increasing utilization of invasive diagnostic as well as therapeutic interventions has significantly increased the rate of iatrogenic cases of pneumothoraces. These cases may have considerable increased morbidity and mortality and account for prolonged hospitalization for the affected patient. Iatrogenic pneumothorax can occur as a complication of multiple procedures, but the leading cause of iatrogenic pneumothorax is transthoracic needle aspiration. The incidence ranged between 20 and 40 percent in three large trials. Two to eight percent of these patients required tube thoracoscopy post procedure. Cox noted that CT evidence of COPD and a smaller lesion (less than 2 cm) correlated with the occurrence of pneumothorax. Other factors associated with pneumothorax in transthoracic needle aspiration were increased depth of the lesion into the lung, diagnosis of COPD, and the severity of the underlying lung disease. This incidence of pneumothorax has remained relatively unchanged as no reported techniques to decrease the risk have been successful (i.e., positioning patients, use of a blood patch, use of fibrin glue). Central venous catheterization carries the second highest risk of iatrogenic pneumothoraces. The risk that has been reported throughout the literature ranges from 2 to 12 percent. Subclavian catheterization carries a higher risk than internal jugular catheterization. Thoracentesis also carries a moderate risk of pneumothorax. The incidence has been reported to be 5 percent. Twenty to 50 percent of these will require chest tube placement. The incidence is increased in patients with COPD. Pneumothorax may also occur with transbronchial biopsy, Wang needle aspiration, liver biopsy, intercostal nerve block, mediastinoscopy, and tracheostomy. Iatrogenic pneumothoraces may have a delayed presentation, but most are apparent within 24 hours after the procedure. Another cause of pneumothorax that is frequently overlooked is chest tube malfunction. Common causes of chest tube malfunction include inadequate securing of the chest tube to the drainage system, failing to fill the U-manometer in the water seal chamber, failing to refill the water in the suction control chamber, and permitting intermittent disconnection of the system during diagnostic or therapeutic studies. Mechanical ventilation is a frequent, potentially lethal cause of iatrogenic pneumothorax. The overall incidence of pneumothorax during mechanical ventilation ranges from 4 to 15 percent, but may be significantly higher in patients

1523 Chapter 87

with underlying inflammatory diseases such as aspiration pneumonia. The incidence of pneumothorax is also increased during mechanical ventilation if patients have chronic pulmonary disease, are on increased amounts of positive endexpiratory pressure, or have right main stem intubation. The incidence of pneumothorax has been reported to occur in 6.9 to 14 percent of patients with ARDS. Another study reported a 48.8 percent incidence of pneumothorax in patients with severe ARDS requiring extracorporeal support. A pneumothorax should be suspected in any patient whose clinical status acutely decompensates on the ventilator. Any patient who demonstrates a sudden increase in tachypnea or becomes dyschronous with the ventilator should be evaluated for a pneumothorax. An increase in the peak and plateau pressure on the ventilator can be a sensitive indicator if the patient is on volume control ventilation. The peak inspiratory pressure often rises suddenly as the lung compliance falls. If the patient is on pressure control ventilation, decreased tidal volumes will be a sign of a pneumothorax. Radiographs of critically ill/mechanically ventilated patients are frequently obtained only in the supine or semisupine position. In a study by Tocino and colleagues, supine and semierect radiographs were obtained in 88 critically ill patients with 112 cases of pneumothorax. The radiologist initially failed to detect the pneumothorax in 30 percent of the cases. The patient with extensive infiltrates, as in those patients with ARDS, may have no suggestion of lung collapse on chest radiograph. In these patients, the only radiological sign which may be evident is that of a deep sulcus on the side of the pneumothorax. Any increased lucency in a supine film should be evaluated by erect or decubitus views to detect the presence of a pneumothorax If erect or decubitus films cannot be obtained, CT scans of the chest may be necessary. Recipients of heart-lung transplants do not have an intact mediastinum. Physicians performing procedures on these patients need to be aware that the patient can develop bilateral pneumothoraces because of this anomaly.

Catamenial Pneumothorax Catamenial pneumothorax (CP) is a rare condition in which women recurrently develop pneumothoraces during their reproductive years, usually in their third or fourth decade of life. Catamenial pneumothorax represents 3 to 6 percent of spontaneous pneumothorax in women. However; more recent studies suggest the incidence of this disorder may actually be much higher. There is no single definitive etiology for CP. One theory suggests pleural and/or diaphragmatic endometrial implants as being responsible for this disorder; however, only one-third of women have implants at the time of thoracotomy. Theories also include peritoneal air entering the thoracic cavity through diaphragmatic defects during menstruation, intrapulmonary implants causing bronchiolar obstruction, and the production of prostaglandin F2Îą by endometrial tissue resulting in bronchiolar and vascular constriction.

Pneumothorax

The diagnosis of this syndrome is based on recurrent pneumothorax occurring within 48 to 72 hours of the onset of menses. The patient classically develops chest pain and dyspnea within this time. It has been reported more likely to occur if the patientâ&#x20AC;&#x2122;s menstrual period is preceded by mental or physical stress. The majority (90 to 95 percent) of catamenial pneumothoraces affect the right hemithorax, but isolated left side or bilateral pneumothoraces have been reported. Medical treatment is aimed at suppressing the ectopic endometrium using oral contraceptives to suppress ovulation. Danazol, a weak androgen, has also been used to suppress ovulation. Gonadotropin-releasing hormone (GnRH) and the GnRH agonist Lupron have also been used to effectively suppress CP. If menses is not suppressed, there is a 50 percent recurrence rate within 1 year. Surgical treatment for CP including thoracoscopy with closure of any diaphragmatic defects, stapling of any blebs, and pleural abrasion have all been used to prevent recurrent pneumothorax. Hysterectomy with bilateral oophorectomy will induce surgical menopause and thus prevent pneumothorax.

Pneumothorax in Acquired Immunodeficiency Syndrome Patients with acquired immunodeficiency syndrome (AIDS) have a significantly increased risk of developing a pneumothorax. About 2 to 5 percent of patients with AIDS experience pneumothorax unrelated to trauma or a pulmonary procedure. In one study, pneumothorax complicated 1.2 percent of all 599 HIV patient admissions over 3 years. Mortality was increased (31 percent) in those who had a pneumothorax vs. 6 percent in those who did not. Pneumothorax in patients with AIDS is associated with multiple infectious etiologies. Pneumocystis jiroveci, pyogenic infections, Kaposiâ&#x20AC;&#x2122;s sarcoma, cytomegalovirus, pulmonary Cryptococcus, Coccidiomycosis, and mycobacterial disease have all been associated with spontaneous pneumothoraces. Most patients have a CD4+ count less than 100 cells/mm4 . The risk of spontaneous pneumothorax in HIV patients is higher if the patient is receiving inhaled pentamidine, smokes cigarettes, or presents with a pneumatocele on chest radiograph. The majority of HIV patients presenting with a pneumothorax have active PCP infection, therefore, evaluation and treatment for PCP is recommended in any patient with AIDS who presents with a spontaneous pneumothorax. The large numbers of pneumothoraces seen in patients with Pneumocystis jiroveci are thought to be secondary to the high incidence of subpleural cystic cavities and subpleural necrosis associated with this entity. Extensive tissue invasion within the alveolar interstitium is common in severe PCP and may result in subpleural necrosis. These cystic changes are thought to be due to repeated episodes of inflammation and cytotoxic effects of HIV on pulmonary macrophages. These lesions occur most frequently at the apices of the lungs and consist of necrotic alveoli filled with Pneumocystis jiroveci organisms, macrophages, eosinophilic exudate, and fibrous

1524 Part X

Disorders of the Pleural Space

material. Histological examination of patients who have recovered from Pneumocystis jiroveci demonstrates both subpleural blebs and bullae as well as pneumatoceles. Because of the necrotizing nature of the pneumonia, spontaneous pneumothorax is notoriously difficult to treat. Persistent air leaks often require tube thoracostomy for 3 to 4 weeks, and up to one-fourth of patients require surgical intervention. The incidence of bilateral cystic disease in these patients is extremely high, and the incidence of contralateral pneumothorax was about 50 percent in one study. Therefore, if surgical intervention is planned, some authors recommend preoperative CT scans of the chest and median sternotomy in patients with significant bilateral disease. Others recommend early thoracoscopic therapy in good surgical candidates to avoid prolonged hospitalization.

Tuberculosis With the rise of AIDS, the frequency of pulmonary tuberculosis has increased within the general population. Tumbarello et al. found 6.8 percent of HIV patients with pulmonary tuberculosis developed a pneumothorax. All pneumothoraces associated with tuberculosis should be treated and often require prolonged periods of chest tube drainage. In cases of tuberculosis, surgery should not be considered until the patient has received antituberculous therapy for at least 6 weeks.

CLINICAL FEATURES The main symptoms with the development of a pneumothorax are chest pain and dyspnea, which occur in 95 percent of patients. The pain is usually acute, localized to the side of the pneumothorax, and typically pleuritic. Cough, hemoptysis, orthopnea, and Hornerâ&#x20AC;&#x2122;s syndrome are uncommon manifestations of a pneumothorax. A small percentage of patients are asymptomatic or complain only of generalized malaise. Spontaneous pneumothorax usually occurs at rest, and fewer than 10 percent of them occur during strenuous exercise. In primary spontaneous pneumothorax, both the dyspnea and chest pain may subsequently abate over the first 24 hours. This may explain why nearly half of patients have symptoms for 2 days before seeking medical attention and why 18 percent wait for more than a week. Most patients with secondary spontaneous pneumothorax have more severe symptoms than patients with PSP, and dyspnea frequently seems out of proportion to the size of the pneumothorax. Small pneumothoraces (less than 20 percent) are usually not detectable on physical exam. In patients with obstructive lung disease, even larger pneumothoraces may be difficult to detect since decreased breath sounds and hyperresonance may already be present in patients with obstructive lung disease. On physical exam, vital signs are usually normal, with the exception of moderate tachycardia. Exam-

ination of the chest may reveal the affected side to be larger and move less during respiration. Tactile fremitus is absent, the percussion note is hyperresonant, and breath sounds are absent or reduced on the side with the pneumothorax. Hammanâ&#x20AC;&#x2122;s sign may be detected. This sign, also heard with pneumomediastinum, has been described as crunching or clicking noises synchronous with the heartbeat but influenced by respiration and body position. Severe tachycardia, with a heart rate above 140 beats a minute, hypotension, cyanosis, or tracheal deviation, suggests the possibility of a tension pneumothorax. Arterial blood gases often show hypoxemia and perhaps hypocarbia from hyperventilation. Hypoxemia is usually mild in primary spontaneous pneumothorax when less than 25 percent of the lung is affected. When more than 25 percent of the lung is involved, pulmonary shunts occur more frequently and hypoxemia may be severe. In patients with secondary spontaneous pneumothorax, pulmonary reserve is already diminished and life-threatening hypoxemia and hypercarbia may be present. In a study by Dines et al., the mean PaO2 was 48 mmHg and the mean PcO2 was 58 mmHg when patients with emphysema presented with a spontaneous pneumothorax. Patients with a left pneumothorax may show changes suggesting an anterolateral myocardial infarction. A rightward shift of the frontal QRS axis and clockwise rotation of the heart result in a diminution of precordial R-wave voltage, a decrease in the QRS amplitude, and precordial T-wave inversion. These electrocardiographic features differ from a transmural myocardial infarction because of the absence of STsegment elevation or significant Q waves. An anterior subendocardial infarction may present with T-wave inversion but without the rightward shift in the frontal axis. The electrocardiographic changes with a left pneumothorax may normalize when the patient is in the upright or right lateral decubitus position.

RADIOGRAPHIC APPEARANCE The diagnosis of a pneumothorax is established by demonstrating the outer margin of the visceral pleura (and lung) separated from the parietal pleura (and chest wall) by a lucent gas space devoid of pulmonary vessels (Fig. 87-3). The pleural line may be difficult to detect with a small pneumothorax unless high-quality upright films are obtained. In erect patients, pleural gas collects over the apex, and the space between the lung and chest wall is most notable there. In the supine position, gas migrates along the broad ventral surface of the lung, making detection on a frontal radiograph difficult. In the supine position, the juxtacardiac area, lateral chest wall, and subpulmonic region are the best areas to search for evidence of pneumothorax. When a suspected pneumothorax is not definitely seen on an inspiratory film, an expiratory film may be helpful. At end-expiration, the constant volume of the pneumothorax gas is accentuated by the reduction in the

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Figure 87-3 Patient with nodular silicosis and a spontaneous secondary pneumothorax. The visceral pleural line is clearly seen with the absence of vascular workings beyond the pleural line. There are cicatricial bullae in both bases.

size of the hemithorax. Therefore, the pneumothorax may be more easily recognized. Similar accentuation can be obtained with lateral decubitus studies of the appropriate side. However, several recent studies have showed that the expiratory films have little or no advantage over upright inspiratory films in the diagnosis of pneumothorax. The recent BTS guidelines do not recommend the routine use of expiratory chest films in the evaluation of suspected pneumothorax. It is very important to differentiate the pleural line of a pneumothorax from that of a skinfold, clothing, tubing, or chest wall artifact. Careful inspection of the film may show that the artifact extends beyond the thorax, or that lung markings are visible beyond the apparent pleural line. In the absence of underlying lung disease, the pleural line of a pneumothorax usually parallels the shape of the chest wall. Artifactual densities generally do not parallel the course of the chest wall over their entire length. Avascular bullae or thinwalled cysts can be mistaken for a pneumothorax. The pleural line caused by a pneumothorax is usually bowed at its center toward the lateral chest wall. As opposed to a pneumothorax, the inner margins of bullae or cysts are, in general, concave rather than convex and do not exactly conform to the contour of the costophrenic sulcus. A pneumothorax with a pleural adhesion may also simulate bullae or lung cysts. A synechia tends to form a straight line connecting the lung to the parietal pleura; bullae or cysts have rounded edges. Such features

Pneumothorax

are not 100 percent specific, and if there is any doubt as to whether the patient has a bulla or cyst or a pneumothorax, a CT scan should be obtained as CT can usually differentiate the two. Pleural effusions may occur coincident with pneumothorax in up to 20 to 25 percent of cases. Hemopneumothorax occurs in 2 to 3 percent of cases of spontaneous pneumothorax. Bleeding is believed to represent rupture or tearing of vascular adhesions between the visceral and parietal pleura as the lung collapses. Quantification of the size of a pneumothorax is helpful; unfortunately, however, the methods for quantifying lack uniformity and are by no means precise. Light suggested the measurement of the average diameters of the collapsed lung and of the affected hemithorax, with the cubing of these diameters to estimate the percentage of collapsed lung. For example, if the diameter of the collapsed lung is 6 cm and the diameter of the hemithorax is 10 cm, the collapsed lung is estimated by the formula 100 â&#x2C6;&#x2019; 63 /103 . Thus, the estimated size of the pneumothorax is 78 percent. Rhea and coworkers proposed the use of a nomogram to calculate the size of the pneumothorax. With this method, the average intrapleural distance is calculated by measuring the interpleural distance at the apex and at the midpoints of both the upper and lower lungs. These three values are then averaged, and the number is reported on a nomogram, which gives an estimated size of the pneumothorax. An example of these calculations is shown in Fig. 87-4. The most common radiographic manifestations of tension pneumothorax are mediastinal shift, diaphragmatic depression, and rib cage expansion (Fig. 87-5). Any significant degree of displacement of the mediastinum from the midline position on maximum inspiration, or any depression of the diaphragm, should be taken as evidence of tension. The degree of lung collapse is an unreliable sign for or against the presence of a tension pneumothorax, since underlying lung disease may prevent collapse even in the presence of tension. Ultrasound can be used to both detect pneumothoraces as well as direct the site of drainage. CT scans of the chest are being used with increasing frequency in patients with pneumothorax. CT scans may be necessary to diagnose pneumothorax in critically ill patients when upright or decubitus films are not possible. CT scans may prove helpful in predicting the rate of recurrence in patients with spontaneous pneumothorax. One study demonstrated that patients who have larger or more numerous blebs on thoracic CT scans are more likely to have recurrence. Traumatic pneumothoraces, if large, can be detected both clinically and with chest radiography. However, a small post-traumatic pneumothorax may be easily missed by both physical exam and chest radiograph. One prospective series revealed that 51 percent of trauma patients presented with an occult pneumothorax that was not seen on initial chest radiograph, but identified on CT imaging. In another large series looking at multiple trauma patients, 4.4 percent had a pneumothorax and 38.8 percent of these were detected only by CT scan. Early incorporation of a routine CT scan in all

1526 Part X

Disorders of the Pleural Space

Figure 87-5 Right tension pneumothorax in a young patient with staphylococcal endocarditis and septic emboli. There is marked depression of the right hemidiaphragm, shift of the mediastinum, and subcutaneous emphysema. Note: The pulmonary artery catheter, endotracheal tube, and nasogastric tube (midchest) are all displaced to the left.

Observation

Figure 87-4 Estimation of the size of the pneumothorax according to the method described by Light et al. (From Beauchchamp, in Pearson (ed), Textbook of Thoracic Surgery, 1995, 1043.)

patients with chest trauma or multiple traumatic injuries may be required to successfully diagnose traumatic pneumothoraces.

THERAPY The basic tenets of therapy for pneumothoraces are to evacuate the space, achieve closure of the leak, and either prevent or reduce this risk. A variety of treatment methods and adjuncts exist. The choice of therapy depends on many factors, including the clinical status of the patient, the cause of the pneumothorax, evidence for concomitant lung disease, prior history of pneumothorax, risk of recurrence, and, finally, the experience and preferred techniques of the physicians caring for the patient as well as the availability of specific therapeutic options. Major categories of treatment methods are listed below, followed by suggested guidelines for their application.

Simple observation of the patient with a pneumothorax requires evidence that the air leak is sealed (i.e., that there is no further progression of the pneumothorax). This form of management is generally reserved for asymptomatic patients with a small (greater than 20 percent) unilateral pneumothorax. A suggested protocol is the performance of serial chest radiographs over the initial 24 hour to assess for further progression of the pneumothorax. Some have suggested that this approach could be performed safely on an outpatient basis with close observation and limited patient activity. This form of management is risky because complications may occur rapidly, with potential morbidity. In one study of observation, 5 percent mortality was reported owing to the development of tension pneumothorax from an unrecognized pleural leak. Inpatient monitoring during the initial phase of therapy also allows the use of adjunct measures such as supplemental oxygen, which increases the rate of absorption of pleural gas. Depending on the circumstances and level of patient compliance, continued follow-up may be done on an outpatient basis.

Aspiration Aspiration of a pneumothorax has been advocated by some; with varied levels of success. These reports have prompted the British Thoracic Society to recommend simple aspiration as first line therapy for all patients with first time spontaneous pneumothorax. This is in contrast to the American College of Chest Physicians Delphi Consensus Statement on this issue illustrating the controversial nature of this form of therapy. A meta-analysis of a randomized controlled trial

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of simple aspiration versus chest tube insertion concluded that simple aspiration was advantageous because of shorter hospitalization times and no significant difference in recurrence rates at 1 year. In these studies, approximately 66 percent of patients had resolution of their pneumothorax. Patients with secondary or a recurrence of spontaneous pneumothorax generally do not have good results with simple aspiration. The procedure consists of insertion of a 16- or 18gauge plastic catheters under local anesthesia using sterile technique. The recommended point of insertion is the second anterior intercostal space in the midclavicular line. The catheter is connected to a three-way stopcock and a large-volume syringe. Aspiration is performed until no further gas can be withdrawn. Follow-up chest radiographs are performed. Again controversy exists regarding a second attempt at aspiration only if the first attempt is unsuccessful. If large volumes are aspirated without resolution or the second attempt is unsuccessful, a tube thoracostomy should be performed. Long-Term Aspiration This entails the placement of an indwelling catheter into the pleural space for continual removal of the interpleural gas. The classic method is the use of standard tube thoracostomy. For uncomplicated pneumothorax without evidence of significant amounts of fluid or blood, one may use tubes ranging in size from No. 16- to 24-French to minimize the discomfort of a larger tube in the intercostal space. The tube is then connected to a pleural drainage system. Commercial systems commonly employ variations on the three-chamber system (Fig. 87-6). The three-chamber system consists of a fluid collection chamber attached to a waterseal chamber to allow egress of gas from the pleural space, but in a one-way fashion. The final connection is to a manometer bottle, which regulates the degree of suction being applied to the system. After placement of tube thoracostomy, care should be taken with regard to immediate placement to suction because of the potential for postexpansion pulmonary edema (see below). In many cases it may be prudent to leave the tube to water seal and allow the lung to expand gradually. Once the majority of the pneumothorax is evacuated, suction is applied for the next 24 hours. If an air leak exists, as evidenced by continual or intermittent egress of gas through the water seal chamber, suction is maintained. Once there is no evidence of an active air leak, the tube may be placed to underwater seal. After an additional period of observation of 12 to 24 hours, the chest tube may be removed if the pneumothorax does not recur. Tube thoracostomy alone will result in closure of an air leak in most cases by complete evacuation of the pleural space and apposition of the visceral and parietal pleura. Persistence of an air leak for more than 72 hours generally presages a leak that will not close by this regimen and should prompt consideration of more aggressive therapy, usually surgical with or without some form of pleurodesis.

Pneumothorax

In order to have a less traumatic method of placement of an indwelling tube, as well as to minimize the discomfort from a large-bore tube in the intercostal space, a variety of smaller catheters have been suggested for use as an interpleural drain. The method of placement is similar to needle aspiration in terms of preparation and location of entry. Once the pleural space is entered with the needle, the Seldinger technique is used to pass a soft tip wire. The 8-French pigtail catheter is then placed over the wire into the pleural space and the wire withdrawn. The catheter is left in place and attached to the pleural drainage system as described in the preceding. Potential problems with smaller catheters relate to a greater propensity for blockage of the tube. Also, the smaller size makes them more prone to kinking, clotting from blood or fluid, and sealing around the tube by the lung, resulting in a loculated pneumothorax. In cases in which the pneumothorax is associated with significant amounts of blood or fluid, tube thoracostomy using a larger-bore chest tube (26- to 32French) is recommended. Use of these types of catheters has created the possibility of a form of hybrid therapy in which these catheters are placed and simple aspiration performed as noted. If the lung fails to re-expand or the volume of air obtained is excessively large, suggesting a continued air leak, the catheter may be left in and connected to longer-term drainage. A variation on the use of pleural drainage systems has been the substitution of a one-way valve to permit greater mobility by the patient. The most common is the Heimlich flutter valve, which may have some application in cases in which long-term indwelling catheterization is required but surgical therapy is declined or not possible. This valve is not widely recommended, however, owing to a potential for problems with blockage, which may not be immediately recognized on an outpatient basis.

Pleurodesis Pleurodesis is an adjunct to the other forms of therapy. The goal is to achieve pleural symphysis, or adhesion of the visceral and parietal pleura to obliterate the pleural space. Sealing the visceral and parietal pleura together will prevent future air leaks and prohibit the lung from â&#x20AC;&#x153;falling awayâ&#x20AC;? from the chest wall. The basic mechanism entails chemical or physical irritation of the pleural surface to promote an inflammatory response and subsequent adhesion formation. The goal of pleurodesis is to prevent recurrence in both PSP and SSP. There is good consensus for the use of pleurodesis in both; however, when and how to achieve pleurodesis depends on both the kind of pneumothorax as well as if there has been a recurrence. Chemical pleurodesis may be used in combination with tube thoracostomy or surgical therapy. In patients who are unable to undergo a surgical procedure (e.g., severe comorbidity), pleurodesis can be achieved with administering the sclerosing agent through a chest tube. The success of the antibiotics (tetracycline, doxycycline, minocycline) and talc by slurry have been shown to have results that are better than

1528 Part X

Disorders of the Pleural Space

Figure 87-6 A. Three-bottle chest tube drainage system. The system consists of a collection bottle, a water-seal bottle, and a suction-control bottle. The collection bottle allows sterile drainage from the pleural spaces. The water-seal bottle acts as a one-way valve in the absence of suction, and the suction bottle allows for the regulation of negative pressure applied to the pleural space. B. Commercially available, compartmentalized plastic drainage system.

chest tube drainage alone, but not as good as thorascopic treatment. As an adjunct to tube thoracostomy, the chemical of choice is suspended in fluid and instilled through the tube. The tube is clamped for 6 to 8 hours, then placed back to either suction or water seal. Periodically changing patient position during this period is believed to effect more even distribution of the irritant. General requirements for the performance of chemical pleurodesis via the tube are that pleural fluid output be less than 150 to 200 ml/day and that there be no air leak. Success is largely dependent on apposition of the visceral and parietal pleura during the period of inflammation while

the tube is clamped. Excessive pleural fluid will dilute the sclerosing agent, and an air leak will allow the lung to separate from the chest wall. Pleurodesis in the face of an air leak has been tried, but in our experience it has rarely been successful. The ideal agent should be effective, safe, easy to administer, and widely available and affordable. A number of pleural irritants have been suggested, including quinacrine, silver nitrate, bleomycin, autologous blood, antibiotics (tetracyclines), and talc. Minor side effects of pleurodesis with a sclerosing agent include chest pain and low-grade fevers. Tetracycline was shown to be very effective in creating sufficient pleural fibrosis formation when compared to

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hydrochloric acid, quinacrine, nitrogen mustard, bleomycin, or sodium hydroxide. A randomized study comparing the recurrence rates in PSP after drainage alone with that of drainage plus tetracycline or talc found recurrence rates of 36, 13, and 8 percent, respectively. Tetracycline, however, is no longer commercially available. Minocycline and doxycycline have been suggested as replacements for tetracycline with experimental data that suggest equal efficacy. Typical doses of these antibiotics are 0.5 to 1.0 g of doxycycline in 50 to 100 ml normal saline and 600 mg of minocycline in 50 to 100 ml of normal saline. Talc has also been shown to be a very effective sclerosing agent when applied as a slurry via a chest tube or by talc poudrage during thoracoscopy. In an experimental study, talc was noted to be as efficacious as mechanical abrasion. In a meta-analysis, talc achieved a “success rate” of 91 percent. Doses between 2 to 10 g of talc in 100 to 200 ml of normal saline have been reported. There is no standardized practice when using talc administered by chest tube. The drawbacks of talc slurry are prolonged pleural drainage and inhomogeneity of deposition. The distribution of talc may lead to loculation and incomplete symphysis. The advantages are it can be performed easily at the bedside. There are data, however, that suggested an increased incidence of adult respiratory distress syndrome associated with the use of talc as a sclerosant. The size of the talc particles (less than 15 µm) and the dose (greater than 5 g) may be associated with a higher incidence of ARDS. In a comprehensive literature review, Sahn et al. found acute respiratory failure in 0.15 percent of patients treated with talc poudrage. As an adjunct to surgical therapy, the most commonly described material is talc. Sterile, asbestos-free talc is insufflated during thoracoscopy or thoracotomy to coat the visceral pleural surface. Typically, 2 to 10 g are used. Mechanical pleurodesis is performed as part of a surgical procedure. It may consist of simple abrasion of the parietal pleural surface or may entail stripping of the parietal pleura (pleurectomy). The second method has a greater potential for complications, including injury to an intercostal neurovascular bundle or excessive bleeding from the large raw surface area. Also considered in this category is the use of an Nd:YAG laser or an argon beam coagulator, which essentially cauterizes the pleural surface. Experimental studies have not borne out their effectiveness. The performance of pleurodesis is somewhat controversial owing to the degree of pleural symphysis that can be obtained and with these methods. Either talc or mechanical pleurodesis, especially pleurectomy, may result in rather significant adhesion formation. Clearly there is a considerable reduction in the incidence of recurrence. However, in some cases, there are concerns that future surgical procedures, such as pulmonary resection, open lung biopsy, and lung transplantation, may be hampered by this degree of pleural symphysis. The application of pleurodesis thus depends on an assessment of the risk of recurrent pneumothorax and the potential morbidity to the patient should a recurrence occur versus the potential for later operative procedures in

Pneumothorax

the thorax. One suggested compromise is limitation of the pleurodesis to the apical area, as this is the most common location for air leaks to occur. Later thoracic procedures may be done, albeit with more difficulty, by entrance inferior to the area of pleurodesis and subsequent adhesion lysis apically. Localized pleurodesis is not possible when it is performed as an adjunct to tube thoracostomy. A second potential compromise is the use of tetracycline analogs such as minocycline or doxycycline. Experimental studies and anecdotal reports indicate that with the use of tetracycline, the degree of pleural symphysis and density of adhesions are not as great as with talc or mechanical pleurodesis.

Operative Therapy Operative treatment is generally thought to be the most effective in assuring expansion of the lung, with complete evacuation of the pleural space, and providing for the best means of reducing the risk of recurrence. In addition, it provides a means of potentially identifying an air leak and closing it. However, increased patient discomfort, risks of general anesthesia, and greater costs of the procedures, combined with moderate success of the less invasive methods, result in restricted application of surgery for pneumothorax. Operative therapy is indicated in cases in which the above-mentioned, less invasive techniques have failed, with a persistence or recurrence of the pneumothorax, or in cases of initial presentation of patients with factors suggesting increased risk of later recurrence. This risk of recurrence also includes an assessment of the potential morbidity to the patient should another pneumothorax occur. Longitudinal studies have indicated that after tube thoracostomy treatment of a spontaneous pneumothorax, the recurrence rate is approximately 30 percent. Among patients in whom the disease recurs once, the subsequent recurrence rate continues to increase. Evidence suggests that a more definitive procedure—namely, surgery—is indicated with the first recurrence. In patients with underlying lung disease, such a large bulla is also believed to have an increased risk of recurrence, and in most cases, surgery is indicated for the initial episode. Patients who have high-risk lifestyles, such as pilots or scuba divers, or patients who may not have ready access to medical care may possess a relative indication for surgical treatment of a first occurrence of spontaneous pneumothorax because of the risk to the patient should a pneumothorax occur. Patients who present with bilateral or tension pneumothorax may also fall in this category of morbidity assessment. Patients with a pneumothorax from any cause who have a persistent air leak despite chronic aspiration therapy should also be considered for operative therapy. An air leak that fails to close after 72 hours of suction has a very low chance of closing spontaneously. This is the recommended time for surgical referral. Finally, patients in whom the previous forms of therapy result in incomplete re-expansion of the lung should be considered for surgery. This situation may reflect loculation of the pneumothorax or trapping of the

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lung by a fibrotic “peel,” which will require surgery to be released.

Thoracoscopy In recent years, a greater emphasis on “minimally invasive surgery,” and the advent of improving technology and video assistance, video-assisted thoracoscopic surgery (VATS) has become a popular surgical modality. Less postoperative discomfort and decreased length of hospital stay have made this a more accepted procedure. The decreased morbidity is the result of the ability to examine the pleural space and manipulate the lung without significant muscle division or rib spreading. In most cases, the technique requires general anesthesia with double-lumen endotracheal ventilation (single lung ventilation). Those patients who are high risk (elderly or significant underlying lung disease) can undergo this procedure under local and epidural anesthesia. Up to three separate ports are placed in the intercostal spaces to effect installation of the camera as well as manipulating devices. The entire lung can be inspected and a search for the air leak carried out. Generally speaking, the apical area is the location, and this area can then be closed with the use of a stapler. In patients with concomitant lung disease, particularly COPD, the staple line can be reinforced with the aid of bovine pericardium to minimize persistence of air leaks. The pleural surface can then be abraded or talc insufflated, as mentioned, to achieve some degree of pleural adhesion following re-expansion of the lung. Long-term follow-up of recurrence rates has shown results similar to those for open thoracotomy. Stapled resection of bullae and talc poudrage can be performed safely. The less invasive nature of VATS compared to open thoracotomy has prompted earlier and more frequent surgical referral. While the risks associated with general anesthesia remain, overall costs are generally less than thoracotomy owing to a decreased postoperative period. The cost of VATS as an initial procedure for spontaneous pneumothoraces may be less in the course of the treatment of the disease as compared with more conservative therapies for both PSP and SSP. These conclusions; however, are not based on prospective randomized trials and should be verified in larger prospective studies. Open Thoracotomy Classically, thoracotomy was believed to be the ultimate and most effective form of therapy for pneumothorax. Recurrence rates are generally less than 2 percent. Thoracotomy allows examination of the lung for the site of an air leak, enables lysis of previous adhesions that may lead to a loculated pneumothorax, and enables the release of a fibrotic peel that occasionally forms, leading to incomplete re-expansion of the lung. Drawbacks include the potential risks associated with general anesthesia, increased costs, and the significant amount of patient discomfort. Discomfort is generally most severe with a standard lateral or posterolateral thoracotomy with muscle division and rib spreading.

In an effort to minimize the level of discomfort, variations have been developed, including the use of smaller incisions, so-called muscle-sparing thoracotomies, and the axillary thoracotomy. Lung examination and air leak closure and possible pleurodesis or pleurectomy then can still be performed. While thoracoscopy has supplanted thoracotomy as the surgical treatment of pneumothorax in many institutions, open thoracotomy remains a valuable option in the treatment of complicated cases.

Suggested Guidelines for Therapy Based on the relative efficacy of the various forms of therapy (Table 87-1), combined with relative risks for the major categories of pneumothorax, the following guidelines are suggested. Primary Pneumothorax Patients with a first-time primary spontaneous pneumothorax who are asymptomatic and whose pneumothorax is thought to be less than 20 percent may be treated with observation and sometimes adjunct measures, including the use of supplemental oxygen. Patients with primary spontaneous pneumothorax who are symptomatic or whose pneumothorax is greater than 20 percent should undergo an attempt at catheter aspiration. Subsequent small- or large-tube thoracostomy is indicated for failure of simple aspiration. Patients who undergo successful tube thoracostomy with complete lung re-expansion and absence of an air leak may be considered for further chemical pleurodesis, with doxycycline or talc as the suggested agent. This will reduce the risk of recurrence, but it should not completely obviate the ability to perform later surgical procedures. Patients with tube thoracostomies that have persistent air leaks for more than 72 hours should be referred for surgical therapy. Because of the progressive increase in risk of recurrence, patients with their first recurrence of a primary pneumothorax should undergo chemical pleurodesis or be referred for surgical therapy, preferably thoracoscopy with stapling of any air leak and pleural abrasion or chemical pleurodesis. Indications for surgery in primary pneumothorax are listed in Table 87-2. Secondary Pneumothorax In general, therapy for secondary pneumothorax should be more aggressive because of the higher rate of recurrence due to the underlying lung pathology. Specific conditions with pneumothorax as a common occurrence are as listed below. COPD

Most cases of pneumothorax in patients with COPD should be treated with some form of long-term aspiration, typically tube thoracostomy. In patients who are not good surgical candidate chemical pleurodesis with doxycycline or talc should be performed once there is complete reexpansion and absence

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Table 87-2 Indications for Surgery in Primary Spontaneous Pneumothorax First episode Prolonged air leak Incomplete re-expansion of lung Associated single large bulla Occupational hazard (flight personnel, divers) Absence of medical facility in isolated areas Tension pneumothorax∗ Hemopneumothorax∗ Bilateral pneumothorax∗ Second episode Ipsilateral recurrence Contralateral recurrence after first pneumothorax∗ ∗ Relative

indication.

of an air leak. In COPD patients who are good surgical candidates or in patients with a persistent air leak longer than 72 hours, more aggressive therapy should be considered. Recommended therapy would include thoracoscopy, VATS, or thoracotomy with talc insufflation, mechanical pleurodesis, stapling resection, and/or pleurectomy. This approach provides a better means of achieving a lower risk of recurrent pneumothorax. Cystic Fibrosis

In a retrospective review of patients with cystic fibrosis and pneumothorax, the entire spectrum of therapeutic options were utilized as clinically indicated. Patients undergoing surgical therapy did better and had fewer episodes of recurrence and complications. Therefore, this is the primary recommendation for this subgroup of patients. Because of the growing application of lung transplantation to patients with cystic fibrosis, localized pleurodesis is recommended as an adjunct to surgical closure of the air leak. AIDS

For most AIDS patients presenting with a pneumothorax, tube thoracostomy is the primary mode of initial treatment. Because of the high primary and secondary treatment failure rates, patients who have no air leak with complete lung reexpansion should undergo talc slurry pleurodesis. For patients with a persistent air leak who are felt to be poor surgical risks because of severe debilitation, a Heimlich valve may be utilized. For patients who are deemed good risks for surgery, thoracoscopy with talc insufflation is recommended. Other Conditions

While there are insufficient data to make firm recommendations for the following situations, some suggestions are

Pneumothorax

offered. Patients having pneumothorax secondary to iatrogenic causes may be treated with observation or aspiration according to the guidelines previously listed. Patients who have a pneumothorax secondary to trauma should have largebore tube thoracostomy, because there is a high association with hemothorax and the margin of safety may be decreased owing to other injury. Patients who experience a pneumothorax while on positive-pressure ventilation should have tube thoracostomy placement to avoid progression to a tension pneumothorax. Patients who present with bilateral pneumothoraces or a tension pneumothorax, but who are not on positive-pressure ventilation, should have placement of tube thoracostomy. Further therapy with regard to chemical pleurodesis versus surgery is dependent on underlying lung pathology.

COMPLICATIONS Tension Pneumothorax A tension pneumothorax is present when the intrapleural pressure is greater than atmospheric throughout expiration and often during inspiration as well. The term expiratory tension pneumothorax has been proposed to highlight the fact that in a spontaneously breathing person, pleural pressure must be negative in relation to atmospheric pressure during part of the respiratory cycle for air to enter the pleural space. The mechanism responsible for tension pneumothorax is the disruption of the visceral or parietal pleura in such a manner that a one-way valve develops. During inspiration, the respiratory muscles contract and create negative intrapleural pressure, allowing for air movement into the pleural space. Then, during expiration, when the expiratory muscles relax, the pleural pressure becomes positive and the one-way valve prevents the egress of air from the pleural space. As a tension pneumothorax progresses, the pleural pressure remains positive during a greater portion of the inspiratory cycle. If the patient is on mechanical ventilation, the alveolar pressure remains positive throughout inspiration and expiration. A tension pneumothorax can occur after any type of pneumothorax; it is independent of the etiology. It can sometimes occur after a spontaneous pneumothorax but is more common after a traumatic pneumothorax, with mechanical ventilation, or during cardiopulmonary resuscitation. The clinical picture associated with the development of a tension pneumothorax is striking. The patient will appear acutely ill, develop severe dyspnea, marked tachycardia, profuse diaphoresis, and cyanosis. On physical examination, the patient may develop profound hypotension and hypoxemia, exhibit distended neck veins, tracheal deviations to the side opposite the pneumothorax, subcutaneous emphysema, and may show unilateral chest hyperinflation. The involved hemothorax will enlarge and there will be widened interspaces. Arterial blood gases reveal severe hypoxemia and can show a severe respiratory acidosis. Chest radiographs

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may show mediastinal shift to the contralateral side of the pneumothorax. Patients receiving mechanical ventilation often develop a sudden increase in their peak and plateau pressures, with an associated decrease in the oxygen saturation. If the patient is on pressure control ventilation and is paralyzed, arterial blood gases will show a respiratory acidosis as the patient is unable to increase his respiratory rate. The development of a tension pneumothorax is a medical emergency requiring immediate chest drainage to relieve the intrapleural pressure. It should be suspected in any patient with a pneumothorax whose condition deteriorates acutely or in any patient with cardiopulmonary collapse after a procedure known to cause a pneumothorax, or with mechanical ventilation. One should also suspect a tension pneumothorax in any patient undergoing cardiopulmonary resuscitation that is difficult to ventilate or develops electromechanical dissociation. A tension pneumothorax may develop because of improper connection of a one-way flutter valve to the chest tube. It can occur even if there is a chest tube in place, due to either malpositioning of the tube or disconnection at the site of tube or the site of the pleural-vac container. When the diagnosis of a tension pneumothorax is considered, the patient should be given a high concentration of oxygen to alleviate the extreme hypoxemia seen with this syndrome. Radiographic documentation may not be possible in an emergency situation. Tension pneumothorax is a clinical diagnosis and therapy should not be held up by confirmation of the chest radiograph. A large-bore needle should be inserted into the second anterior intercostal space. Optimally, the needle should be connected to a syringe partly filled with sterile saline. Air bubbling outward through the fluid confirms the diagnosis. The needle or its plastic outer sheath should be left in place, and the patient should be prepared for immediate tube thoracostomy. The decompensation of the cardiopulmonary status in patients with tension pneumothorax is usually attributed to diminished venous return and marked decrease in the cardiac output, which is the most life-threatening. However, there is also a significant decrease in the Pa O2 , which also needs to be addressed immediately as well. Animal studies demonstrate that cardiac output is maintained by the tachycardia and the increase in negative intrathoracic pressure during inspiration. Deterioration has been shown to be related to severe hypoxemia, probably be˙ Q) ˙ mismatch in the cause of increased shunting and (Va/ compressed lung. Preterminally, animals develop CO2 retention and respiratory acidosis. The importance of negative intrathoracic pressure swings in maintaining cardiac output was demonstrated by the precipitous fall in cardiac output when mechanical ventilation was initiated.

Bronchopleural Fistula A bronchopleural fistula is a communication between the pleural space and the bronchial tree. It is a rare, but seri-

ous complication associated with several pulmonary conditions. In the setting of a spontaneous or nonspontaneous pneumothorax, it is consistent with a prolonged air leak. Most air leaks seal within 24 to 48 hours after tube thoracoscopy. Only 3 to 5 percent of patients with pneumothorax have a persisting air leak. If an air leak persists for more than 48 hours, continuous suction for 8 to 10 days results in only minimal increase in pulmonary healing. Current ACCP guidelines recommend if the leak persists over 4 days, the patient should be evaluated for surgery to close the air leak and perform a pleurodesis procedure to prevent recurrence. Thoracoscopy is the preferred procedure for managing bronchopleural fistulas. Use of an additional chest tube may occasionally help, but surgery should be considered after 3 to 4 days of tube drainage. Patients with cystic fibrosis or COPD are at increased risk for the development of persistent bronchopleural fistula. For those who are not candidates for thoracotomy, the fistula may be localized by bronchoscopic balloon catheter occlusion and subsequently injected with a variety of substances to promote sealing of the air leak. Fibrin glue, liquid bioadhesive (isobutyl 2-cyanocrylate), sterile gelatin sponge, and even lead shot have been used for this purpose. Autologous “blood patch” pleurodesis has also been accomplished, using 50 to 100 ml of the patient’s blood and injecting it into the chest tube. In our experience, however, these patients almost all come to thoracoscopic surgery because these procedures usually fail, and the air leak persists for more than 7 to 10 days.

Re-expansion Pulmonary Edema Re-expansion pulmonary edema (REPE) is a rare but potentially lethal condition that can occur with the rapid reexpansion of a collapsed lung (after a varied period of time) after tube thoracostomy is used to drain air (pneumothorax) or fluid (pleural effusion) from the pleural space. The pulmonary edema is most commonly unilateral (ipsilateral to the re-expanded lung), but on occasion, can become bilateral, sometimes requiring intubation and mechanical ventilation. Although rare, this syndrome is potentially fatal. Although the mortality is not well defined, in 1988, Mahfood and colleagues reviewed the literature of reexpansion pulmonary edema and found only 53 cases, but 11 (21 percent) were fatal. The incidence in the literature is unknown. There were no cases reported in the Veterans Administrative Cooperative study of more than 200 patients with spontaneous pneumothoraces. The single largest retrospective study (n = 21) reported an incidence of 14 percent. It is likely that both fatal and nonfatal cases are under reported in the literature. The pathogenesis of REPE is not completely understood. A number of mechanisms have been suggested. It appears that at least to some degree, REPE is due to increased permeability of the pulmonary capillaries that are damaged

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by mechanical stress during re-expansion of the lung. Reperfusion injury due to free radicals may also be responsible for increased capillary permeability. Other theories include ischemia reperfusion injury, free radical injury, decreased surfactant, airway obstruction, and decreased lymphatic flow. There are several factors that have been evaluated and associated with an increase in the incidence of REPE. The duration of pneumothorax prior to drainage has been shown to be significant. Animal models demonstrate that reexpansion pulmonary edema occurs when a pneumothorax has been present for 3 days or more and the lung has been expanded with more than –20 cm H2 O pleural pressure. The severity of the pneumothorax may also be predictive of developing REPE. In Matsuura’s series, no patient with a pneumothorax less than 30 percent of the lung field versus 17 percent of patients with total collapse and 44 percent of patients with tension pneumothorax developed this complication. Lastly, the method (with suction or without suction) and the rate of expansion (too rapid) have also been implicated as a potential risk factor. Probably there is no single factor that predicts the likelihood of developing REPE, and they are all important when trying to prevent REPE. The clinical presentation of REPE can be relatively benign or present as a life-threatening event. When serious, its onset is sudden and dramatic. Onset can be immediate, with the majority of patients presenting with symptoms within 1 hour and all are symptomatic within 24 hours. Typically, patients will have a severe persistent cough and develop chest pain immediately or within an hour after chest tube thoracostomy. The patients develop hypoxemia, tachypnea, tachycardia, and often hypotension. It is characterized by decreased pulmonary compliance and patchy or diffuse alveolar infiltrates in the re-expanded lung. Symptoms usually progress for 24 to 48 hours. If the patient survives the first 48 hours, recovery is usually complete. Treatment is supportive and sometimes, if severe enough, patients require mechanical ventilation. The best option is to try to prevent REPE. There are no randomized controlled trials to support a particular preferred method to prevent REPE. However, when thoracostomy is performed for a spontaneous pneumothorax of unknown duration, the tube initially should be connected to underwater-seal drainage rather than to negative pressure. If the lung fails to fully expand after 12 to 24 hours, negative pressure can be applied to the pleural space.

SUGGESTED READING Abolnik IZ, Lossos IS, Zlotogora J, et al.: On the inheritance of spontaneous pneumothorax. Am J Med Genet 40:155–158, 1991. Andrivet P, Kamael D, Teboul JL, et al.: Spontaneous pneumothorax: Comparison of thoracic drainage vs. imme-

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diate or delayed needle aspiration. Chest 108:335–339, 1995. Baumann MH, Strange C, Heffner JE, et al.: for the ACCP pneumothorax consensus group. Management of spontaneous pneumothorax: An American College of Chest Physicians Delphi consensus statement. Chest 119:590– 602, 2001. Bense L, Lewander R, Eklund G, et al.: Nonsmoking, non alpha 1-antitrypsin deficiency-induced emphysema in nonsmokers with healed spontaneous pneumothorax, identified by CT of the lungs. Chest 103:433–438, 1993. Cardy CM, Maskell NA, et al.: Familial spontaneous pneumothorax and FBN1 mutations.Am J Respir Crit Care Med 169;1260–1262, 2004. Cox JE, Chiles C: Transthoracic needle aspiration biopsy: Variables that affect risk of pneumothorax. Radiology 212:615–618, 1999. Despars JA, Sassoon CS, Light RW: Incidence and significance of iatrogenic pneumothorax. Chest 98:138S, 1990. Devanand A, Koh, MS, Ong TH, et al.: Simple aspiration versus chest-tube insertion in the management of primary spontaneous pneumothorax: A systematic review. Respir Med 98:579–590, 2004. Flume PA: Pneumothorax in cystic fibrosis. Chest 123:217– 221, 2003. Gustman P, Yerger L, Wanner A: Immediate cardiovascular effects of tension pneumothorax. Am Rev Respir Dis 127:171–174, 1983. Henry M, Amold T, et al.: BTS guidelines for the management of spontaneous pneumothorax. Thorax 58:39–52, 2003. Kennedy L, Sahn SA: Talc pleurodesis for the treatment of pneumothorax and pleural effusion. Chest 106:1215–1222, 1994. Light RW: Diseases of the pleura: The use of talc for pleurodesis. Curr Opin Pulm Med 6:255–258, 2000. Marshall MB, Zahoor A, et al.: Catamenial pneumothorax: optimal hormonal and surgical management. Eur J CardioThor Surg 27:662–666, 2005. Melton LJ, Hepper NG, Offord KP: Incidence of spontaneous pneumothorax in Olmsted County, Minnesota: 1950 to 1974. Am Rev Respir Dis 120:1379–1382, 1979. Noppen, M. Schramel F: Pneumothorax Eur Respir Monogr 7:279–296, 2002. Pastores SM. Garay SM. Naidich DP, et al.: Review: Pneumothorax in patients with AIDS-related Pneumocystiscarinii pneumonia. Amer J Med Sci 312:229–234, 1996. Rhea JT, DeLuca SA, Greene RE: Determining the size of pneumothorax in the upright patient. Radiology 144:733– 736, 1982. Sahn SA: Talc should be used for pleurodesis. Am J Respir Crit Care Med 163:2023–2026, 2001. Sahn SA, Hefner J: Spontaneous pneumothorax. N Engl J Med 342:868–874, 2000. Schramel FM, Golding, et al.: Expiratory chest radiographs do not improve visibility of small apical pneumothoraces by enhanced contrast. Eur Respir J 9:406–409, 1996.

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Tocino IM, Miller MH, Fairfar WR: Distribution of pneumothorax in the supine and semierect critically ill adult. AJR Am J Roentgenol 144:901–905, 1985. Tschopp J-M, Rami-Porta R, Noppen M, et al.: Management of spontaneous pneumothorax: State of the art. Eur Respir J 28:637–650, 2006.

Tumbarello M, Tacconelli E, Pirronti T, et al.: Pneumothorax in HIV-infected patients: Role of Pneumocystis carinii pneumonia and pulmonary tuberculosis. Eur Respir J 10:1332–1335, 1997. Wu W, Teixerira LR, Light RW: Doxycycline pleurodesis in rabbits. Comparison of results with and without chest tube. Chest 114:563–568, 1998.

88 Malignant Mesothelioma and Other Primary Pleural Tumors Daniel H. Sterman

Leslie A. Litzky Steven M. Albelda

I. MALIGNANT MESOTHELIOMA Epidemiology Etiology Molecular Pathogenesis Pathology Histology Immunohistochemistry Molecular Profiling Clinical Presentation Radiographic Presentation Positron Emission Tomography Laboratory Studies Mesothelin and Other Novel Serum Markers Diagnosis Staging Clinical Course and Complications Mortality Paraneoplastic Syndromes

III. CURRENT APPROACHES TO TREATMENT OF MESOTHELIOMA Chemotherapy Radiation Therapy Surgical Approaches to Treatment of Mesothelioma Treatment of Nonpleural Forms of Mesothelioma IV. NEW THERAPEUTIC APPROACHES Immunotherapy ‘ ‘ Targeted’’ Therapy Gene Therapy V. OTHER PRIMARY PLEURAL NEOPLASMS Clinical Presentation Radiography Gross Pathology Microscopic Path ology Treatment Other Primary Pleural Tumors

II. PROGNOSTIC FACTORS

The pleura is a membranous structure covering the entire surface of the lung and lining the inside of the chest cavity. It is composed of a thin mesothelial layer with underlying fibroblasts and varying amounts of collagenous fibrous tissue with interdigitating capillaries and venules. The most common tumors of the pleura are metastatic neoplasms, predominantly of lung, breast, or colonic origin. Tumors arising primarily from the pleura are rare, but still constitute a variety of benign and malignant lesions from sev-

eral different cells of origin, some of which have yet to be identified.

MALIGNANT MESOTHELIOMA The most common primary malignant tumor of the pleura is malignant mesothelioma, an insidious neoplasm with a dismal prognosis arising from the mesothelial surfaces of the

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pleural and peritoneal cavities, as well as from the tunica vaginalis and pericardium. Eighty percent of all cases of mesothelioma are pleural in origin.

Epidemiology The incidence of mesothelioma in the United States is estimated to be 2200 cases per year, with reported rates increasing by as much as 50 percent in the past decade. Incidence is also increasing in Europe, Japan, and Australia. In Great Britain mesothelioma death rates rose from 153 people in 1968 to 1848 people in 2001. Similar numbers of deaths are expected annually until the year 2015. After that time, mesothelioma rates are expected to drop in England and other developed countries because of legislation aimed at reducing asbestos exposure in the workplace and the general environment. In contrast, mesothelioma incidence rates are predicted to escalate for much longer times in the Third World because of poor regulation of asbestos mining and widespread industrial and household utilization of asbestos.

Etiology Asbestos Exposure Inhalational exposure to asbestos has been clearly established as the predominant cause of malignant mesothelioma in humans. Approximately 70 percent of cases of pleural mesothelioma are associated with documented asbestos exposure. In ancient Greece, the philosopher Pliny first established the association between asbestos exposure and lung disease by making the observation that slaves working in asbestos mines were less healthy than other slaves. It was not until 1960, with the publication by Wagner and colleagues of a series of 33 mesothelioma cases occurring in a crocidolite mining community in South Africa, that the etiologic connection between asbestos and mesothelioma was established. Wagnerâ&#x20AC;&#x2122;s study was soon followed by several other accounts of mesothelioma afflicting asbestos workers at locations around the world. In addition to asbestos miners and workers, other occupations at especially high risk include plumbers/pipefitters, mechanical engineers, ship and boat building and repairing. Although the lifetime risk of developing mesothelioma among asbestos workers is thought to be as high as 8 to 13 percent, there is no direct correlation of pleural disease incidence to the amount or duration of asbestos exposure. The absence of a definite dose-response relationship between asbestos and pleural mesothelioma is of significant concern because as many as 8 million persons living in the United States have been occupationally exposed to asbestos over the past 50 years. Also, many well-documented cases of mesothelioma occur after very brief or low-level exposures to asbestos (i.e., spouses of asbestos workers exposed by washing clothes). Asbestos is not a specific compound, but the commercial name for a group of hydrated magnesium silicate fibrous minerals divided into two major types: the serpentines and the amphiboles. Serpentine chrysotile fibers are spiral-shaped and pliable, whereas the amphiboles (crocidolite, amosite,

tremolite, anthophyllite, actinolite) are long and needle-like. The carcinogenicity of certain types of asbestos is thought to be due, in part, to the physical properties of the fibers rather than their chemical composition. Fibers with a high length-to-width ratio, such as crocidolite, which are able to more readily penetrate through the lung to the pleural surface, are considered more carcinogenic. Among the remaining asbestos fibers, amosite has an intermediate carcinogenic risk, chrysotile the lowest. It is unclear whether the cases of mesothelioma attributed to chrysotile exposure are caused by the chrysotile itself or by contamination with tremolite fibers.

Molecular Pathogenesis The latency period from asbestos exposure to the development of mesothelioma ranges from approximately 20 to 50 years, suggesting the necessity of multiple genetic alterations for eventual malignant transformation of the mesothelium. Despite extensive investigatory effort, the exact mechanisms of asbestos carcinogenesis have not yet been fully elucidated. In rodent model systems, asbestos fibers act like tumor promoters in combination with a carcinogen, eliciting proliferation of mesothelial cells. Asbestos fibers can also interact with the mitotic spindle to cause missegregation of chromosomes and aneuploidy. In rat pleural mesothelial cells, asbestos fibers and erionite have been shown to induce the protooncogenes c-fos and c-jun in a prolonged and dose-responsive manner. Several growth factors, secreted by mesothelial/mesothelioma cells in an autocrine fashion, have been implicated in various stages of mesothelioma tumorigenesis. Platelet-derived growth factors A and B (PDGF A and B), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), basic fibroblast growth factor (bFGF), and transforming growth factor-Î˛1, 2, and 3 (TGF Î˛1, 2, and 3) constitute a complex mixture of autocrine and paracrine stimuli for mesothelioma cell proliferation as well as initiation of tumor angiogenesis. There is also evidence implicating aberrant activation of the Wnt signaling pathway in mesothelioma. It has been well established that chronic inflammation predisposes to cancer development. Asbestos fibers appear to stimulate the production of chronic oxidative stress in lung macrophages and other cells for many years. In animal models, crocidolite fibers clearly induce specific DNA adducts (8hydroxydeoxyguanosine, 8-OHdG) associated with oxidative damage in the DNA from peritoneal cells and macrophages of asbestos-exposed animals. These same type of 8-OHd DNA adducts have been observed in the blood lymphocytes of asbestos-exposed individuals decades after exposure suggesting very chronic exposure to oxidant stress. Analysis of explanted human mesotheliomas and cultured human mesothelioma cell lines has revealed a number of cytogenetic aberrations that may predispose to the development of the malignant phenotype. Partial or total loss of chromosomes 1, 3, and 4, deletions of 9p, and monosomy of chromosome 22 are the most common abnormalities seen. For mesotheliomas, 9p deletions have been associated with the loss of function of the p16INK4 cdk inhibitor, a putative

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tumor suppressor gene, engendering unchecked cdk4mediated phosphorylation of the retinoblastoma 1 (Rb1) gene product and leading to loss of regulation of cell division. Monosomy 22, the most frequent numerical cytogenetic abnormality in mesothelioma, has recently been correlated with mutations in the neurofibromatosis 2 (NF2) tumor suppresser gene—mutations more commonly associated with acoustic neuromas, schwannomas, and meningiomas. The product of NF2, Merlin, appears to inhibit cell proliferation and cell cycle progression by repressing cyclin D1 expression as well as inhibiting invasiveness. The ubiquitous presence of the Wilms’ tumor suppresser gene (WT1) in human mesotheliomas raises the possibility that alterations in this gene or binding of the WT1 gene product to the p53 tumor suppressor may predispose to mesothelial cell carcinogenesis. Viral Oncogenes Simian virus-40 (SV-40) is a polyoma virus with oncogenic potential in humans. Its actions are thought to result from inactivation of tumor suppressor genes such as the retinoblastoma gene (Rb) and wild-type p53 (wt p53) by a peptide known as the SV-40 large T-antigen (Tag). SV-40 is a potent oncogenic virus in human and rodent cells; importantly, SV-40 DNA sequences have been identified in brain tumors, osteosarcomas, and lymphomas. Cellular and animal studies have shown that crocidolite asbestos and SV40 can act as cocarcinogens. Several studies have documented the presence of SV-40 in a significant proportion of mesothelioma cases (some of which did not have obvious asbestos exposure), as well as in cases of atypical mesothelial proliferation. As an example, one report examined 35 archival mesothelioma specimens and found that SV-40-like sequences were present in 86 percent of cases. However, the possibility that technical factors can produce false-positive results suggestive of SV-40 infection also has been raised. Despite the fact that there was worldwide dissemination of SV-40 contaminated polio vaccines in the 1950s and 1960s, there is no convincing epidemiological evidence linking SV-40 exposure to the development of malignant mesothelioma. Nonetheless, it is possible that Tag interference with Rb and wt p53 may play an accessory role in the carcinogenesis of malignant mesothelioma. If this hypothesis is validated, novel strategies of vaccination to prevent mesothelioma, or molecular techniques to improve early diagnosis may become possible. Genetic Predisposition Gene polymorphism studies are in their early stages in asbestos-exposed populations. Some suggestive associations in DNA repair genes with mesothelioma development have been reported, but need validation. Hirvonen et al. described an increased incidence of mesothelioma among asbestos-exposed individuals in Finland found to be lacking the glutathione-S-transferase M1 (GSTM1) gene and carrying the “slow-acetylator” type of the N-acetyltransferase 2

Malignant Mesothelioma and Other Primary Pleural Tumors

(NAT-2) gene. The GSTM1 gene is important in the detoxification of several carcinogens, including polycyclic aromatic hydrocarbons; NAT-2 is associated with the biotransformation of aromatic amines. Some genetically predisposed families have been identified, but without idenfication of a specific “mesothelioma” gene. Other Etiologic Factors The development of malignant pleural mesothelioma has also been associated in rare cases with other etiologic factors, including therapeutic irradiation, intrapleural thorium dioxide (Thorotrast), and inhalation of other fibrous silicates such as erionite. Epidemiologic studies of a region in central Anatolia (Turkey) with an abnormally high incidence of pleural mesothelioma (22 per 10,000 individuals over 25 years old) implicated routine household use of a locally ubiquitous silicate, erionite, as a potential etiologic agent. However, it appears that only specific families (who appear to have as yet to be defined genetic abnormality) are susceptible to eroniteinduced mesothelioma.

Pathology Gross Pathology The vast majority of malignant mesotheliomas involving the pleura are those tumors that diffusely involve the pleura and are properly termed “diffuse malignant mesothelioma.” A rare localized gross variant of malignant mesothelioma that forms a single mass attached to the pleura but is otherwise microscopically identical to diffuse malignant mesothelioma has been described and termed “localized malignant mesothelioma.” Diffuse malignant mesothelioma begins as multiple discrete nodules that, in earlier stages, tend to preferentially involve the parietal pleura over the visceral pleura. In time, these nodules tend to coalesce on the visceral and parietal pleural surfaces with subsequent fusion of the pleurae. Progressive tumor growth typically leads to partial or complete encasement of the lung with rinds of pleural tumor that can be several centimeters in thickness, but may show only minimal penetration of the underlying lung parenchyma (Fig. 88-1). Advanced cases show more extensive spread along interlobar fissures, deeper invasion into the underlying lung parenchyma and through the diaphragm, as well as contiguous involvement of the chest wall, pericardium, and mediastinum. Although it is rare for patients with mesothelioma to present clinically as metastatic disease, it is not at all true that peribronchial lymphovascular spread, regional lymph node metastases, and extrathoracic hematogenous metastases are uncommon. Seventy percent of patients have mediastinal lymph node involvement at autopsy. Hematogenous metastases follow the exact same pattern of spread as non–small cell lung carcinomas with involvement of the contralateral lung and pleura, liver, adrenals, bone, brain, and kidney.

Histology The 2004 revision of the WHO classification of pleural tumors recognizes four major histological subtypes—epithelioid,

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Figure 88-1 A. Transverse section of an extrapleural pneumonectomy surgical specimen with the entire right lung, parietal and visceral pleurae, portions of pericardium, and the majority of the right hemidiaphragm. Note the thick rind of tumor along the pleural surface encasing the lung and invading the diaphragm. B. Postmortem mesothelioma specimen with overnight formalin inflation and fixation. The right lung pictured is covered by a thick, whitish rind of tumor involving the entire pleural surface, which has also infiltrated and demarcated the interlobar fissures.

sarcomatoid, desmoplastic and biphasic. In the 2004 WHO classification, the use of the term “well-differentiated papillary mesothelioma” is restricted to an exceptionally rare and distinctive mesothelial tumor that has bland cytologic features, stout papillary architecture, and a tendency toward superficial spread without invasion. Part of the diagnostic utility of the WHO classification is that each subtype is associated with a particular differential diagnosis that guides the pathology work-up. This work-up requires additional time and expense. Multiple sections may be taken and ancillary studies are usually required for definitive diagnosis. From a prognostic perspective, most studies have shown that the purely epithelioid subtype has the longest survival but these differences in survival, on the basis of histological subtype, are within the range of only a few months. It should be recognized that the larger the tissue sample, the more frequent the histological variation and the higher the incidence of biphasic tumors. The epithelioid variant is the most common with a wide range and mix of histological patterns. Typical histo-

logical appearances of this subtype include tubulopapillary, glandular/microglandular, and solid sheet-like patterns (Fig. 88-2A). A myxoid matrix may be prominent and may be mistaken for mucin, but this matrix is actually hyaluronate and shows hyaluronidase-sensitive staining with Alcian blue. Sarcomatoid mesotheliomas can also have a wide variety of histological patterns. The most frequently encountered pattern is that of fibroblastic-like spindle cells arranged in storiform, fascicular, or haphazard patterns that mimic a fibrosarcoma (Fig 88-2B). Other variants include a malignant fibrous histiocytoma-like tumor and malignant mesotheliomas with malignant smooth muscle, chrondroid, osseous, or rhabdomyoblastic differentiation. Desmoplastic mesotheliomas, by definition, have areas of densely collagenized tissue with atypical cells arranged in a storiform or “patternless” pattern. This pattern should comprise at least 50 percent of the tumor. The deceptively bland appearance of the tumor makes its separation from fibrous pleuritis exceedingly difficult, particularly with limited

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Figure 88-2 A. Photomicrograph of an epithelial malignant mesothelioma. These sheets of pleomorphic cells are epithelial in appearance, with eosinophilic cytoplasm and fairly well defined cell borders. Note the cytoplasmic vacuoles, which can lead to confusion with a signet ring type of adenocarcinoma. By electron microscopy, these vacuoles can be shown to contain crystallized hyaluronic acid (H&E, Ă&#x2014;400). B. Photomicrograph of a sarcomatoid malignant mesothelioma. This tumor has a malignant mesenchymal appearance with bizarre spindled cells and a growth pattern resembling that of a sarcoma. These cells demonstrated strong cytokeratin positivity on immunohistochemical staining, distinguishing this tumor from a sarcoma (H&E, Ă&#x2014;400). C. Photomicrograph of a biphasic malignant mesothelioma. This tumor demonstrates several areas of epithelioid histology with a papillary growth pattern seen against a background of spindled and more poorly differentiated epithelioid cells (H&E, Ă&#x2014;200).

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sampling. Studies that have examined the criteria used for diagnosis have highlighted the importance of “interface biopsies” in which unequivocal evidence of invasion into the underlying adipose tissue, skeletal muscle, or lung may be demonstrated. Other criteria, which may require multiple tissue sections to detect, include obvious sarcomatoid areas, foci of necrosis, and distant metastases. Bone metastases similarly may be deceptively bland and confused with a primary benign fibrous tumor of bone. Biphasic mesotheliomas have both epithelioid and sarcomatoid components (Fig. 88-2C ). Each component should represent at least 10 percent of the tumor for the designation of biphasic. Biphasic mesotheliomas represent about 30 percent of cases. As previously noted, the percentage of biphasic tumors, which have a prognosis that is intermediate between the epithelioid and sarcomatoid subtypes, increase with larger tumor samples.

Immunohistochemistry Immunohistochemistry (IHC) has largely replaced electron microscopy as the gold standard for diagnosis. This is because of the comparative low cost, ease, and greater availability of immunohistochemistry, as well as the expanded array of commercially available antibodies that are reliable markers of mesothelial differentiation. Because there is no single marker with sufficiently high enough sensitivity and specificity for malignant mesothelioma, it is standard practice for pathologists to employ a panel of markers (both positive and negative) to confirm the diagnosis of malignant mesothelioma. Institutions will vary somewhat in their selection of which markers to include and these panels are typically re-

fined as publications appear with comparative utility studies. As in any instance in which immunohistochemistry is used as an adjunct in tumor diagnosis, careful consideration must be given to the tumor’s histological appearance as well as the clinical-radiographic context and the differential diagnosis that is generated from this information. Broad-spectrum cytokeratin (CK) antibody cocktails are extremely useful in the diagnosis of malignant mesothelioma. In epithelioid tumors, strong and diffuse cytokeratin positivity can be used to exclude the rare case of large-cell lymphoma, epithelioid vascular tumors, or melanoma involving the pleura. CK reactivity usually differentiates malignant mesotheliomas from many sarcomas, although there are occasional cytokeratin negative sarcomatoid mesotheliomas as well as focally CK-positive sarcomas. Although CK positivity does not distinguish malignant mesothelioma from reactive lesions, positive cytokeratin staining may help to highlight invasion into adjacent structures. Common affirmative immunohistochemical markers, which, if positive, can be used to support a diagnosis of malignant mesothelioma include calretinin, CK5/6, the Wilms’ tumor-I (WT1) antigen, and D2-40 (Fig. 88-3). These markers are most useful in the narrow differential diagnosis of malignant epithelioid mesothelioma vs. primary pulmonary adenocarcinoma. It should be noted that these markers do not invariably exclude other tumors, including metastases from non-pulmonary primary sites. A wide variety of markers can be used to support a diagnosis of adenocarcinoma, as opposed to malignant mesothelioma. Markers such as CEA, Leu-M1 (CD15), thyroid transcription factor-1 (TTF-1), Ber-EP4, B72.3, Bg8, and MOC 31 are commonly included in such panels. The sensitivity and specificity of

Figure 88-3 Electron micrograph of a human mesothelioma cell showing abundant microvilli arising from the cell surface and prominent desmosomes (×10,500; inset, ×30,000). (Courtesy of Dr. Giuseppe G. Pietra, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia.)

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both the affirmative mesothelioma markers as well as the adenocarcinoma markers vary greatly when the differential diagnosis is broadened to include other subtypes of primary pulmonary carcinoma such as squamous cell carcinoma or metastases from extrapulmonary sites such as the kidney and ovary. Both categories of markers are generally less reliable in the differential diagnosis of sarcomatoid lesions. The immunohistochemical panel that is recommended for the initial evaluation of a sarcomatoid tumor involving the pleura includes cytokeratins (including AE1/3, CAM5.2, CK18, and CK7), calretinin, and D2-40. If other types of sarcomas are being considered, then the marker panel should be expanded accordingly to include antibodies such as CD31, CD34, desmin, myoglobin, and S-100.

Malignant Mesothelioma and Other Primary Pleural Tumors

ing adenocarcinomas from epithelioid malignant mesotheliomas. Mucicarmine and periodic acid-Schiff (PAS) with diastase are the two most frequently used. These stains are technically easy to perform, inexpensive, and rapid. Care must be taken to exclude the possibility of false-positive staining that can be seen with hyaluronate. The use of histochemical staining (Alcian blue with hyaluronidase) to detect the high levels of hyaluronic acid in mesothelioma cells was used far more frequently before the widespread use of immunohistochemistry. Electron microscopy had traditionally been considered the gold standard for the diagnosis of malignant mesothelioma and ultrastructural analysis can still be useful in occasional problematic cases. The predominant epithelioid form is composed of polygonal cells with numerous long surface microvilli, prominent desmosomes, and abundant tonofilaments (Fig. 88-4). Electron microscopy of the sarcomatoid variant reveals the presence of elongated nuclei, cytokeratin and vimetin filaments, as well as copious rough

Other Ancillary Studies Histochemical stains for the presence of intracytoplasmic mucin are still commonly used as a means of differentiat-

Figure 88-4 A. Photomicrograph of an epithelial mesothelioma (H&E, ×400). B. Photomicrograph of epithelial mesothelioma demonstrating positive nuclear staining with an antibody to the Wilms’ tumor 1 (WT1) gene product (×400). C. Photomicrograph of an adenocarcinoma metastatic to the pleura (H&E, ×400). D. Photomicrograph of pleural adenocarcinoma stained with an anti-WT1 antibody (×400). Only minimal background staining is present.

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endoplasmic reticulum, some intracellular attachments, and rare microvilli. Electron microscopic studies may be inconclusive in poorly differentiated tumors of either subtype and have no utility in the diagnosis of desmoplastic malignant mesothelioma. Molecular analysis can be performed on formalin-fixed, paraffin-embedded tissue to demonstrate the X:18 translocation characteristic of synovial sarcoma—a biphasic or monophasic sarcomatoid tumor that can involve the pleura. As discussed at the end of the chapter, synovial sarcoma should be considered in the differential diagnosis of a pleural tumor with a biphasic or monophasic spindle cell appearance.

stages of disease, physical findings may include unilateral dullness to percussion throughout the hemithorax, palpable chest wall masses, and scoliosis toward the side of the malignancy.

Radiographic Presentation The most common initial radiographic manifestation of pleural mesothelioma is a large unilateral pleural effusion, often with contralateral mediastinal shift (Fig. 88-5 A). Sixty percent of patients have right-sided lesions; putatively related to the gravitational predilection for inhaled asbestos fibers and

Molecular Profiling As compared with routine histological evaluation and classification, the examination of multiple expressed genes and/or proteins within individual tumors may be more informative for making diagnoses, estimating prognosis, and response to therapy. The development of microarray methodology, which permits the expression of thousands of genes to be assayed simultaneously, represents a powerful technique to read the “molecular signature” of an individual patient’s tumor, a process termed gene expression profiling. Gene expression profiling studies have been used to identify genes with potential pathogenic significance, such as aurora kinases or key inhibitors of apoptosis proteins. Profiles have also been identified that help to reliably differentiate different subtypes of mesothelioma. By using gene expression ratios, it is possible to reliably distinguish between epithelioid mesothelioma and lung adenocarcinoma or ovarian carcinomas from peritoneal mesotheliomas. An area of active investigation (and some debate) is the use of expression profiles as a means of predicting outcome and clustering groups of patients with pleural mesothelioma into those with good risk (i.e., more likely to be cured using aggressive therapy) and poor risk disease (i.e., with a low cure rate despite aggressive therapy). Some groups have found this approach to be highly predictive, whereas others suggest the the accuracy has been overestimated. Given these provocative early findings, it is highly likely that these expression-based assays will be increasingly used for diagnostic and therapeutic decisions in mesothelioma.

Clinical Presentation Malignant pleural mesothelioma most commonly presents in the fifth to seventh decades of life. Most patients diagnosed with mesothelioma earlier in life have a history of childhood asbestos exposure. The most frequent presenting symptoms of pleural mesothelioma are nonpleuritic chest pain (60 to 70 percent of patients), dyspnea (25 percent), and cough (20 percent). Some patients are asymptomatic at diagnosis, with unilateral pleural effusions found incidentally on routine chest radiographs. Mesothelioma is typically a unilateral disease—only 10 percent of patients with mesothelioma have bilateral involvement at presentation. In more advanced

Figure 88-5 A. Posteroanterior chest radiograph in a patient with malignant pleural mesothelioma demonstrating significant right-sided pleural effusion and diffuse pleural thickening associated with marked volume loss of the right hemithorax. No definite calcified pleural plaques are seen. B. Computed axial tomographic image from a patient with pleural mesothelioma, illustrating complete encasement of the ipsilateral lung with a thick rind of tumor, neoplastic invasion of the interlobar fissures, small residual pleural effusion, and marked unilateral volume loss.

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dusts to travel directly to the right lower lobe airways. Occasionally, mesothelioma can present as a pleural mass or with diffuse pleural thickening with involvement of the interlobar fissures in the absence of pleural effusion. Only 20 percent of patients with pleural mesothelioma have radiographic signs of asbestosis (i.e., bibasilar interstitial fibrosis), although many have evidence of pleural plaques and/or calcifications. In later stages of disease, ipsilateral mediastinal shift is seen secondary to encompassment of the lung by a thick rind of tumor and resultant significant unilateral loss of lung volume. Patients with advanced mesothelioma may also have radiographic findings of mediastinal widening owing to direct tumor invasion or lymph node involvement, enlargement of the cardiac margins secondary to pericardial invasion with effusion, and evidence of rib destruction or soft tissue masses extending from the chest wall. Chest computed tomography (CT) is important in detecting invasion of chest wall, ribs, and mediastinal structures (Fig. 88-5B). Coronal magnetic resonance imaging (MRI) is helpful in discerning the extent of disease, particularly extension of pleural mesothelioma through the diaphragm into the peritoneal cavity. In one study of 65 patients with pleural mesothelioma, MRI was directly compared with CT scanning. The overall diagnostic accuracy for mediastinal nodal disease was approximately 50 percent for both modalities, but MRI outperformed CT for detection of diaphragmatic invasion (82 percent versus 55 percent accuracy, respectively, p = 0.01), and for detecting invasion of endothoracic fascia or chest wall (69 percent versus 46 percent percent, p = 0.05).

Positron Emission Tomography The role of positron emission tomography (PET) imaging, particularly PET/CT, in the care of patients with mesothelioma is multifold. It can be used in diagnosis and staging by evaluating the extent of pleural disease, establishing mediastinal lymph node involvement, evaluating tumor invasion into the lung and thoracic wall, and aid in diagnosing extrathoracic metastases. It is becoming particularly useful to assess the treatment response to chemotherapy, and radiotherapy and also plays an important role in the planning of radiation treatment. The role of PET scanning with 18-fluorodeoxyglucose (FDG) in staging and preoperative evaluation is evolving. In a small study of 28 patients with suspected pleural mesothelioma who underwent 18-FDG PET scanning followed by thoracoscopic or open surgical biopsy, PET was shown to be better than CT for differentiating malignant from benign pleural processes. Uptake of FDG was significantly higher in malignant lesions, and an overall sensitivity and specificity of 91 and 100 percent could be achieved with PET scanning for the detection of malignant as compared with benign disease. However, hypermetabolic lymph nodes were detected in 12 patients (of whom nine had a normal CT scan), and only five had histologically proven malignant nodal disease. In a small pilot study done by Carretta et al., PET assessment demonstrated pleural lesions in 12/13 patients with

Malignant Mesothelioma and Other Primary Pleural Tumors

malignant pleural disease (malignant pleural mesothelioma in ten patients, adenocarcinoma in two and liposarcoma in one), also revealing distant metastases in two patients. A patient with an epithelial mesothelioma had a false-negative result. Buchmann et al. demonstrated the accuracy of FDGPET in 16 patients with pleural changes, and showed that PET correctly classified all malignant changes (12/12), and all patients (4/4) who had no FDG uptake had benign pleural disease (fibroma, tuberculous pleurisy, empyema, and pleural fibrosis). PET scan appears more sensitive than CT for finding extrathoracic disease, but has limited sensitivity for locoregional staging (i.e., determining potential resectability). In one retrospective study, 60 patients with malignant pleural mesothelioma were identified who had undergone PET scanning pre-operatively and the results of clinical staging were compared with surgical and pathologic results. FDG uptake was detected in 59, and the one false-negative case had disease limited to the parietal pleura (stage IA). The sensitivity of PET scanning for determining the presence of T4 (unresectable) disease was only 19 percent (7 of 21 patients). Among the 31 patients whose nodal status was assessed pathologically, only one of nine patients with N2 disease was correctly identified by PET scan, and the overall sensitivity for nodal disease was only 11 percent. One of the potential future uses of PET that needs to be further evaluated is its utilization in the screening of patients with a history of significant asbestos exposure. These patients may potentially harbor microscopic disease, not apparent on CT or MRI, which may be amenable to early aggressive therapy. Because of the limits of detection of current 18-FDG PET technology, the use of PET for screening for pleural mesothelioma may await the development of novel radiopharmaceuticals. Another exciting area is the use of PET scans to predict survival and response to therapy. One study has found that patients with high standardized uptake value tumors had decreased survival. Another study showed that decreased radiopharmaceutical uptake on follow-up PET scans performed early after treatment may be an excellent predictor of overall clinical response.

Laboratory Studies Although there are no specific pleural fluid biomarkers for malignant mesothelioma, evaluation of pleural fluid chemistries may still be beneficial. Effusions associated with mesothelioma are strongly exudative, with elevated protein concentrations in the range of 4 to 5 g/dL and a lymphocytic predominance. Pleural fluid lactate dehydrogenase (LDH) concentrations often exceed those of patients with carcinomatous pleural effusions, with levels greater than 600 IU/L. In patients with advanced disease and extensive involvement of visceral and parietal pleura, pleural fluid pH, and glucose are commonly low. In patients with mesothelioma, the presence of a low pleural fluid pH denotes both a poor overall prognosis, as well as refractoriness to attempts at achieving palliative

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pleurodesis. In addition, the pleural effusion associated with mesothelioma is characteristically highly viscous, presumably because of elevated concentrations of hyaluronic acid. An increased pleural fluid hyaluronidase level is suggestive but not diagnostic of mesothelioma. The cytokine profile of pleural effusions related to mesothelioma is somewhat unique in that the tumor constituitively produces high concentrations of interleukin-6 (IL-6) and transforming growth factor-β (TGF-β), but relatively low levels of IL-1β and tumor necrosis factor-α. These elevated intrapleural levels of IL-6 in patients with malignant mesothelioma are postulated to induce systemic manifestations such as fever, cachexia, and thrombocytosis. Pulmonary function testing typically demonstrates a restrictive pattern resulting from pleural effusions, tumor encasement of the lung, or chest wall involvement.

Mesothelin and Other Novel Serum Markers There is increasing evidence for clinical utility for a monoclonal antibody-based serum assay for a soluble form of the protein mesothelin, SMRP. Mesothelin is a 40-kDa glycoprotein that is found on the cell surface of normal mesothelial cells, mesothelioma, and ovarian cancer cells. Increased levels of soluble mesothelin (SMRP) were found in serum samples from 37 of 44 patients with mesothelioma (87 percent), compared with three of 160 patients with other cancers or inflammatory lung or pleural diseases (2 percent), and none of 28 controls without a past asbestos exposure. For the present time, SMRP levels will likely play an adjunctive role in the diagnosis of patients with mesothelioma. It is intriguing to posit that SMRP may also play a role in screening of highrisk patients for incipient mesothelioma, given the fact that 7 of 40 asbestos-exposed individuals in the original Lancet report had elevated levels; four of whom subsequently developed mesothelioma or lung cancer within 1 to 5 years. Other serum markers, such as osteopontin, are also being evaluated.

Diagnosis The differential diagnosis of malignant pleural mesothelioma includes both benign and malignant processes. Inflammatory reactions such as chronic, organized empyema can mimic the dense pleural thickening and large, viscous pleural effusions characteristic of mesothelioma. As discussed, epithelial mesotheliomas can be extremely difficult to distinguish grossly and histologically from metastatic adenocarcinoma to the pleura from any number of primary sources, including lung, breast, stomach, kidney, ovary, and prostate. Sarcomas such as fibrosarcoma and malignant fibrous histiocytoma can present in similar fashion and infiltrate like sarcomatous mesotheliomas. The mixed-cellular type of mesothelioma can bear a significant histological resemblance to sarcomatoid carcinomas and synovial sarcoma. Accurate diagnosis of malignant mesothelioma is important in the event of subsequent litigation, for proper epidemiologic records and appropriate therapeutic intervention. Thoracentesis or closed pleural biopsy can often establish the diagnosis of pleural malignancy but may not provide enough

diagnostic material to confirm the presence of mesothelioma. Cytologic evaluation of pleural fluid is helpful for detecting the presence of malignancy but has difficulty in distinguishing epithelioid mesothelioma from adenocarcinoma and the sarcomatoid type from fibrosarcomas or hemangiopericytomas. Immunohistochemical markers and monoclonal antibodies may aid in differentiating mesothelioma from adenocarcinoma on cytology specimens. In addition, certain cytopathological features of cells obtained from pleural fluid have been found to correlate well with the presence of mesothelioma, including papillary aggregates, multinucleation with atypia, cell-to-cell apposition, nuclear pleomorphism, and macronucleoli. Gene expression ratios may also be increasingly helpful in this regard. Surgical intervention, via video-assisted thoracoscopic biopsy or open thoracotomy, is often necessary to firmly establish the diagnosis. Boutin and colleagues from Marseille prospectively evaluated thoracoscopy for the diagnosis of malignant pleural mesothelioma in 188 consecutive patients from 1973 to 1990 and found that thoracoscopic biopsy was diagnostic in 98 percent of cases, compared with only 26 percent for thoracentesis alone, and 39 percent for fluid cytology and closed pleural biopsy. These procedures were performed under local anesthesia in an endoscopy suite with minimal morbidity or complications. Concurrent bronchoscopy may be important in distinguishing between mesothelioma and metastatic adenocarcinoma of the lung, as endobronchial lesions are rarely seen in mesothelioma. In addition, mediastinoscopy plays an increasingly important role in the diagnosis and staging of mesothelioma, as recent studies have documented the significant negative prognostic implications of mediastinal nodal invasion in this disease. Approximately 10 percent of patients who undergo a diagnostic procedure for mesothelioma seed the biopsy site with tumor cells, later developing chest wall recurrences. This complication can potentially be prevented by prophylactic radiation therapy to the surgical incision or thoracentesis sites.

Staging The staging of malignant mesothelioma has proved to be more controversial than that of many other tumors. The most commonly used schema was devised by Butchart in 1976 (Table 88-1). Although useful, its ability to predict survival is weakened by lack of inclusion of lymph node involvement and chest wall invasion. For this reason, the Union Internationale Contre le Cancer (UICC) in 1990 first proposed a staging system based on the TNM (tumor/node/metastasis) standard used for many other tumors. More recently, Rusch and colleagues from the International Mesothelioma Interest Group (IMIG) proposed an updated staging system based upon tumor descriptors, providing precise anatomic definitions of the local extent of the primary tumor. This staging system (Table 88-2) was designed to provide the framework for proper analysis of prospective clinical trials of new treatment modalities.

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Table 88-1

Table 88-2

Butchart Staging System

International Mesothelioma Interest Group (IMIG) Staging System

Stage I

Tumor confined within the “capsule” of the parietal pleura

Stage II

Tumor invading chest wall or involving mediastinal structures

Stage III

Tumor penetrating diaphragm to involve peritoneum; involvement of opposite pleura; lymph node involvement outside the chest

Stage IV

T1a: Tumor limited to ipsilateral parietal pleura T1b: Tumor involving ipsilateral parietal pleura, with scattered foci of tumor on visceral pleural surface

Tumor involving all ipsilateral pleural surfaces with diaphragmatic invasion or extension into underlying pulmonary parenchyma

Involvement of the endothoracic fascia; mediastinal fat; solitary, resectable chest wall focus; or nontransmural pericardial invasion

Diffuse extension into chest wall, peritoneum, spine, mediastinal organs, contralateral pleura, internal surface of pericardium or myocardium

No regional lymph nodes metastases

Metastases in the ipsilateral bronchopulmonary or hilar lymph nodes

Metastases in the subcarinal or ipsilateral mediastinal lymph nodes

Metastases in the contralateral mediastinal or internal mammary lymph nodes or any supraclavicular node metastasis

Distant blood-borne metastases

Clinical Course and Complications Mesothelioma exerts its morbidity and mortality via inexorable local invasion. Patients typically develop shortness of breath and chest pain as tumor and fibrosis gradually obliterate the pleural space and replace any pleural fluid. As the tumor spreads, it covers both visceral and parietal pleural surfaces, encasing the ipsilateral lung with a thick, fibrous peel that extends into interlobar fissures and occasionally into lung parenchyma. Deoxygenated blood is shunted through the trapped lung, leading to significant dyspnea and hypoxemia that is often refractory to supplemental oxygen. Dyspnea also results from abnormal chest wall mechanics secondary to tumor invasion into ribs as well as intercostal nerves and muscles. Local invasion of crucial thoracic structures can result in dysphagia, hoarseness, cord compression, brachial plexopathy, paralysis, Horner’s syndrome, and superior vena cava syndrome. Hilar and mediastinal lymph node involvement occurs in less than 50 percent of patients but is a harbinger of poor prognosis. Transdiaphragmatic spread into the abdominal cavity rapidly leads to intraperitoneal dissemination, with encasement of the mesentery, and small and large bowel. Local invasion into the pericardial space can lead to pericardial effusion and tamponade. Distant metastatic disease, by hematogenous spread, is unusual in mesothelioma but may present in liver, bone, brain, adrenals, thyroid, and kidney. Metastatic disease is typically an end-stage manifestation of malignant mesothelioma.

Mortality Median survival of patients with mesothelioma is between 9 and 12 months and varies depending on stage, histological subtype, and concomitant medical problems. Patients with pleural mesothelioma die from local extension and respiratory failure, primarily related to spread to the contralateral hemithorax. As mentioned, tumor extension below the diaphragm may result in death from small bowel obstruction. Patients may also die from arrhythmias, heart

Staging Stage I

Ia: T1aN0M0 Ib: T1bN0M0 Stage II T2N0M0 Stage III Any T3M0, any N1M0, any N2M0 Stage IV Any T4, any N3, any M1

failure, or stroke caused by tumor invasion of the heart or pericardium.

Paraneoplastic Syndromes Disseminated intravascular coagulation, migratory thrombophlebitis, thrombocytosis, Coombs-positive hemolytic anemia, hypoglycemia, and hypercalcemia associated with secretion of a parathyroid hormone–like peptide have all been described in the setting of mesothelioma.

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PROGNOSTIC FACTORS Poor prognosis at the time of presentation is indicated by the presence of thrombocytosis, leukocytosis, low hemoglobin, fever of unknown origin, sarcomatoid or mixed histology, age greater than 65 to 75 years, poor performance status, and male gender. Good prognosis at presentation is associated with epithelial histology; stage I disease; age under 65 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; absence of chest pain; and the presence of symptoms for more than 6 months prior to diagnosis. The prognostic scoring systems derived by the Cancer and Leukemia Group B (CALGB) and the European Organization for Research and Treatment of Cancer (EORTC) are the most useful clinical prognostic scoring schemes available. CALGB Prognostic Index The CALGB evaluated the impact of clinical characteristics on the survival of 337 patients treated with chemotherapy for advanced mesothelioma in sequential phase II treatment studies over a 10-year period. In multivariate analysis, serum lactate dehydrogenase (LDH) greater than 500 IU/L, poor performance status, chest pain, platelet count over 400,000/ÂľL, non-epithelial histology, and age older than 75 years jointly predicted poor survival. Six distinct prognostic subgroups were generated with median survival times ranging from 1.4 to 13.9 months. The median survival overall was 7 months. This prognostic schema was subsequently validated in an American phase II trial evaluating the investigational agent Ranpirnase, and in an independent European data set. EORTC Prognostic Scoring System Similarly, the EORTC reviewed data from 204 adults who were entered into five consecutive phase II trials over 9 years. When five factors were taken into consideration (poor performance status, high WBC count, male gender, sarcomatoid cell type, and the certainty of the diagnosis), good and bad prognostic groups could be delineated, with 1-year survival rates of 40 and 12 percent, respectively. Median survival from the date of study entry was 8.4 months.

CURRENT APPROACHES TO TREATMENT OF MESOTHELIOMA Over the past decade, advances have been made that have improved our ability to treat malignant pleural mesothelioma. We have evidence that some of these treatments are increasing the quality and quantity of life for patients with mesothelioma. Multimodality treatment programs that combine surgical cytoreduction with novel forms of radiation therapy and more effective chemotherapy combinations may offer significant increases in survival for certain subgroups of mesothelioma patients. Innovative palliative approaches have proved successful in alleviation of the symptoms experienced by many mesothelioma patients. Experimental treatments

such as immunotherapy and gene therapy present a window of hope for all mesothelioma patients, and in the future, may be combined with â&#x20AC;&#x153;standard therapyâ&#x20AC;? in multimodality protocols.

Chemotherapy Over the past 20 years, several phase II single-agent and combination chemotherapy studies have been performed in mesothelioma. These studies have demonstrated some evidence of anti-tumor activity with anthracyclines, platinum derivatives, and anti-metabolites. Combination chemotherapy has been associated with higher overall response rates, but not, until recently, longer median survivals. The current standard of care for first-line chemotherapy in mesothelioma patients with good performance status is combination treatment with cisplatin and pemetrexed. Pemetrexed (Alimta, Eli Lilly and Company, Indianapolis, IN) is an anti-folate compound which targets multiple enzymes in the folate metabolism pathway. Pemetrexed is a potent inhibitor of thymidilate synthase (TS), the rate-limiting step in the synthesis of thymidilate, which is required for DNA synthesis and is also the enzyme inhibited by the cytotoxic agents 5-fluorouracil and raltitrexed. In 2003, Vogelzang and colleagues reported the results of a phase III randomized clinical trial in chemotherapy-naive mesothelioma patients comparing treatment with pemetrexed and cisplatin with cisplatin monotherapy. A total of 456 patients were randomized: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the cisplatin only arm ( p = 0.020, two-sided log-rank test). The hazard ratio for death of patients in the combination arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months ( p = 0.001). Response rates were 41.3 percent in the pemetrexed/cisplatin arm versus 16.7 percent in the control arm ( p less than 0.0001). The addition of folic acid and vitamin B12 to chemotherapy resulted in reduction in the severity and frequency of hematologic and non-hematologic toxicities in the pemetrexed/cisplatin arm. Another randomized Phase III study of cisplatin with a newer-generation antifolate, raltitrexed (Tomudex), showed very similar, small but significant, increases in survival. The combination of gemcitabine and carboplatin is also a valid first-line option in the treatment of mesothelioma owing to its acceptable toxicity profile, good response rate, and palliative effects. A Northern Italian Phase II study of gemcitabine and carboplatin in patients with pleural mesothelioma reported a 26 percent partial response rate, a median response duration of 55 weeks; and significant palliative benefit, 46 percent with less dyspnea, 40 percent with weight gain, and 26 percent with pain reduction. Median survival for patients in this study was 66 weeks. There is, however, no current standard of care for second-line chemotherapy in mesothelioma following

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treatment with cisplatin and pemetrexed. The most commonly used second-line regimens include gemcitabine, or other drugs with single-agent activity such as vinorelbine. There exists insufficient evidence to recommend second-line chemotherapy as a standard treatment. Patients with adequate performance status should be enrolled onto clinical trials of second-line treatment.

in this initial series, a second series from the Dana-Farber Cancer Center suggested there was a significant increase in severe toxicity. In that report, six of 13 patients developed fatal pneumonitis.

Radiation Therapy

Surgery for malignant pleural mesothelioma can be diagnostic, palliative, and even potentially curative in its intent. Although not infrequently associated with substantial morbidity, surgical management has made significant strides in palliating the major symptoms of the disease, as well as potentially offering some improvement in survival for highly selected patients. The increased use of thoracoscopy, as well as novel biomarkers, has facilitated early diagnosis of mesothelioma in more patients, at which point they may be candidates for more aggressive attempts at definitive surgical treatment (along with neo-adjuvant/adjuvant therapies). However, definitive surgical intervention is only possible in a small percentage of patients; furthermore, fewer than 25 percent of those eligible for aggressive surgical intervention will be alive at 5 years, and even fewer will be disease-free at that time point. The vast majority of of pleural mesothelioma patients have locally advanced disease at the time of presentation, which, along with advanced age and/or other co-morbid medical illnesses, often precludes aggressive surgical intervention.

Contrary to the prevailing wisdom that malignant pleural mesothelioma is a radioresistant neoplasm, it has been demonstrated that mesothelioma cell lines are actually more responsive to ionizing radiation in vitro than non–small cell lung cancer cell lines. External-beam radiation therapy for mesothelioma is, however, limited by the large treatment volumes required and the radiation sensitivity of the surrounding organs (heart, lung, esophagus, spinal cord). Although palliative radiotherapy with an attempt to treat the entire involved pleural surface is technically difficult, and associated with a high risk of radiation pneumonitis, myelitis, hepatitis, and myocarditis, it can provide effective local palliation in up to 50 percent of patients. There are anecdotal reports of long-term survivors following high-dose external beam irradiation, and even intrapleural administration of radioactive isotopes. Most studies have shown no significant effect upon overall survival in patients with mesothelioma. However, radiation therapy may play a role by preventing chest wall recurrences after thoracoscopy/thoracotomy and in improving local control after pleurectomy or extrapleural pneumonectomy. Mesothelioma frequently implants along the tracts of biopsies, chest tubes, thoracoscopy trocars, and surgical incisions, producing uncomfortable subcutaneous nodules. This can be prevented with prophylactic radiotherapy. In a small randomized trial, Boutin and colleagues demonstrated that 21 Gy administered in three daily fractions, 10 to 15 days after thoracoscopy, decreased local recurrence from 40 to 0 percent. Multimodality approaches commonly include adjuvant radiation following surgery, although there are no randomized trials that demonstrate its efficacy. Because the lung remains in place after pleurectomy, radiotherapy doses must be lower than when EPP is performed. The Radiation Oncology group at the University of Texas M.D. Anderson Cancer Center reported encouraging results using intensity-modulated radiotherapy (IMRT) following EPP. Using careful treatment planning and IMRT, radiation doses of up to 50 to 60 Gy were possible without severe toxicity. With the combination of EPP and IMRT, local recurrences after surgery were virtually eliminated; however, novel distant disease patterns have begun to emerge. These data suggest that the combination of EPP and IMRT requires an additional treatment modality (i.e., chemotherapy or immunotherapy) to limit distant tumor growth. Although intensity-modulated radiotherapy (IMRT) following EPP appeared to be more effective for local disease control

Surgical Approaches to Treatment of Mesothelioma

Pleurodesis The most common and discomforting symptom in mesothelioma is debilitating dyspnea from large, unilateral pleural effusions. A reasonable palliative approach is complete drainage of the pleural effusion (by tube thoracostomy or video thoracoscopy) and introduction of a sclerosing agent into the pleural space (by instillation or insufflation) to induce pleurodesis. At present, the most widely used compound for pleurodesis is sterile, asbestos-free talc, administered either as a powder or a slurry. Thoracoscopic application (poudrage) may be more successful than other methods of pleurodesis (e.g., by tube thoracostomy). The effect of talc may be enhanced by an ability to induce apoptosis in some mesothelioma cell lines in vitro. The presence of bulky tumor in the pleural space, or “trapping” of the lung by a thick visceral pleural peel of tumor compromises the efficacy of pleurodesis in patients with pleural mesothelioma. In the setting of “trapped lung,” the use of semi-permanent tunneled intrapleural catheters (Pleurx Catheter, Cardinal Health, Dublin, OH) for intermittent drainage of recurrent effusions provides excellent palliation of dyspnea. Pleuro-periotoneal shunting, an alternative approach for dealing with lung entrapment in pleura mesothelioma, carries the overt risk of malignant seeding of the peritoneal cavity. The primary concern regarding the use of tunneled pleural catheters in mesothelioma is the

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development of tumor implants at the insertion site or along the subcutaneous tunnel. Pleurectomy Parietal pleurectomy, i.e., open surgical stripping of the pleura from the apex of the lung to the diaphragm, is more successful than talc pleurodesis in reducing the recurrence of pleural effusion in mesothelioma. More recently, thoracoscopic pleurectomy has been employed to achieve similar results as the open procedure, but with less morbidity. Complete parietal and visceral pleurectomy (pleurectomy/decortication), however, has not been shown to prolong survival in patients with mesothelioma. Some investigators have evaluated the combination of pleurectomy/decortication with postoperative intrapleural therapy, external beam irradiation, and/or systemic chemotherapy. One single institution study reported a median survival of 22.5 months and a 2-year survival rate of 41 percent in a group of 27 patients, predominantly with the epithelial subtype. There is no evidence, however, for better survival for mesothelioma patients who underwent pleurectomy/decortication compared with those treated with extrapleural pneumonectomy. Extrapleural Pneumonectomy Extrapleural pneumonectomy (EPP) is a radical surgical procedure involving complete removal of the ipsilateral lung along with the parietal and visceral pleura, pericardium with portions of the phrenic nerve, and the majority of the hemidiaphragm. EPP achieves the greatest degree of cytoreduction, and, because the lung has been removed, allows higher radiation doses to be delivered to the ipsilateral hemithorax. It is the only debulking procedure possible when a thick tumor rind obliterates the pleural space. There are a small group of long-term survivors following EPP when it is a component of a multimodality treatment program, suggesting that this procedure may alter the natural history of the disease in appropriately selected patients with early stage disease. Unfortunately, the utility of EPP is limited by the availability of skilled surgeons who routinely perform this technically demanding procedure, and the few patients who are candidates for it. EPP alone is an excellent means of palliating the profound dyspnea and orthopnea associated with the severe ventilation/perfusion mismatch resulting from lung encasement by mesothelioma. However, EPP alone has no influence on survival in the absence of adjuvant therapy. In most EPP series, median survival from surgical debulking alone is less than 2 years, and 10 to 20 percent of operated patients are 5year survivors, with biphasic/sarcomatoid histology and/or involvement of mediastinal lymph nodes conferring a poorer prognosis and lack of demonstrable survival benefit from surgical intervention. Several approaches for adjuvant therapy in conjunction with EPP have been studied: The investigators at Brigham and Womenâ&#x20AC;&#x2122;s Hospital in Boston have combined EPP with

sequential postoperative chemotherapy and up to 55 Gy of adjuvant radiation therapy to the postoperative hemithorax. More recently, the Brigham Thoracic Program has been investigating the role of hyperthermic intracavitary chemotherapy as an adjuvant to maximal cytoreductive surgery, in combination with hemithoracic irradiation and systemic chemotherapy. In addition, several investigators have evaluated the utility of post-resectional photodynamic therapy (PDT) with or without adjuvant chemotherapy or immunotherapy. However, one randomized trial conducted by Pass and colleagues at the National Cancer Institute failed to confirm any benefit for adjuvant PDT compared with surgery alone. Other novel multicenter clinical trials combine maximal surgical debulking with adjuvant IMRT or alternatively assess the role of neoadjuvant chemotherapy prior to cytoreductive surgery to improve long-term outcomes. EPP in these contexts is designed as a cytoreductive, not a curative procedure. It is associated with significant morbidity (major in up to 25 percent) and an operative mortality that exceeds 5 percent, depending upon the experience of the center and the preoperative condition of the patient. Therefore, patients must be carefully selected.

Treatment of Nonpleural Forms of Mesothelioma Patients with peritoneal mesothelioma, the second most common form of mesothelioma after the pleural form, most often present with abdominal pain, distention, and ascites, but may have symptoms for several months prior to establishment of a definitive diagnosis. In addition, peritoneal mesothelioma can be associated with hypoalbuminemia, night sweats, inguinal and umbilical hernias, and hypercoagulability. Laboratory investigations show an increased platelet count in about 50 percent of patients and many patients also have elevation of the tumor marker CA-125. As with pleural mesothelioma, single-agent general chemotherapy for the peritoneal variant has a response rate of 10 to 15 percent, whereas combination chemotherapies, such as cisplatin plus pemetrexed, improve the response rate to about 25 percent. Immunotherapeutic agents such as interferons and various cytokines may have a role in treating this disease, especially when the amount of disease is minimal. Patients diagnosed with peritoneal mesothelioma appear to have a better overall prognosis relative to the pleural form. This may reflect the technical ease of delivery of intraperitoneal chemotherapy as well as the capacity for multiple resections/debulking of peritoneal masses. One-third of 25 patients with peritoneal mesothelioma in a DanaFarber phase II series remain disease-free at 2 to 3 years after treatment. Multimodality treatment protocol includes surgical debulking followed by intraperitoneal administration of cisplatin, doxorubicin, and gamma interferon, second laparotomy with attempted resection of any residual disease and intraoperative hyperthermic perfusion with cisplatin and mitomycin followed subsequently by whole abdominal

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radiotherapy. The median overall survival of the 27 patients treated in this study was 68 months. Pericardial mesothelioma is quite rare, but characteristically presents with pericardial effusion, and often tamponade physiology. Mesotheliomas of the tunica vaginalis are even less common than the pericardial variant, but typically present with a bloody hydrocele. There is no effective therapy for mesothelioma of the pericardium or tunica vaginalis other than palliation; these neoplasms share the dismal prognosis of the pleural form of the disease.

NEW THERAPEUTIC APPROACHES Despite the small but significant improvement in survival achieved with intensive multimodality therapy for mesothelioma, it is obvious that less morbid, more effective interventions are needed. Many investigators over the past two decades have attempted to treat this disease primarily by direct instillation of chemotherapeutic and other compounds into the pleural space, but with minimal success. Based on reports that mesothelioma patients with greater amounts of intratumoral lymphocytic infiltration had improved median survival rates, several groups have looked at immunotherapy as an alternative means of achieving better tumor response rates.

Immunotherapy The use of compounds to stimulate an antitumor immune response against pleural malignancy stemmed from the observation that patients who developed empyemas postthoracotomy for primary lung carcinoma had improved survival rates. Subsequently, intrapleural bacille Calmette-Gu´erin (BCG) was studied as a surgical adjuvant, but no significant benefit was seen. Several systemic immunotherapies have been administered to patients with mesothelioma, including interleukin-2 (IL-2) and interferon-gamma (IFN-γ), both of which demonstrated limited efficacy and significant side effects. Subcutaneous IFN-α-2a was found to have some efficacy, one complete response, and three partial responses out of 25 patients studied and was well tolerated clinically. One European phase I and II studies of intrapleural IL-2 administered by continuous infusion via an intrapleural catheter revealed a 19 percent partial response rate with marked dose-related toxicity, primarily the development of ipsilateral empyemas. Of note were the high ratios of intrapleural/systemic IL-2 levels approaching 1000:1, particularly in the highest doses. Boutin and colleagues in Marseilles, France, pioneered the intrapleural administration of immunostimulants to treat mesothelioma, and demonstrated significant local tumor responses with both intrapleural IL-2 and IFN-γ. Most impressive were the results of intrapleural IFN-γ in patients with early-stage mesothelioma (Butchart stages I and II). A total of 89 patients were treated over 46 months with an overall

Malignant Mesothelioma and Other Primary Pleural Tumors

response rate of 20 percent. Eight patients had histologically confirmed complete responses and nine had partial responses with greater than 50 percent reduction in tumor volume. Overall, patients with stage I disease had a response rate of 45 percent. The effectiveness of IFN-γ against mesothelioma was thought to be mediated in part by direct inhibitory effects on mesothelioma cell growth as well as by decreased intrapleural IL-6 production, with resultant activation of tumor-directed macrophages and cytotoxic T-lymphocytes. Other groups have demonstrated only limited activity with the combination of intrapleurally administered autologous activated macrophages and interferon-gamma. The overall response rate was 11 percent (two of 19 enrolled patients), with one patient having a partial response that lasted for 30 months. Immunotherapy trials in Australia demonstrated some significant tumor regression with repeated intralesional injection of GM-CSF, but with substantial complications related to the catheters used for cytokine instillation.

‘‘Targeted’’ Therapy The identification of active platelet–derived growth factor and epidermal growth factor pathways in some mesothelioma cell lines suggested that novel agents which inhibited these pathways might prove useful clinically, either alone, or in combination with cytotoxic chemotherapy. Unfortunately, early-phase clinical trials of imatinib mesylate and gefitinib, inhibitors of the tyrosine kinase enzymes inherent to the PDGF and EGF pathways, respectively, have failed to demonstrate any significant clinical benefits. Clinical trials are ongoing with other novel “targeted” agents, such as the antiangiogenic agents, bevacizumab and thalidomide, and the copper-chelating agent, tetrathiomolybdate, which removes copper, which is a key co-factor in tumor angiogenesis.

Gene Therapy In the absence of other effective, nontoxic therapies for malignant mesothelioma, several groups of investigators have looked to the newly evolving technologies of gene therapy for new treatment modalities. Gene therapy is attractive because mesothelioma remains localized initially and pleural access is to the tumor easy and safe. A large number of approaches have been used in cell culture and in animal models. Gene therapy vectors have included liposomal/DNA complexes and modified herpes, vaccinia, and adenoviruses. Transgenes have included suicide genes, cytokines, tumor suppressor genes (i.e., p53), and pro-apoptotic genes. Studies have also been done using replication-competent, but tumor selective adenoviruses and herpes viruses as well as carrier cells. Some Phase I clinical trials have also been performed. These include the instillation of recombinant adenovirus (rAd) genetically engineered to contain the herpes simplex virus thymidine kinase “suicide gene” (HSVtk). The rationale for the suicide gene approach for mesothelioma was that administration of Ad.HSVtk into the pleural cavity would sensitize the cells to the normally non-toxic antiviral agent

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ganciclovir (GCV). The vector was well tolerated, gene transfer was seen at higher doses, and a number of patients had clinical responses, including patients with minimal radiographic evidence of disease 7 years after Ad.HSVtk/GCV with no other intervening anti-neoplastic therapy. The HSVtk gene was also introduced into patients using an irradiated allogeneic ovarian cancer cell line. No information on clinical responses has been reported. A second adenoviral trial was recently completed using immunogene therapy delivering the cytokine interferon-beta (IFN-β), which has a number of anti-tumor immune effects. The vector was well tolerated, resulted in detectable pleural IFNβ levels in most patients, and was accompanied by anti-tumor immune responses in 7 of 10 patients. A number of patients with low tumor burdens had disease stability or clinical responses. A modified vaccinia virus expressing interleukin-2 has been injected intratumorally into six patients. The vector was well tolerated, but no clinical responses were noted. Gene therapy approaches thus appear promising but still in the experimental stage.

OTHER PRIMARY PLEURAL NEOPLASMS Solitary fibrous tumors of the pleura had been previously referred to in the literature as “benign mesothelioma.” This is an inappropriate expression; both in terms of histogenesis and the potential for confusion with malignant mesothelioma. Solitary fibrous tumors (SFTs) have also been called localized fibrous tumor because of the occasional incidence of multiple masses. Solitary fibrous tumor is a mesenchymal tumor of probable fibroblastic origin and similar tumors have been described in other extrathoracic sites. It is important to note that there is no significant association of solitary fibrous tumors with asbestos exposure or other environmental agents. Although the peak age range of affected patients is similar (40 to 70 years), solitary fibrous tumors can affect patients of all ages, including children as young as 5 years old. In addition, there is no significant association of benign fibrous tumors of the pleura with asbestos exposure or other environmental agents.

Clinical Presentation Patients with solitary fibrous tumors of the pleura are usually asymptomatic and are diagnosed incidentally at routine chest radiography, but they can present with nonpleuritic chest pain, dyspnea, cough, or pleural effusion. A significant proportion (up to 40 percent) of patients present with symptomatic hypoglycemia, thought to be secondary to elaboration of insulinlike growth factors. Clubbing of fingers and toes is common, as are diffuse arthralgias, but the incidence of pulmonary hypertrophic osteoarthropathy is controversial.

Radiography Benign fibrous tumors typically present radiographically as large, rounded, well-circumscribed pleura-based masses, but occasionally they can appear to be intraparenchymal. Some

of these masses can be very large (over 15 cm in diameter) and can cause clinically significant compression of the lung. About 17 percent present with an ipsilateral pleural effusion. Asbestos-related pleural plaques are rarely seen in association with SFTs.

Gross Pathology The typical solitary fibrous tumors of the pleura arises from a pedicle off of the visceral pleura surface and rarely invade the visceral pleura itself (Fig. 88-6 A). They are usually well circumscribed, firm, often pedunculated masses that vary in size from 1 cm to more than 30 cm in diameter. When sectioned, the cut surface has a whorled appearance. Attention should be paid to areas of hemorrhage or necrosis. Malignant solitary fibrous tumors have been described, although they are less frequent.

Microscopic Pathology Histologically, solitary fibrous tumors have what has been described as a “patternless pattern” (Fig. 88-6B). Sections typically show alternating areas of hypocellularity and hypercellularity with short fascicles of interlacing spindle cells, creating a storiform pattern. These fascicles are interspersed between areas of variably collagenized tissue. A hemagiopericytomalike branching vascular pattern is also quite typical. Histological criteria that may predict a malignant course include high cellularity, infiltrative growth, moderate to marked cytologic atypia, and high mitotic rate (greater than 4 mitoses per 10 high-power fields). Immunohistochemical stains confirm the diagnosis. These tumors are CD34 (Fig. 88-6C ) and bcl-2 positive but cytokeratin negative. Malignant SFTs are not always positive for CD34 and bcl-2; therefore, the diagnosis requires the exclusion of other malignant tumors such as malignant mesothelioma, monophasic synovial sarcoma, and peripheral nerve sheath tumors.

Treatment Surgical resection of solitary, benign fibrous tumors of the pleura is curative with little risk of recurrence. There is typically a discrete separation between the tumor and underlying compressed lung, so pulmonary resection is usually unnecessary. Some tumors may require a limited chest wall resection. A small percentage of patients develop recurrences several decades after surgical resection and may die from extensive local disease. Some of these recurrent, localized fibrous tumors of the pleura demonstrate more aggressive histological features but are often successfully cured by surgical excision, in particular the pedunculated lesions.

Other Primary Pleural Tumors As discussed in the differential diagnosis of sarcomatoid mesotheliomas, there are other relatively rare malignant mesenchymal tumors that can be primary within the pleura. These tumors include vascular tumors (pleural epithelioid hemangioendothelioma/angiosarcoma) and synovial sarcoma.

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Figure 88-6 A. Gross photograph of a surgically resected, solitary, benign pleural fibrous tumor. Note the wellcircumscribed nature of this firm, slightly lobulated mass with its smooth-cut surface and punctate areas of hemorrhage and necrosis. (Courtesy of Dr. Matt van de Rijn, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia.) B. Photomicrograph of a typical solitary fibrous tumor demonstrating the ‘‘patternless-pattern”(H&E, ×400). (Courtesy of Dr. Matt van de Rijn.) C. Photomicrograph of a section of solitary fibrous tumor stained with an antibody directed against CD-34, a cell surface marker found commonly on endothelial cells and some smooth muscle and vascular tumors (×400). Positive staining for CD-34 helps distinguish these lesions from mesotheliomas and other pleural neoplasms. (Courtesy of Dr. Matt van de Rijn.)

Pleural epithelioid hemangioendothelioma is a low- to intermediate-grade vascular tumor. High-grade epithelioid vascular tumors are termed epithelioid angiosarcoma. The clinical presentation of patients with these tumors, as well as the radiographic features and gross appearance, are essentially identical to malignant mesothelioma. Patients present with diffuse pleural thickening, pleural effusion, and/or chest pain. Microscopic examination with the ancillary use of immunohistochemistry is required for diagnosis. These tumors usually have a biphasic pattern with nests of epithelioid cells embedded within a spindle cell stroma. The ep-

ithelioid cells characteristically have intracytoplasmic vacuoles and the associated stroma typically has a distinctive mxyo-hyaline or chondroid appearance. As with malignant mesotheliomas, a tubopapillary pattern may also be present. Vascular differentiation is demonstrated by strong positive staining with one or more endothelial markers (CD31, CD34, Fli1, or factor VIII). Cytokeratin positivity may also be present and can be misleading if the diagnosis of a vascular tumor is not considered. These tumors behave aggressively and there is, at the current time, no effective therapy.

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The diagnosis of pleural synovial sarcoma has improved with increased awareness and the greater availability of molecular testing for its distinctive X:18 translocation that now can be demonstrated in formalin-fixed paraffin embedded tissue. Synovial sarcomas present as either a biphasic epithelioid and spindled cell tumor or as a monophasic spindle cell tumor. In either instance, synovial sarcoma can be mistaken for malignant mesothelioma or a pulmonary sarcomatoid carcinoma. On average, patients tend to be younger than those with malignant mesothelioma but there is a wide reported age range that encompasses older patients into their eighth decade. There is a similar overlap in clinical presentation with malignant mesothelioma that includes chest pain, pleural effusions, dyspnea, and pneumothorax. Although pleural synovial sarcoma is more commonly a localized, solid tumor, diffuse pleural thickening does occur. The tumors can be quite large (mean size of 13 cm) and can have areas of necrosis and cystic degeneration. There are some histological features that are suggestive of synovial sarcoma, in particular its long interweaving fascicles, but the immunohistochemical profile of these tumors is not distinctive. The epithelioid component may show focal positive staining for cytokeratin, EMA, CEA, or BER-EP4. The spindled cell component may express calretinin. Confirmation of the diagnosis requires molecular testing for the X:18 translocation. Pleural synovial sarcoma is an aggressive disease with a generally poor prognosis.

SUGGESTED READING Benard F, Sterman D, Smith RJ, et al: Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest 114:713, 1998. Boutin C, Rey F, Gouvernet J, et al: Thoracoscopy in pleural malignant mesothelioma: A prospective study of 188 consecutive patients. Cancer 72:389–403, 1993. Carbone M, Pass HI, Rizzo P, et al: Simian virus 40-like DNA sequences in human pleural mesothelioma. Oncogene 9:1781–1790, 1994. Curran D, Sahmoud T, Therasse P, et al: Prognostic factors in patients with pleural mesothelioma: The European Organization for Research and Treatment of Cancer experience. J Clin Oncol 16:145, 1998. England DM, Hochholzer L, McCarthy MJ: Localized benign and malignant fibrous tumors of the pleura: A clinicopathologic review of 223 cases. Am J Surg Pathol 13:640– 658, 1989. Fitzpatrick DR, Peroni DJ, Bielefeldt-Ohmann H: The role of growth factors and cytokines in the tumorigenesis and immunobiology of malignant mesothelioma. Am J Respir Cell Mol Biol 12:455–460, 1995. Flores RM, Akhurst T, Gonen M, et al: Positron emission tomography predicts survival in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 132:763–768, 2006. Gordon GJ, Rockwell GN, Godfrey PA, et al: Validation of genomics-based prognostic tests in malignant

pleural mesothelioma. Clin Cancer Res 11:4406–4414; 2005. Granville L, Laga AC, Allen TC, et al: Review and update of uncommon primary pleural tumors. A practical approach to diagnosis. Arch Pathol Lab Med 129:1428–1443, 2005. Heelan RT, Rusch VW, Begg CB, et al: Staging of malignant pleural mesothelioma: Comparison of CT and MR imaging. AJR Am J Roentgenol 172:1039–1047, 1999. Hodgson JT, McElvenny DM, Darnton AJ, et al: The expected burden of mesothelioma mortality in Great Britain from 2002 to 2050. Br J Cancer 92:587–593, 2005. Huncharek M: Genetic factors in the aetiology of malignant mesothelioma. Eur J Cancer 31A:1741–1747, 1995. Kroczynska B, Cutrone R, Bocchetta M, et al: Crocidolite asbestos and SV40 are cocarcinogens in human mesothelial cells and in causing mesothelioma in hamsters. Proc Natl Acad Sci USA 103:14128–14133, 2006. Mossman BT: Carcinogenesis and related cell and tissue responses to asbestos: A review. Ann Occup Hyg 38:617–624, 1994. Ordonez NG: What are the current best immunohistochemical markers for the diagnosis of epithelioid mesothelioma? A review and update. Hum Pathol 38:1–16, 2007. Pass HI, Liu Z, Wali A, et al: Gene expression profiles predict survival and progression of pleural mesothelioma. Clin Cancer Res 10:849–859, 2004. Pass HI, Lott D, Lonardo F, et al: Asbestos exposure, pleural mesothelioma, and serum osteopontin levels. N Engl J Med 353:1564–1573, 2005. Robinson BW, Creaney J, Lake R et al: Mesothelin-family proteins and diagnosis of mesothelioma. Lancet 362:1612, 2003. Robinson BW, Lake RA: Advances in malignant mesothelioma. N Engl J Med 353:1591–603, 2005. Rusch VW: A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 108:1122– 1128, 1995. Sterman DH, Albelda SM: Advances in the diagnosis, evaluation and management of malignant pleural mesothelioma. Respirology 10:266–283, 2005. Sugarbaker DJ, Flores RM, Jaklitsch MT, et al: Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: Results in 183 patients. J Thorac Cardiovasc Surg 117:54, 1999. Travis WD, Brambilla E, Muller-Hermelink HK, et al., eds. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France, IARC Press, 2004. van der Most RG, Robinson BW, Nelson DJ: Gene therapy for malignant mesothelioma: Beyond the infant years. Cancer Gene Ther 13:897–904, 2006. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636–2644, 2003.

PART

XI Diseases of the Mediastinum

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89 Nonneoplastic Disorders of the Mediastinum Cameron D. Wright

I. ANATOMY Boundaries Compartments Lymphatics II. PNEUMOMEDIASTINUM Anatomic Considerations Spontaneous Pneumomediastinum Pneumomediastinum Associated with Mechanical Ventilation Pneumopericardium III. ACUTE MEDIASTINITIS Mediastinitis from Esophageal Perforation Tracheobronchial Perforation

ANATOMY Boundaries The mediastinum is defined as the potential space between the two pleural cavities bounded by the sternum anteriorly, the vertebral column posteriorly, the thoracic inlet superiorly, and the diaphragm inferiorly (Fig. 89-1). The major mediastinal structures are the heart and great vessels, the trachea and main bronchi, and the esophagus, all closely related to one another and connected by loose connective tissue. Hence, air or infection can disseminate widely throughout the mediastinal space, contained laterally only by the mediastinal pleural reflections. The mediastinum communicates with both the neck and the retroperitoneum, and these portals can also serve as routes of egress from the mediastinum. Fascial planes connect the neck, mediastinum, and retroperitoneum and thus facilitate movement of air or infection from one location to another.

Descending Necrotizing Mediastinitis Mediastinitis from Direct Extension Poststernotomy Mediastinitis Anthrax Mediastinitis IV. CHRONIC MEDIASTINITIS Fibrosing Mediastinitis Superior Vena Cava Syndrome Other Compression Syndromes V. MISCELLANEOUS MEDIASTINAL PATHOLOGY Foramen of Morgagni Hernias Mediastinal Repositioning in Postpneumonectomy Syndrome Spontaneous Mediastinal Hemorrhage

Compartments Several subdivisions of the mediastinum have been emphasized in the surgical and radiologic literature but there is no consensus. Most often, three compartments are proposed: anterior, middle (visceral), and posterior (paravertebral sulcus) (Fig. 89-2). The boundaries of these divisions are not agreed upon, further emphasizing their nonanatomic origins. Shields proposed a simple three-compartment subdivision in 1972, which makes both anatomic and surgical sense. The anterior compartment is bounded by the sternum and the anterior surface of the pericardium and great vessels. The middle (visceral) compartment extends from the posterior limit of the anterior compartment to the anterior surface of the vertebral columns and then to the thoracic inlet. The posterior compartment (paravertebral sulcus) extends from the anterior surface of the vertebral column to the anterior surface of the paravertebral ribs. The structures in these compartments are listed in Table 89-1. The pericardial

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Figure 89-1 A. Lateral view of the mediastinum as seen through a right thoracotomy. B. Lateral view of the mediastinum as seen through a left thoracotomy. (From LoCicero J: Median sternotomy and thoracotomy, in Shields TW (ed): Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, p 95, with permission.)

sac is the only true compartment of the mediastinum and it provides a strong barrier to infection. Subdividing the mediastinum into compartments proves most helpful when one is interpreting a plain radiograph that shows a

Table 89-1 Contents of Mediastinal Compartments Anterior

Middle

Thymus gland Pericardium

Posterior Azygos and hemiazygos veins

Pericardial fat

Heart

Lymph nodes

Trachea and Thoracic duct main bronchus Esophagus

Symphathetic trunk

Aorta Figure 89-2 Compartments of the mediastinum. Note continuity of visceral (middle) compartment with the neck and retroperitoneum. (From Shields TW: The mediastinum and its compartments, in Shields TW (ed): Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, p 4, with permission.)

Phrenic and vagus nerves Lymph nodes

Intercostal nerves

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mediastinal mass. Knowledge of the contents of the involved compartment facilitates arriving at a proper diagnosis.

Lymphatics The mediastinal lymphatic system is quite complex and variable. Mediastinal lymph nodes are interconnected; thus, involvement of one group of lymph nodes in a pathological process frequently leads to involvement of other groups. Just as subdividing the mediastinum into compartments, naming individual nodal stations is somewhat arbitrary and leads to the mistaken notion that these nodal stations are discrete. To the contrary, the mediastinum is covered in a dense network of lymphatic vessels and lymph nodes with no predictable boundaries. Nonetheless, there are commonly accepted nodal stations that have clinical importance, especially in the staging of lung cancer. The lymph node map proposed by Naruke in 1978 has been widely accepted and serves as a standard for communication of lymph node involvement (Fig. 89-3).

Nonneoplastic Disorders of the Mediastinum

PNEUMOMEDIASTINUM Pneumomediastinum (mediastinal emphysema) is an uncommon condition but now is being seen with increasing frequency due to the common use of mechanical ventilationâ&#x20AC;&#x201D; specifically, certain modes of mechanical ventilation. Air (or gas) outside the normal confines of the respiratory and gastrointestinal tracts is always abnormal and always requires explanation. Treatment is directed at the underlying abnormality if one can be identified.

Anatomic Considerations Pneumomediastinum is frequently associated with other forms of extra-alveolar air, including pulmonary interstitial emphysema, pneumopericardium, pneumothorax, subcutaneous emphysema, pneumoretroperitoneum, and pneumoperitoneum. The key to understanding the distribution of extra-alveolar air lies in the recognition of the common fascial planes that unite these areas. In the neck, the deep layer of the deep cervical fascia ensheaths the trachea and esophagus as they descend into the mediastinum. The trachea and esophagus are thus enclosed in this visceral space; therefore, air or infection can readily travel from the mediastinum to the neck or retroperitoneum (Fig. 89-4). This fascial plane extends into the hilum of the lung and merges with the bronchovascular sheaths that surround the terminal bronchioles, arteries, and veins. The bronchovascular sheath also merges with and is continuous with the pericardium. After alveolar rupture, air enters the perivascular interstitium and dissects proximally within the bronchovascular sheath toward the mediastinum (Fig. 89-5). Air can then enter the pericardial space, resulting in pneumopericardium, or it may dissect along the adventitia of the great vessels (Fig. 89-6). Mediastinal air can also decompress by extension into the cervical, subcutaneous, and retroperitoneal spaces. A pneumomediastinum that ruptures into the free pleural space results in a pneumothorax. Pneumothorax may also result from air dissecting out toward the visceral pleural surface of the lung and rupturing. Macklin, in 1944, in an elegant experimental cat model, confirmed this theory of progression of extra-alveolar air following alveolar rupture. Pneumomediastinum usually results from a ruptured alveolus due to a Valsalva maneuver or mechanical ventilation. There are many other possible sources, however, which must be considered when the physician has to manage a patient with pneumomediastinum (Table 89-2). Dental procedures, especially those on the mandible with the addition of compressed air to maintain a clear field, are an occasional cause of mediastinal emphysema.

Spontaneous Pneumomediastinum Figure 89-3 Lymph node groups of the lungs and mediastinum. (From Naruke T, Suemasu K, Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76:832â&#x20AC;&#x201C;839, 1978, with permission.)

Idiopathic spontaneous pneumomediastinum is a rare selflimited condition that most commonly affects young adult men. Hamman, in 1939, described crepitation synchronous with the heartbeat in these patients. The majority of patients

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Figure 89-4 Soft tissue compartments of the neck, thorax, and abdomen demonstrating continuity of visceral space between regions. (From Maunder RJ, Pierson DJ, Hudson LD: Subcutaneous and mediastinal emphysema. Arch Intern Med 144:1447â&#x20AC;&#x201C;1453, 1984, with permission.)

with spontaneous pneumomediastinum have predisposing factors that cause increase in airway pressure, which leads to alveolar rupture. Most commonly, this results from straining against a closed glottis, as during vomiting, coughing, or exercising. Other mechanisms include sudden and/or severe increases in lung volume, as occur during marijuana smoking, inhaling of cocaine, and/or during a seizure. Localized airway obstruction from tumor, foreign bodies, asthma, or parenchymal lung disease can also cause alveolar rupture.

An accurate history is most important in order to define the mechanism in a particular patient. Spontaneous pneumomediastinum almost always presents with substernal pain, often pleuritic, which may radiate to the neck or back. Patients may experience, either separately or in combination, dyspnea, dysphagia, odynophagia, and dysphonia. Air in the subcutaneous tissues of the neck produces a characteristic change in voice quality, a higher-pitched nasal tone, that the experienced clinician easily recognizes. Examination often reveals palpable subcutaneous emphysema in the neck. Auscultation of the chest may reveal a crunching or clicking sound heard over the pericardium, synchronous with the heartbeat (Hammanâ&#x20AC;&#x2122;s sign). Low-grade fever is present in about one-third of cases and mild leukocytosis in about one-half. Nonspecific electrocardiographic changes, such as ST-T wave changes and ST elevation, may also be present. A chest radiograph usually demonstrates a thin radiolucent strip along a mediastinal fascial plane, most commonly along the left heart border. The aortic knob may be highlighted as well (see Fig. 89-6). Computed tomography (CT) is more sensitive in detecting air than are plain radiographs (Fig. 89-7). Air may be evident deep in the neck as well as in the subcutaneous tissue. The differential diagnosis is broad and includes musculoskeletal, pleural, pulmonary, cardiac, and esophageal causes. Although most patients who present are not acutely ill, an occasional patient may suffer an acute, catastrophic onset with hypotension and hemodynamic compromise. Esophageal perforation is the condition most likely to be confused with spontaneous mediastinal emphysema. Worrisome features suggestive of esophageal perforation include recent esophageal instrumentation, a history of esophageal problems, severe retching, the presence of a pleural effusion, or shock. A contrast esophagogram should be obtained immediately if there is any question of an esophageal perforation, since a delay in making this diagnosis often proves fatal. A high index of suspicion regarding esophageal perforation should always be present whenever a patient presents with mediastinal emphysema. Treatment of spontaneous mediastinal emphysema is supportive and is primarily directed at pain relief and reassurance. Appropriate management of contributing causes such as foreign bodies, asthma, and parenchymal lung disorders should be instituted. The patient should be followed both clinically and radiographically to exclude another cause for mediastinal emphysema and detect a possible pneumothorax. Prompt resolution is the rule. Supplemental oxygen to hasten reabsorption (similar to that proposed for pneumothorax) has been reported but is probably not necessary. Needle aspiration or skin incision to relieve subcutaneous emphysema is almost never necessary. Prophylactic tube thoracostomy is unnecessary. For patients who present with minimal findings and a clear inciting factor (such as coughing), only a short period of observation in the emergency department is required.

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Figure 89-5 Possible routes of air following alveolar disruption. Air from the alveolus (A) enters perivascular interstitium (B), dissecting proximally within bronchovascular sheath toward mediastinum (C). As mediastinal pressure rises, decompression occurs in cervical (D), subcutaneous, and retroperitoneal (E) soft tissue spaces. A pneumothorax is possible if the pleura (F) is ruptured. (From Maunder RJ, Pierson DJ, Hudson LD: Subcutaneous and mediastinal emphysema. Arch Intern Med 144:1447â&#x20AC;&#x201C;1453, 1984, with permission.)

Pneumomediastinum Associated with Mechanical Ventilation Mechanical ventilation is commonly associated with pneumomediastinum and may often lead to life-threatening tension pneumothorax. Alveolar rupture results from high peak inspiratory pressures, which increase alveolar pressures in patients with abnormal airways or parenchyma (decreased compliance). Classic predisposing factors include high tidal volumes, high levels of positive end-expiratory pressure (PEEP), and â&#x20AC;&#x153;fightingâ&#x20AC;? the ventilator. Air trapping with occult positive end-expiratory pressure (auto-PEEP) is probably an underrecognized cause of barotrauma. It is not clear if one mode of ventilation (pressure-controlled versus volume-limited) is associated with a decreased incidence of barotrauma. Unlike spontaneous mediastinal emphysema, pneumomediastinum occurring in a patient on mechanical ventilation is potentially catastrophic because of its frequent association with tension pneumothorax. The chest radiograph should be closely examined to detect even a small pneumothorax and, if such is present, tube thoracostomy should be promptly performed. Obviously, a sudden deterioration marked by hypotension and increased pulmonary pressures

Figure 89-6 Lateral radiograph of a middle-aged patient with an acute asthma attack requiring hospital admission. Mediastinal air is seen outlining the aorta and esophagus. This resolved spontaneously.

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Table 89-2 Etiology of Pneumomediastinum Upper respiratory tract Head and neck infection Fracture of facial bones Trauma to hypopharynx and larynx (especially intubation) Dental procedures (especially mandibular) Lower respiratory tract Trauma Bronchoscopy, especially therapeutic bronchoscopy (i.e., YAG laser, rigid core-out, and transbronchial biopsy) Lung Trauma Surgery Spontaneous alveolar rupture Straining and Valsalva maneuver Local airway obstruction Scuba diving Mechanical ventilation Gastrointestinal tract Esophageal perforation Perforated viscus Infection Acute mediastinitis Descending necrotizing mediastinitis Air from outside the body Trauma Surgery (especially mediastinoscopy, tracheostomy, and sternotomy) Pneumoperitoneum (especially with laparoscopic hiatus hernia repair) Source: Adapted from Pierson with permission.

should prompt immediate attention with insertion of unilateral or bilateral chest tubes, depending on the clinical examination. The issue of inserting a tube prophylacticaly is controversial and unresolved. At a minimum, a thoracostomy tray should be kept at the patient’s bedside and the nursing staff reminded of the signs of a pneumothorax in a mechanically ventilated patient. If a physician is not readily available around the clock, it may be advisable to perform bilateral prophylactic tube thoracostomy in certain patients. Removing the patient from mechanical ventilation as soon as possible is appropriate. Since this is seldom possible, efforts should be directed at minimizing alveolar distention. These efforts include relief of bronchospasm, minimizing “fighting” the ventilator, reduc-

ing tidal volume and PEEP, and manipulation of inspiratory flow and timing to reduce auto-PEEP.

Pneumopericardium Pneumopericardium as a form of barotrauma is much more frequent in neonates, presumably due to immature fascial planes. Hemodynamically significant tamponade is also much more likely to occur in infants rather than adults and has resulted in collapse and death. Pericardial drainage with a subxyphoid tube should be performed promptly in the neonate. In the adult, drainage should be performed only if there is hemodynamic embarrassment.

ACUTE MEDIASTINITIS Acute mediastinitis is a life-threatening disorder that causes severe morbidity in the afflicted patient. All three mediastinal compartments can be affected; the anterior compartment most commonly after sternotomy for cardiac surgery, the middle compartment usually from esophageal perforation, and the posterior compartment from direct extension from the lung or spine. Instrumental perforation of the esophagus is the most common cause of acute mediastinitis in the United States. A summary of the causes of acute mediastinitis is presented in Table 89-3.

Mediastinitis from Esophageal Perforation Instrumental perforation of the esophagus now accounts for almost one-half of all esophageal perforations. Perforation is more common after rigid esophagoscopy, dilation of a stricture, and pneumatic dilation for achalasia, but it also occurs after variceal sclerosis, esophageal tube placement (nasogastric, Sengstaken-Blakemore, and salivary bypass tubes), and simple flexible esophagoscopy. Boerhaave’s syndrome (postemetic rupture) was described in 1724 but still represents a diagnostic challenge and remains a major consideration in patients with otherwise unexplained mediastinitis (Fig. 89-8). Patients usually present with the abrupt onset of severe substernal chest pain, which is pleuritic after forceful vomiting or retching. Dyspnea is common even in the absence of pneumothorax. Shock develops quickly and the patient usually appears gravely ill. Examination reveals tachypnea, tachycardia, fever, hypotension, splinting of the chest and abdomen, and cervical emphysema. Radiographic findings may show cervical or mediastinal emphysema, pneumothorax, and (commonly) pleural effusion. Noncontrast radiographic studies are normal in 10 to 30 percent of cases of esophageal perforation. A contrast esophagogram (usually with watersoluble contrast) should be performed immediately when the diagnosis is suspected, but one should be aware that this study has a false-negative rate of 10 percent. A chest CT scan is the next best study in a patient in whom esophageal perforation is suspected but who has a negative esophagogram. Prompt

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Figure 89-7 Computed tomography of a man with an 8-hour-old postemetic esophageal rupture. Posteroanterior radiograph was normal. Mediastinal air is seen outlining trachea and esophagus.

diagnosis and, therefore, a high index of suspicion are essential, as the frequency of complications and the mortality rate are directly dependent on the time elapsed between perforation and treatment. The differential diagnosis is broad and includes perforated ulcer, acute pancreatitis, myocardial infarction, pneumonia, aortic dissection, and pulmonary embolism. Treatment should be instituted urgently and involves surgical debridement of necrotic tissue, secure closure of the perforation, correction of any distal obstruction, and wide drainage, usually performed through a left thoracotomy. Appropriate broad-spectrum antibiotics with anaerobic coverage and the maintenance of proper nutrition are also integral components of the management plan. Esophagectomy is occasionally required in the presence of a perforated, nondilatable stricture, a destroyed esophagus in which direct repair is not possible, or cancer. Nonoperative treatment is rarely appropriate but may be instituted in highly selected cases (i.e., contained, asymptomatic instrumental perforations) in which a significant interval has passed and the patient is clinically stable. Mortality is less than 10 percent if the perforation is recognized and repaired within 24 h, whereas mortality increases to 30 to 40 percent if more than 24 h have elapsed between perforation and repair. The mortality rises even higher with advanced age of the patient.

due to the less noxious nature of its contents and better containment. Intubation is now the most frequent cause of tracheobronchial injury, but it should be avoidable with gentle and proper technique. Blood in the airway, airway obstruction (infrequent), subcutaneous and mediastinal emphysema, and pneumothorax are the common presenting signs. Prompt

Table 89-3 Etiology of Acute Mediastinitis Esophageal perforation Instrumental Postemetic (Boerhaaveâ&#x20AC;&#x2122;s syndrome) Trauma Foreign body Operative injury Caustic ingestion Cancer Direct extension Tracheobronchial perforation Descending necrotizing mediastinitis Direct extension (pulmonary and pancreatitis)

Tracheobronchial Perforation Tracheobronchial perforation is rare and is most commonly seen following trauma or instrumentation. Severe mediastinitis is rare after tracheobronchial disruption, presumably

Poststernotomy mediastinitis Anthrax mediastinitis

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Mediastinitis from Direct Extension Necrotizing pneumonias may cause mediastinitis by direct extension, most often in immunocompromised patients. Aspergillosis of the posterior mediastinum has been reported with increasing frequency and is highly lethal. Treatment involves reversal of immunosuppression (if possible), appropriate antibiotic therapy, and surgical drainage and debridement. Pancreatitis can extend from the retroperitoneum into the mediastinum and may present as a mediastinal process with evidence of mediastinitis. Pancreatic pseudocysts can also erode into the mediastinum and cause pleural effusions with increased levels of amylase. Treatment is directed at providing adequate drainage of the pseudocyst, usually by internal drainage into the stomach. The pleural effusion(s) may require tube thoracostomy drainage.

Poststernotomy Mediastinitis

Figure 89-8 Water-contrast esophagogram of a patient with Boerhaaveâ&#x20AC;&#x2122;s syndrome. Note extensive extravasation of contrast and mediastinal emphysema.

recognition and operative repair are necessary and yield excellent results, although small tears in the cervical trachea may often be managed with antibiotics alone, without operation.

Descending Necrotizing Mediastinitis Mediastinitis occasionally develops after severe deep cervical infections that originate from the oropharynx. Most patients present with a mixed aerobic and anaerobic infection. Previously these infections had a fulminant, often lethal course with mortality as high as 40 percent. Extension of the cervical infection down the prevertebral or visceral space into the mediastinum leads to this syndrome of descending necrotizing mediastinitis. Computed tomography should be performed on all severe neck infections to identify signs of mediastinitis that may not be clinically apparent. Aggressive surgical drainage (cervical, substernal, and transthoracic) and antibiotics have reduced mortality, though prompt management is essential.

Sternal wound infection with resulting mediastinitis is a relatively new entity, which emerged in the era of modern cardiac surgery. The incidence remains low at 0.5 to 1 percent of all sternotomies, but such infection is a source of major morbidity, prolonged hospital stay, and significant mortality (0 to 30 percent; average, 15 percent). Multivariate analysis has demonstrated that prolonged preoperative stay, reoperation, blood transfusions, and re-exploration for bleeding are significant risk factors. The presence of diabetes mellitus and use of internal thoracic artery grafts (which may devascularize the sternum) also are significant risk factors. Organisms commonly isolated include Staphylococcus epidermidis and aureus, various gram-negative organisms, as well as Candida species and atypical mycobacteria. The etiology appears to be a combination of intraoperative contamination and hematogenous seeding of mediastinal clot in the early postoperative period. Breaks in technique during the operation or inadequate sterilization of instruments before it probably cause the majority of these infections. Most patients with poststernotomy mediastinitis have an insidious presentation with low-grade fever and leukocytosis, wound problems (erythema, drainage, sternal instability), and eventually bacteremia. Infections caused by gramnegative organisms tend to become manifest earlier than those caused by gram-positive organisms. Most infections occur within the first or second week following the operative procedure. A high index of suspicion must be maintained so that an early diagnosis can be made and appropriate treatment instituted. Wound aspiration, local wound exploration, and a CT scan aid in making the diagnosis. Exploration in the operating room remains the definitive diagnostic maneuver and material should be obtained for culture at that time if it has not been obtained before or has been unrevealing. If the infection is relatively early and the bony sternum appears viable, debridement, drainage, and saline (or antibiotic) irrigation with reclosure are indicated. Although it may seemingly violate time-honored surgical principles (leaving

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contaminated wounds open, to close by secondary intention), primary closure of the early infected sternum yields excellent results in many patients if adequate debridement is carried out. Of course, proper and prolonged antibiotic therapy is necessary. Reported mortality rates approach zero for these early infections if managed appropriately. Late sternal wound infections with mediastinitis present a more formidable challenge, in part due to the extensive sternal osteomyelitis and necrotic soft tissue which, when debrided, result in significant dead space, thereby creating a favorable environment for continued bacterial proliferation and persistent infection. Most surgeons favor extensive sternal debridement, usually with total sternal excision and rotation of pectoralis muscle flaps (bilateral) or transposition of gastrocolic omentum to fill the dead space with viable tissue. The presence of prosthetic material, such as sutures, Teflon pledgets, or prosthetic grafts further complicates the problem and may lead to catastrophic hemorrhage with a fatal outcome. Mediastinitis in the presence of a prosthetic aortic graft is a particularly disastrous complication.

Anthrax Mediastinitis Anthrax, caused by Bacillus anthracis, was previously found primarily in the Middle East, with farm animals as the primary reservoir. Following the advent of substantial immigration and bioterrorism, anthrax has been diagnosed in the United States and has been prominent in the mainstream media. An index case of fatal inhalational anthrax complicated by hemorrhagic mediastinitis due to bioterrorism in the United States has been reported in detail. The inhalation of anthrax spores allows entry into the lungs with subsequent transport to the mediastinal lymph nodes by alveolar macrophages. A hemorrhagic mediastinitis typically quickly ensues and death is common. Gram-positive bacilli are present in tissue specimens, and the initial treatment involves the initial use of either ciprofloxacin or doxycycline plus one or two additional antimicrobial agents with activity against B. anthracis.

CHRONIC MEDIASTINITIS Granulomatous mediastinitis is a disease of the mediastinal lymph nodes usually resulting from infection by Histoplasma capsulatum and occasionally from tuberculosis or other fungi. In certain areas of the country (Mississippi river valley) where Histoplasma is endemic, this disease is fairly common. Coalescence of caseous mediastinal lymph nodes can result in a single large mass that incites a considerable fibrotic response, which can result in encapsulation and produce a mediastinal granuloma. The right paratracheal area is the most common site for development of an encapsulated mass. When calcification is absent and the patient presents with what appears to be mediastinal adenopathy, a tissue diagnosis is required to exclude malignancy. With progressive increase in the size of this “benign” mass, compression of the trachea, superior

Figure 89-9 Barium swallow of an elderly woman with a history of treated tuberculosis with symptomatic diverticulum of midesophagus adjacent to the subcarinal lymph nodes.

vena cava, or esophagus can occur. In a report from the Mayo Clinic, 34 percent of patients with mediastinal granuloma went on to develop mediastinal fibrosis over a 2-year period. Based on such reports, most authors suggest that there exists a spectrum of disease ranging from mediastinal granuloma to fibrosing mediastinitis. Caseating lymph nodes can also erode into and rupture in the esophagus, be associated with esophageal diverticula (Fig. 89-9), and erode into the airway, causing obstruction or bleeding. Mediastinal granulomas should be excised if symptomatic. Although complete excision is possible, the intense surrounding fibrosis places important structures at risk for operative injury. Evacuation of the granulomatous mass is usually a safer option. Specimens for culture and special stains should be obtained at the time of operation, but organisms can rarely be identified or grown in culture. Mediastinal lymph nodes involved by the granulomatous process may become calcified as individual masses and— because of the proximity of lymph nodes to the tracheobronchial tree—ultimately erode into the airway. Erosion into the airway, if it occurs, does so over a prolonged period of time and may remain asymptomatic, only to be noted if a bronchoscopy is performed for some other indication. The presence of calcified lymph node masses within the bronchi

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is referred to as broncholithiasis and may also present with symptoms of obstruction or bleeding. Symptomatic broncholithiasis should prompt bronchoscopy for documentation of findings only. Rarely, if ever, should broncholiths be removed bronchoscopically, the exception being the occasional “stone” that is completely free within the bronchus. An effort to remove a broncholith that is not completely detached from the wall of the bronchus may be accompanied by catastrophic hemorrhage due to the close proximity of pulmonary artery branches to the bronchus. Most symptomatic broncholiths should be removed at thoracotomy, where the pulmonary artery may be managed. These can be extremely difficult and hazardous operations and should be carried out by thoracic surgeons experienced in the management of granulomatous disease. Usually lobectomy or segmentectomy is required, since removal of the calcified mass will almost certainly take a portion of the bronchial wall. Fistulas occurring between the trachea and esophagus or esophagus and mediastinum should be closed and reinforced with viable tissue. There is no consensus regarding management of large asymptomatic mediastinal granulomas but some have recommended excision to forestall the development of fibrosing mediastinitis. This, however, remains controversial.

Fibrosing Mediastinitis Fibrosing mediastinitis may cause a variety of clinical syndromes due to the compression and/or erosion of vital mediastinal structures by the dense fibrous tissue reaction that is present. Although the syndrome itself is rare, the common causative agents—Histoplasma and, rarely, Mycoplasma tuberculosis—are relatively ubiquitous. Other very rare causes include other fungi, silicosis, the drug methysergide, autoimmune disorders, and familial multifocal fibrosclerosis. Goodwin proposed the currently accepted (by most) hypothesis that fibrosing mediastinitis results from a delayed hypersensitivity reaction to fungal, mycobacterial, or other antigens. Pathological features include the presence of dense fibrotic tissue surrounding the trachea and hila of the lungs, often extending into contiguous structures. Compression of the airway, pulmonary arteries, or veins may occur because of this process. Histological features include dense hyalinized collagenous tissue, aggregates of plasma cells and lymphocytes, and occasionally granulomas. Cultures are almost always negative, as are special stains for organisms. Symptoms are primarily caused by compression of vital mediastinal structures. Fibrosis around the right peritracheal area commonly causes superior vena cava syndrome. Subcarinal fibrosis can extend posteriorly to encase the esophagus or extend laterally to involve the pulmonary veins. Hilar fibrosis can obstruct either the tracheobronchial tree or pulmonary arteries (Fig. 89-10). Rarely, constrictive pericarditis or obstruction of the trachea or proximal main bronchi can also occur. The signs and symptoms may progress over a period of time.

Superior Vena Cava Syndrome The most common mediastinal compression syndrome seen in fibrosing mediastinitis is the superior vena cava (SVC) syndrome, which occurs in 20 to 50 percent of patients. In the vast majority of patients, the SVC syndrome is due to malignant disease; fibrosing mediastinitis is the most common benign cause. Patients present with distention of the veins in the neck; edema and plethora of the face, neck, and arms; and central nervous system complaints such as headache and visual disturbances. Men often note as a first sign an increase in collar size; and symptoms become worse upon bending over. Because this syndrome is usually of gradual onset, venous collaterals develop over the anterior chest wall and, in many patients, provide adequate decompression (Fig. 89-11). Confirmation of the diagnosis of SVC syndrome is easily made with contrast CT or venography, which demonstrate blockage of contrast at the thoracic inlet and the presence of collateral vessels. Bilateral upper extremity venograms demonstrate the precise anatomy of the involved veins and are helpful if surgical decompression is contemplated. Surgical bypass is reserved for patients with intractable symptoms and is performed by connecting an unobstructed large brachiocephalic vein to the right atrial appendage with a graft of either a saphenous vein or an externally supported polytetrafluoroethylene graft. Favorable long-term results have been reported. Percutaneous angioplasty and stenting of a stenotic superior vena cava has been reported, but long-term follow-up is limited.

Other Compression Syndromes Tracheobronchial compression is also common and leads to dyspnea, obstructive pneumonias, wheezing, hemoptysis, cough, and the middle lobe syndrome (see Fig. 89-10). A localized stenotic area can be dilated sometimes, but often pulmonary resection is required, usually of the right middle and occasionally lower lobes. Resection is the procedure of choice if chronic infection has been present. Bronchoplastic procedures are appropriate sometimes if lung parenchyma remains normal. The placement of stents into the trachea and/or mainstem bronchi may allow for adequate management of a compressed airway. A Y-bifurcation stent and individual self-expanding stents placed in the trachea or bronchi are available. Airway management must be individualized based on findings at bronchoscopy. Complete or partial unilateral or bilateral pulmonary artery obstruction can result from fibrosing mediastinitis (see Fig. 89-10). Dyspnea and signs of right heart failure can be present. The differential diagnosis should include chronic pulmonary thromboembolism. The fibrosis may also extend to involve the pulmonary veins, producing pulmonary venoocclusive disease. Some patients present with complaints similar to those of patients presenting with mitral stenosis: dyspnea, cough, and hemoptysis. Surgical correction of these disorders is rarely possible due to the extreme fibrosis present around the vessels. If the situation is unilateral, a pneumonectomy may be an alternative.

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A B

Figure 89-10 Mediastinal fibrosis due to histoplasmosis in a middle-aged nurse with narrowing of the trachea and main bronchi as well as occlusion of the right pulmonary artery. A. Posteroanterior radiograph demonstrating focal infiltrate in right lower zone with right hilar fullness. B. Lateral radiograph demonstrating a mass centered around the carina with mild narrowing of the distal trachea. C. Computed tomography shows calcified mass around bronchus intermedius with mild compression of bronchus. D. Pulmonary angiogram demonstrates complete occlusion of right pulmonary artery beyond the anterior trunk due to mediastinal fibrosis. The left pulmonary artery was moderately narrowed. E. Oblique tomogram demonstrating narrowing of distal trachea and left main bronchus. F. Oblique tomogram demonstrating narrowing of right bronchus intermedius with large mass of lymph nodes anterior and posterior to the airway.

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Figure 89-10 (Continued )

Esophageal obstruction is not uncommon in fibrosing mediastinitis, and the middle third of the esophagus is most frequently involved because of its relationship to the subcarinal space. Dilation, enucleation of scar, and resection are therapeutic options. Fistulas may also occur between the subcarinal lymph nodes and the esophagus or into the tracheobronchial tree. Operative treatment for fistula formation is directed at closing the fistula and separating structures using viable tissue such as muscle. An esophageal diverticulum may form from inflammatory adherence to the subcarinal lymph nodes but is usually asymptomatic (see Fig. 89-9). Corticosteroids have not proved of benefit in fibrosing mediastinitis despite its obvious inflammatory nature. The majority of reports of treatment with chemotherapeutic agents directed against the suspected causative organism have been negative. Urschel reported success in six patients who were treated with prolonged ketoconazole therapy. Patients were selected based on an increased sedimentation rate and histoplasmosis complement fixation titer and were given ketoconazole following appropriate surgical decompression. These patients are probably not typical or representative of most patients with fibrosing mediastinitis but rather closer to those with granulomatous mediastinitis.

MISCELLANEOUS MEDIASTINAL PATHOLOGY Figure 89-11 Patient with SVC syndrome secondary to mediastinal fibrosis due to histoplasmosis. Numerous dilated and tortuous collateral veins present on the chest wall are characteristic of chronic SVC obstruction.

Foramen of Morgagni Hernias Hernias occurring through the foramen of Morgagni are rare causes of cardiophrenic angle masses (Fig. 89-12). The hernia

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Figure 89-12 Foramen of Morgagni hernia. This man presented with substernal discomfort and heaviness. Incarcerated omentum was present in the hernia sac. A. Posteroanterior radiograph demonstrating large, smooth mass obscuring the right cardiophrenic angle. B. Lateral radiograph showing large, smooth substernal mass.

results from failure of the normal fusion of the diaphragmatic components during embryologic development. Small hernias are usually asymptomatic but large ones can contain the entire omentum, transverse colon, and even stomach and thus cause symptoms. Symptoms include substernal discomfort and dyspnea; rarely, they may point to intestinal obstruction. The diagnosis is now easily confirmed by CT and operative repair is always indicated.

Mediastinal Repositioning in Postpneumonectomy Syndrome Following pneumonectomy, airway compression may be caused by extreme mediatinal shift and rotation, manifested by herniation and overdistention of the remaining lung. This problem is rare but is more common after right pneumonectomy. It may also occur after left pneumonectomy, especially in the presence of a right aortic arch. The problem has been particularly noted in children but also occurs in younger adults. When extreme shift of the mediastinum occurs after pneumonectomy, compression of the main bronchus occurs against the aorta and/or vertebral column (Fig. 89-13). Patients may develop disabling dyspnea, stridor, and recurrent pulmonary infections.

Computed tomography confirms the diagnosis, and pulmonary function studies generally show severe obstruction, flattened flow-volume loops, and an increase in the ratio of residual volume to total lung capacity. Bronchoscopy delineates the extent of airway compression and is helpful in assessing any malacia that may be present. Operative repair is indicated and consists of mediastinal repositioning through the original thoracotomy incision by placing expandable saline breast prostheses (see Fig. 89-13). In the absence of severe malacia, airway compression is relieved and clinical results are excellent. Management of residual airway malacia is troublesome and is probably best handled by internal stenting.

Spontaneous Mediastinal Hemorrhage Spontaneous mediastinal hemorrhage is quite rare. Mediastinal hemorrhage due to aortic dissection, contained rupture of a thoracic aortic aneurysm, or iatrogenic injury is much more common. Symptoms are usually of sudden onset and consist of substernal pain, dyspnea, and, rarely, hemodynamic compromise. The hemorrhage is usually brief and self-limited. Treatment is supportive, and secondary causes of mediastinal hemorrhage must be excluded. Mediastinal fibrosis has rarely been reported following mediastinal hemorrhage.

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Figure 89-13 Thirty-year-old woman with previous left carinal pneumonectomy for granular cell tumor with postpneumonectomy syndrome. She presented with worsening dyspnea, which worsened with recumbency. She became asymptomatic after mediastinal repositioning. A. Posteroanterior radiograph demonstrating marked overexpansion of right lung with mediastinal shift. Right tracheobronchial tree appears narrowed. B. Computed tomography scan confirming severe compression of right bronchus intermedius against the spine. C. Posteroanterior radiograph early after mediastinal repositioning with 1000 mL of saline implants. D. Computed tomography scan at level of bronchus intermedius after mediastinal repositioning demonstrating relief of bronchial compression.

SUGGESTED READING Abolnik I, Losser IS, Brewer R: Spontaneous pneumomediastinum: A report of 25 cases. Chest 100:93–95, 1991. Bush LM, Abrams BH, Beall A, et al: Index case of fatal inhalational anthrax due to bioterrorism in the United States. N Engl J Med 345:1607–1610, 2001.

Cole FH Jr, Cole FH, Duckworth HK: Mediastinal emphysema secondary to dental restoration. Ann Thorac Surg 52:139– 140, 1991. Dines DE, Payne WS, Bernatz PE, et al: Mediastinal granuloma and fibrosing mediastinitis. Chest 75:320–324, 1979. Dixon TC, Meselson M, Guillemin J, et al: Medical progress— anthrax. N Engl J Med 341:815–825, 1999.

1569 Chapter 89

Goenka MK, Gupta NM, Kochhar R, et al: Mediastinal fibrosis: An unusual cause of esophageal stricture. J Clin Gastroentrol 20:331–333, 1995. Grillo HC, Shepard JO, Mathisen DJ, et al: Postpneumonectomy syndrome: Diagnosis, management and results. Ann Thorac Surg 54:638–651, 1992. Hamman L: Spontaneous mediastinal emphysema. Bull Johns Hopkins Hosp 64:1–21, 1939. Jones WG, Ginsberg RJ: Esophageal perforation: A continuing challenge. Ann Thorac Surg 53:534–543, 1992. LoCicero J: Median sternotomy and thoracotomy, in Shields TW (ed): Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, p 95. Logerstrom CF, Mitchell HG, Graham BS, et al: Chronic fibrosing mediastinitis and superior vena caval obstruction from blastomycosis. Ann Thorac Surg 54:764–765, 1992. Macklin MT, Macklin CC: Malignant interstitial emphysema of the lungs and mediastinum as an important occult complication in many respiratory diseases and other conditions: An interpretation of the clinical literature in the light of laboratory experiment. Medicine 23:281–358, 1944. Mathisen DJ, Grillo HC: Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg 54:1053– 1058, 1992. Maunder RJ, Pierson DJ, Hudson LD: Subcutaneous and mediastinal emphysema. Arch Intern Med 144:1447–1453, 1984. Mole TM, Glover J, Shepard MN: Sclerosing mediastinitis: A report on 18 cases. Thorax 50:280–283, 1995.

Nonneoplastic Disorders of the Mediastinum

Molina JE: Primary closure for infected dehiscence of the sternum. Ann Thorac Surg 55:459–463, 1993. Naruke T, Suemasu K, Ishikawa S: Lymph node mapping and curability at various levels of metastasis in resected lung cancer. J Thorac Cardiovasc Surg 76:832–839, 1978. Pierson DJ: Pneumomediastinum, in Murray JF, Nadal JA (eds): Textbook of Respiratory Medicine. Philadelphia, Saunders, 1994, p 2251. Ralph-Edwards C, Pearson FG: Atypical presentation of spontaneous pneumomediastinum. Ann Thorac Surg 58:1758– 1760, 1994. Shields TW: The mediastinum and its compartments, in Shields TW (ed): Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, p 4. Swartz MN: Recognition and management of anthrax-An update. N Engl J Med 345:1621–1626, 2001. Urschel HC, Razzuk MA, Netto GJ, et al: Sclerosing mediastinitis: Improved management with histoplasmosis titer and ketoconazole. Ann Thorac Surg 50:215–221, 1990. Wells WJ, Fox AH, Theodore PR, et al: Aspergillosis of the posterior mediastinum. Ann Thorac Surg 57:1240–1243, 1994. Wheatley MJ, Stirling MC, Kirsh MM, et al: Descending necrotizing mediastinitis: Transcervical drainage is not enough. Ann Thorac Surg 49:780–784, 1990. Wright CD, Mathisen DJ, Wain JL, et al: Reinforced primary repair of thoracic esophageal perforation. Ann Thorac Surg 60:245–249, 1995.

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90 Congenital Cysts of the Mediastinum: Bronchopulmonary Foregut Anomalies Neel R. Sodha

Malcolm M. DeCamp, Jr.

I. ANATOMY II. EPIDEMIOLOGY III. BRONCHOGENIC CYSTS Embryology and Terminology Presentation and Diagnosis Therapy IV. ENTEROGENOUS CYSTS Embryology and Terminology Presentation and Diagnosis Therapy

Mediastinal masses represent a diverse collection of tumors arising from, and associated with, each of the organs found within the thorax. Cystic lesions account for up to 25 percent of reported mediastinal masses. These cysts may be congenital or acquired or may represent cystic degeneration of a previously solid tumor. In this chapter, we focus on congenital cystic lesions within the mediastinum, specifically addressing bronchopulmonary anomalies arising from the foregut. We briefly consider simple cysts arising from or associated with the thymus, pericardium, and thoracic duct. Many other solid mediastinal neoplasms (dermoids, teratomas, thymomas, parathyroid adenomas, and thyroid goiters) may present with cystic components. These lesions are discussed in other chapters.

ANATOMY Cysts arise in each of the three distinct anatomic regions of the mediastinum (see Chapter 30).

V. NEURENTERIC CYSTS Embryology and Terminology Presentation and Diagnosis Therapy VI. THYMIC CYSTS VII. PERICARDIAL CYSTS VIII. THORACIC DUCT CYSTS

The anterosuperior compartment extends from the manubrium and the first rib inferiorly to the diaphragm. The anterior border of this region is the posterior sternal table, and the posterior margin includes the pericardium and innominate vein. Endocrine lesions, such as thyroid goiters and cystic adenomas of the parathyroid gland, as well as thymic cysts, are found in this compartment. The middle mediastinum is the site of origin of most bronchopulmonary foregut cysts. The boundaries of the middle mediastinum include the pericardial reflections superiorly and anteriorly and the diaphragm inferiorly. The posterior margin of the middle mediastinum is the anterior border of the spine. Pericardial cysts, as well as bronchogenic cysts, are found in this region. The posterior mediastinum extends from the superior aspect of the first thoracic vertebral body inferiorly to the diaphragm. Its anterior border is the ventral aspect of the vertebral bodies, and it extends posteriorly to the articulation of the vertebral transverse process with each rib. The posterior mediastinum includes both costovertebral sulci and segmental nerve roots as well as the sympathetic chain. The structures

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found within the posterior compartment include the esophagus, both vagus nerves, the thoracic duct and azygous vein, as well as the descending aorta. Neurenteric cysts, thoracic duct cysts, as well as some esophageal duplication cysts are found in this area. Lesions that arise primarily within the mediastinum may extend above the chest into the neck or below the diaphragm into the retroperitoneum, where they present as extrathoracic mass lesions.

EPIDEMIOLOGY In reported series of mediastinal masses, the prevalence of primary cysts ranges from 10 to 25 percent and has remained steady for the past 6 decades (Table 90-1) with relatively similar incidences in males and females. Some minor heterogeneity over this time span is accounted for by variations in the ages of patients reported in each series. For example, the relatively low 9 percent incidence of cysts in one series from the 1970s reflects a predominance of adults in this series.

Table 90-1 Prevalence of Primary Cysts in Reported Series of Mediastinal Tumors over the Past 60 years Mediastinal Cysts (%)

Reference

101

Sabiston & Scott∗

1963

Heimberger et al.†

1972

209

1987

400

Davis et al.§

1993

257

Azarow et al.#

1999

124

Whooley et al.¶

2003

806

Takeda et al.¶¶

Year

1952

∗ Sabiston

Benjamin et al.‡

DC Jr, Scott HW Jr: Primary neoplasms and cysts of the mediastinum. Ann Surg 136:777–797, 1952. † Heimberger I, Battersby JS, Vellios F: Primary neoplasms of the mediastinum: A fifteen-year experience. Arch Surg 86:978–984, 1963. ‡ Benjamin SP, McCormack LJ, Effler DB, et al.: Primary lymphatic tumors of the mediastinum. Cancer 30:708–712, 1972. § Davis RD Jr, Oldham HN Jr, Sabiston DC Jr: Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentaion, methods of diagnosis, management and results. Ann Thorac Surg 44:229–237, 1987. # Azarow KS, Pearl RH, Zurcher R, et al.: Primary mediastinal masses: A comparison of adult and pediatric populations. J Thorac Cardiovasc Surg 106:67–72, 1993. ¶ Whooley BP, Urschel JD, Antkowiak JG, et al. Primary tumors of the mediastinum. J Surg Oncol 70:95–99, 1999 ¶¶ Takeda S, Miyoshi S, Minami M, et al. Clinical spectrum of mediastinal cysts. Chest 124:125–132, 2003.

Table 90-2 Origin of Mediastinal Cysts Cyst Type

All Ages (n = 419)

Pediatric Only (n = 70)

Bronchogenic

36%

53%

Enteric

12%

35%

Pericardial

29%

Other

23%

11%

Fontenelle LJ, Armstrong RG, Stanford W, et al.: The asymptomatic mediastinal mass. Arch Surg. 102:98–102, 1971. Haller JA Jr., Mazur DO, Morgan WW Jr.: Diagnosis and management of mediastinal masses in children. J Thorac Cardiovasc Surg. 58:385–393, 1969. Heimburger IL, Battersby JS: Primary mediastinal tumors of childhood. J Thorac Cardiovasc Surg. 50:92–103, 1965. Massie RJ, Van Asperen PP, Mellis CM. A review of open biopsy for mediastinal masses. J Paediatr Child Health. 33:230–233, 1997. Pokorny WJ, Sherman JO. Mediastinal masses in infants and children. J Thorac Cardiovasc Surg. 68:869–875, 1974. Takeda S, Miyoshi S, Minami M, et al.: Clinical spectrum of mediastinal cysts. Chest. 124:125–132, 2003. Whittaker LD Jr., Lynn HB: Mediastinal tumors and cysts in the pediatric patient. Surg Clin North Am. 53:893–904, 1973. Whooley BP, Urschel JD, Antkowiak JG, et al.: Primary tumors of the mediastinum. J Surg Oncol. 70:95–99, 1999. Zambudio AR, Lanzas JT, Calvo MJ, et al.: Non-neoplastic mediastinal cysts. Eur J Cardiothorac Surg. 22:712–716, 2002.

The etiology and distribution of cystic mediastinal masses are different in children and adults. Cysts of foregut origin account for only half of the lesions found in adults, whereas they constitute nearly 90 percent of cystic lesions reported in pediatric series (Table 90-2). Conversely, pericardial cysts account for up to one-third of all cystic lesions in adults, whereas true pericardial cysts are exceedingly rare in children. Among congenital lesions of the foregut and tracheobronchial tree seen in children—including pulmonary sequestrations, congenital lobar emphysema, cystic adenomatoid malformations, arteriovenous malformations, and bronchial atresias—simple foregut cysts (bronchogenic, enterogenous, and neurenteric) compose between 13 and 29 percent of reported cases. Although the relative frequencies of cystic and solid mediastinal masses have remained fairly constant, the advent of cross-sectional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), has increased the detection of all mediastinal lesions.

BRONCHOGENIC CYSTS Embryology and Terminology The primitive foregut gives rise to a variety of aerodigestive organs and tissues, beginning with the pharynx and

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subsequently giving rise to the larynx, upper and lower respiratory tracts, esophagus, stomach, proximal duodenum, liver, pancreas, and associated ducts (see Chapter 5). Cystic malformations of foregut origin may have a variety of epithelial linings that reflect the embryological tissues from which they are derived. The lung bud develops caudally from the laryngotracheal tube, beginning in the fourth week of gestation. By the fifth week, the single bud has divided into right and left main bronchi, which grow into the surrounding splanchnic mesenchyme and are destined to become bronchial cartilage and smooth muscle as well as visceral pleura. Dichotomous branching of the primitive bronchi continues until about the 24th week, when the terminal bronchioles begin to give rise to primitive alveoli. Throughout this period of embryogenesis, abnormal bronchi and bronchioles may form larger saccular structures, which are clinically recognized as bronchogenic cysts. Such saccular malformations may be invested by their own splanchnic mesenchyme (neopleura). Usually abutting on the trachea, carina, or hilum, they are termed mediastinal bronchogenic cysts (Figs. 90-1 and 90-2). Less frequently, these lesions are contained within the pulmonary parenchyma. Rarely do they maintain communication with the respiratory tract. Malformations within the lung are termed intrapulmonary bronchogenic cysts (Fig. 90-3). Some investigators believe that mediastinal bronchogenic cysts arise early in the cycle of bronchial branching, whereas intrapulmonary bronchogenic cysts represent derangements later in fetal development. Because they uniformly arise before alveoli form (at 28

Figure 90-1 A. Posteroanterior radiograph of a smooth-walled paratracheal bronchogenic cyst. B. Computed tomogram of the same paratracheal bronchogenic cyst. Note that the cyst contents are somewhat heterogeneous but generally of lower density than the surrounding mediastinal structures.

weeks), bronchogenic cysts have no gas exchange potential even if their bronchial communications persist.

Presentation and Diagnosis Most patients with bronchogenic cysts have symptoms at the time of diagnosis (Table 90-3). The pediatric population is predisposed to symptomatic cysts secondary to the smaller size of their thorax and more malleable airway. Eraklis and colleagues noted life-threatening respiratory compromise in 70 percent of infants with foregut cysts. Mass effects from the cysts, which caused compression, â&#x20AC;&#x153;ball valving,â&#x20AC;? or differential ventilation, were the predominant causes of distress. These neonates were often cyanotic, with wheezing or stridor, and their radiographs demonstrated inhomogeneous aeration, lobar collapse, and/or mediastinal shift. In a series of nonneonatal children, up to 95 percent had symptoms. Especially in the older children, signs and symptoms of infection led the list of problems. In adults, symptomatic bronchogenic cysts are less common. In the 1950s, a report of a large series indicated that symptoms were present in about one-third of patients. Most of the complaints were due to pain, cough, and dyspnea. More recent series have varied with 75 to 95 percent of patients without symptoms when the lesions were detected. Many patients who are followed without treatment develop subtle, local symptoms and/or signs of secondary infection. Symptoms of chronic infection such as fever and weight loss in the setting of a mediastinal mass on plain films can initially lead to the initial misdiagnosis of lymphoma.

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Figure 90-2 A. Posteroanterior radiograph of a smooth-walled subcarinal bronchogenic cyst. Note that the cyst is distinct from the right heart border (arrows). B. Contrast-enhanced axial CT image of the homogenous, subcarinal bronchogenic cyst. This patient presented with atrial dysrhythmia attributed to left atrial (LA) compression by the cyst. (From DeCamp MM Jr, Swanson SJ, Sugarbaker DJ: The mediastinum, in Baue AE, Geha AS, Hammond GL, et al (eds), Glenn’s Thoracic and Cardiovascular Surgery, 6th ed. Stamford, CT, Appleton & Lange, 1996, pp 643–663.)

Figure 90-3 A. Nonenhanced CT image of an asymptomatic bronchogenic cyst (BC). B. Nonenhanced CT image of the same cyst after 6 months of expectant management. The cyst has ‘‘cavitated” (arrows) indicative of secondary infection. C. Axial CT image with ‘‘lung windows” of the infected, intraparenchymal bronchogenic cyst. Note the associated right lower lobe pneumonitis surrounding the cyst, not appreciated by the ‘‘mediastinal” window in image B.

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Table 90-3 Clinical Characteristics in Cysts in the Mediastinum (Symptoms and Signs)∗ Characteristics

Bronchogenic, n = 47

Esophageal, n=4

Thymic, n = 30

Pericardial, n = 12

Pleural, n=7

Others, n=5

Total, n = 105

Asymptomatic Chest pain Dyspnea Cough Fever Hoarseness Sputum Dysphagia Cyanosis Hemoptysis Others

28 6 3 5 5 1 3 1 0 1 1

3 0 1 0 0 0 0 1 0 0 0

18 6 3 2 1 4 0 1 0 0 1

10 2 0 0 0 0 0 0 0 0 0

6 0 1 0 0 0 0 0 1 0 0

2 1† 0 0 0 0 0 0 0 0 2‡

67 (63.8) 15 (14.3) 8 (7.6) 7 (6.7) 6 (5.7) 5 (4.8) 3 (2.9) 3 (2.9) 1 1 4

∗ Data

are presented as No. or No. (%). pain associated with thoracic duct cyst. ‡ Neurofibromatosis associated with meningocele. Reproduced with permission from Takeda S, Miyoshi S, Minami M, et al. Clinical spectrum of mediastinal cysts. Chest 124:125–132, 2003. † Chest

The presence of a bronchogenic cyst is suggested by plain chest radiographs in up to two-thirds of cases in any age group. The usual appearance is that of a 2- to 10-cm ovoid, smooth, homogeneous mass that abuts on the mediastinum or hilum or splays the carina. An air-fluid level connotes either persistent bronchial communication or secondary infection of the cyst (Fig. 90-3). As mentioned, some cysts (especially in infants) may exert a mass effect, causing airway compression, parenchymal atelectasis, or cardiovascular compression (Fig. 90-2B). In 60 to 65 percent of patients, posteroanterior and lateral plain chest radiographs make it possible to diagnose these lesions and document their precise location. Ultrasonography has been helpful in confirming the cystic nature of mediastinal lesions in infants and children. Prenatal diagnosis is also feasible. Such forewarning allows for the expeditious management of these infants antenataly or at the time of delivery, when most quickly develop symptoms after the lungs are inflated. In the adult, because air within the large lungs is a poor conductor of sound, surface ultrasonography has little to offer in the acoustic visualization of suspected bronchogenic cysts. Cross-sectional imaging techniques, using either CT or MRI, have become the diagnostic procedures of choice for investigating mediastinal masses. These methods provide helpful details of cyst structure, including the density and type of cyst fluid, amount of calcium in the cyst wall, vascularity of the cyst, and the relationships of the cyst to adjacent mediastinal structures. MRI and CT are probably equally useful in the diagnosis of mediastinal-based cysts. CT is superior for the examination of intrapulmonary cysts because of its ability to delineate more sharply the cystic lesion from the surrounding air-filled parenchyma (Figs. 90-1 to 90-3). Characteristic findings on CT include the presence of a smooth, rounded mass with uniform attenuation and an indiscernible wall,

while T2-weighted MR images will demonstrate high signal intensity.

Therapy Bronchogenic cysts are the most commonly treated mediastinal foregut anomaly. They accounted for 60 percent of all mediastinal lesions reported by the Mayo Clinic over a 40-year period. The treatment options for bronchogenic cysts include observation, resection, and aspiration. One option for asymptomatic simple cystic lesions is continued observation (see below). All symptomatic lesions should be removed. Traditionally, a thoracotomy was necessary. Videothoracoscopy is being used with increasing frequency to resect mediastinal cysts with excellent results, low conversion rates to open procedure, and no significant increases in recurrence rates. Urschel and Horan have described piecemeal resection of a mediastinal bronchogenic cyst using a Carlens mediastinoscope introduced through a small suprasternal incision. Treatment of asymptomatic cysts remains controversial. Some surgeons feel the benign nature and unknown natural history of asymptomatic simple cysts, combined with the availability of excellent imaging for observation obviates the need for mandatory surgical intervention. Conversely, two large clinics advocate resection for even asymptomatic lesions. They report a trend in time for asymptomatic patients to develop symptoms. Both reports document a higher incidence of perioperative complications when symptomatic lesions were resected, implying that waiting for symptoms to develop before resection places patients at increased operative risk. Whatever the operative approach, the goal of surgery should be complete excision of all elements of the cyst. Occasional case reports of malignancy arising from the cyst mucosa

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support the general concept of complete resection for any bronchogenic cyst. Partial resection of a bronchogenic cyst may occasionally be necessary if the cyst is found to be adherent to and inseparable from the membranous airway, main pulmonary vessels, or aorta. When subtotal excision is necessary, symptomatic recurrences requiring re-excision have been reported. Aspiration of a cyst to confirm a benign diagnosis and instill a sclerosing agent (ethanol or bleomycin) has been used to manage some cysts. The advent of endobronchial ultrasonography with transbronchial intervention has resulted in an even less invasive management option. Reports of longterm follow-up for this approach to both the diagnosis and therapy of bronchogenic cysts are scant. However, it may represent a useful form of therapy for inoperable patients.

ENTEROGENOUS CYSTS Embryology and Terminology Enterogenous cysts are also termed esophageal duplications. They arise from the elongating esophagus, which separates from the respiratory tract in about the fifth week of gestation (see Chapter 5). As with most intestinal duplications, enterogenous cysts represent failure of normal recanalization during embryogenesis. Most esophageal duplications are of the closed and cystic type. Rarely are they tubular, and communication is preserved with the alimentary tract.

Presentation and Diagnosis Nearly 75 percent of esophageal duplication cysts are recognized in childhood. For unclear reasons, there is a two-to-one predilection for cysts to be on the right side. Symptoms commonly include cough and dyspnea and occasionally stridor. These are clearly related to a mass effect by the cyst on the nearby respiratory tract. Dysphagia is surprisingly infrequent. In asymptomatic patients, the most common clue leading to this diagnosis is the coexistence of other gastrointestinal duplication(s). Unlike bronchogenic cysts, which are always lined with respiratory mucosa, enterogenous cysts may have a variety of epithelial linings, including the squamous epithelium native to the esophagus, or rarely aberrant pancreatic tissue. However, most esophageal duplications have a glandular epithelium with a subset that contains gastric mucosa containing parietal cells capable of acid secretion. The finding of an acid-secreting mucosa in 60 percent of patients with enterogenous cysts lends credence to other case reports of cyst hemorrhage and rupture. Esophageal duplications usually present radiographically as smooth-walled, posterior mediastinal lesions at the base of the right hemithorax (Fig. 90-4 A). A barium swallow demonstrates deviation of the lumen around the cyst, but rarely shows communication with it (Fig. 90-4B). Proximal esophageal dilatation is not common because the cysts usually are not obstructive. In patients with suspected dupli-

cation, a technetium pertechnetate nuclear scan may suggest the presence of ectopic gastric mucosa within the chest. Crosssectional imaging (CT or MRI) is almost routinely employed to characterize the contents of a cyst and to define the relationship of the cyst to contiguous structures (Fig. 90-4C ). The characteristic CT and MR findings are identical to those of bronchogenic cysts, except the wall may be thicker and in closer contact with the esophagus. Endoesophageal ultrasound has provided a useful, minimally invasive tool to investigate these lesions and allow sampling of cyst contents to confirm that the lesion, in an otherwise asymptomatic patient, is benign.

Therapy As in the case of bronchogenic cysts, esophageal duplications are likely to become infected in time. The common occurrence of gastric mucosa within the enterogenous cyst predisposes to spontaneous hemorrhage and/or ulceration. Because of existing symptoms or the natural history of the cyst to become symptomatic, resection is recommended for all enterogenous cysts. Such lesions can be approached through a standard thoracotomy or, at experienced centers, with the videothoracoscope. Despite the lack of communication with the esophageal lumen, cyst resection may leave defects in the esophageal wall that must be meticulously repaired. The esophagus should be closed primarily in layers, and the repair should be reinforced with a locally procured flap of vascularized tissue. Options for buttressing, such as esophageal repair, include the pericardial fat pad, pleura, intercostal muscle, the pericardium itself, or omentum. A case report documenting the occurrence of an adenocarcinoma in an esophageal duplication, which was carefully followed for a long time, underscores the need for resection of these lesions at the time of diagnosis.

NEURENTERIC CYSTS Embryology and Terminology During the third week of normal embryogenesis, the notochord should separate from the primitive foregut (see Chapter 5). If this separation is incomplete, the mesodermal masses, which normally encircle the neural tube, cannot enclose it and vertebral anomalies arise. The attached foregut often spawns an associated mediastinal enteric cyst. The bony abnormalities may include butterfly vertebrae, hemivertebrae, and anterior spina bifida. When enterogenous cysts are found associated or contiguous with vertebral anomalies, the cyst is considered neurenteric.

Presentation and Diagnosis Neurenteric cysts are exceedingly rare. Virtually all present in childhood. More than half of afflicted children have CNS complaints or findings. These include back pain, motor deficits of a lower extremity, and gait disturbance, especially

1577 Chapter 90

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if there is communication with the spinal canal. Often the triad of a mediastinal mass, airway symptoms, and a vertebral anomaly is present. The diagnosis is usually made after detection of vertebral anomalies on the chest radiograph. CT can define the specifics of bony abnormalities and demonstrate extension of the cystic lesion into the spinal canal. This

Figure 90-4 A. Frontal radiograph demonstrating smooth-walled posterior mediastinal mass consistent with an enterogenous cyst. The lesion is easily separable from the right heart border (arrows). B. Barium esophogram of the same patient demonstrating deviation of the true esophageal lumen around the smooth extramucosal lesion, found at resection to be an enterogenous cyst (esophageal duplication). C. Oral and intravenous contrast-enhanced CT image of the enterogenous cyst. The lesion is radiographically inseparable from the esophagus but free of all cardiac structures.

study must often be combined with the injection of intrathecal contrast in order to obtain a CT myelogram. MRI has recently supplanted CT myelography. Because of its ability to image in the axial, coronal, and sagittal planes and the availability of gadolinium as an enhancing agent, MRI provides a complete, noninvasive assessment of the bony abnormality,

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the intraspinal extent of the cyst, and the degree of spinal cord or nerve root compression associated with a neurenteric cyst. Any suspected neurenteric cyst warrants an MRI evaluation of both the thoracic spine and posterior mediastinum.

to grow throughout childhood into adolescence. Cysts within the gland are thought to occur during adulthood, when gland architecture involutes and central cells degenerate and are replaced by fat. Thymic cysts are rare congenital or acquired lesions embryologically derived from the pharyngeal pouches. Although thymic cysts are benign, they must be distinguished from thymomas, germ cell tumors, and lymphomas—all of which may have areas of cystic degeneration. These cysts arise in the anterior mediastinum (Fig. 90-5) and may extend to the middle mediastinal compartment, especially in the aortopulmonary window (Fig. 90-6). Plain radiographs do not differentiate thymic cysts from other nonlobulated thymic masses, therefore CT and MRI are employed for diagnosis. Both CT and MRI demonstrate clear tissue plains separating the cyst from other vital structures (Figs. 90-5 and 90-6). In older people, benign cysts may degenerate and present as a complex, thickened cystic mass with calcified walls that contain heterogeneous fluid (Fig. 90-5). Such lesions are easily confused with a mediastinal teratoma. Excision using an open or video-assisted technique excludes other, more worrisome histologies and is curative.

Therapy This form of congenital cyst accounts for only 5 to 10 percent of all foregut lesions. These cysts are consistently associated with some bony anomaly of the spine. The spectrum of vertebral anomalies extends from fused vertebrae to include butterfly or hemivertebrae. The vertebral abnormality is usually cephalad to the cystic lesion, since the esophagus descends (or the pharynx ascends) during fetal development. Careful imaging of suspected neurenteric cysts is paramount for successful extirpation. MRI is useful to exclude extension of the cystic component into a neural foramen or the spinal canal proper and to exclude an associated meningocele. Such findings would require a staged resection employing a posterior neurosurgical approach first, to decompress the cord or its nerve roots, followed by resection of the mediastinal component by standard thoracotomy or video-assisted technique.

THYMIC CYSTS

PERICARDIAL CYSTS

The thymus is derived from the third pharyngeal pouch. Its development is incomplete at birth, and the gland continues

Pericardial cysts are exceedingly rare in children, suggesting that they may be acquired. However, their common position

Figure 90-5 A. Frontal radiograph of an anterior mediastinal mass inseparable from the right heart border. B. Axial CT image of this mass demonstrates its thick, focally calcified (arrows) wall containing homogenous nonenhancing fluid. At resection what was feared to be a teratoma was found to be a thymic cyst. (From DeCamp MM Jr, Swanson SJ, Sugarbaker DJ: The mediastinum, in Baue AE, Geha AS, Hammond GL, et al. (eds), Glenn’s Thoracic and Cardiovascular Surgery, 6th ed. Stamford, CT, Appleton & Lange, 1966, pp 643–663.)

1579 Chapter 90

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A B

at or near the cardiophrenic angles suggests a possible embryological defect, whereby fusion of the pleuropericardial membranes and the septum transversum of the developing diaphragm is incomplete. Pericardial cysts are simple, smooth-walled cystic lesions (Fig. 90-7) that are commonly located at the lateral basal edge of the pericardium, where it fuses with the diaphragm. They can be mistaken for foramen of Morgagni hernias or prominent pericardial fat pads. They can be differentiated from more solid mediastinal tumors by CT scanning with a computer analysis of the radiographic density of cyst fluid. Pericardial cysts characteristically contain clear, low-density serous fluid; hence their synonym, â&#x20AC;&#x153;spring water cysts.â&#x20AC;? They have no malignant potential and, after aspiration has confirmed the diagnosis, can be followed clinically. Resection should be reserved for cysts that cause symptoms (hemodynamic compromise, arrhythmia, atelectasis) or for change in

Figure 90-6 Equivalent axial-enhanced CT (A) and axial MRI (B) images of an aortopulmonary window mass that appears to compress if not invade the left pulmonary artery (LPA). Coronal MR image (C) of the same lesion demonstrating an intact tissue plane separating the benign thymic cyst (TC) from the pulmonary artery (PA).

radiographic appearance over time. The operative approach, whether endoscopic or open is dependent upon the location, size, and proximity of the cyst to vital structures. Because a cyst often overlies a phrenic nerve, an unroofing procedure or subtotal resection is acceptable therapy if total excision would jeopardize diaphragmatic function. Rarely do pericardial cysts erode into vital structures. Such cases suggest secondary infection of the cyst and may require circulatory support for safe extirpation.

THORACIC DUCT CYSTS Lymphatic channels develop from the lateral plate mesoderm, either as outgrowths of the venous system or by the fusion of mesenchymal clefts into vessels. The lymphatic sacs that

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Figure 90-7 Frontal radiograph of a mediastinal mass, isodense with and inseparable from the right heart border. Thoracoscopy showed this to be a broadly based pericardial cyst (PC).

develop by the second month of gestation, are connected by these primitive lymphatic channels. It is these channels that unite the jugular lymph sacs to the cisterna chyli, which form the thoracic duct. A congenital weakening of the thoracic duct wall is postulated to be responsible for some thoracic duct cysts. Their incidence is exceedingly rare (fewer than 40 cases reported) and histologically they are similar to the thoracic duct with the presence of occasional endothelial cells lining the cyst, occurring anywhere along the course of the duct. Symptoms arise from compression of adjacent structures resulting in dyspnea, cough, or dysphagia. Plain films may demonstrate a posterior mediastinal mass, with CT demonstrating a smooth, homogenous cystic mass (Fig. 908). MRI is superior to CT for evaluation, allowing for superior delineation of the cyst boundaries (Fig. 90-9). Confirmatory

Figure 90-9 MRI scan. Top: coronal T1-weighted imaging showing a low-intensity mass with a well-circumscribed margin (arrow). Bottom: coronal T2-weighted imaging showed a highintensity mass (arrow). (From Chen F, Bando T, Hanaoka N, et al.: Mediastinal thoracic duct cyst. Chest 115:584–584, 1999.)

diagnosis may be made using lymphangiography or the presence of high triglyceride content in cyst aspiration fluid, but these techniques are not commonly employed. Small cysts are generally followed, whereas symptomatic and larger cysts are excised with care taken to ligate all communication with the thoracic duct to avoid postoperative chylothorax.

SUGGESTED READING

Figure 90-8 Axial contrast-enhanced CT scan of the chest revealed a large cystic mass measuring 3 × 5 × 15 cm (arrow) in the posterior mediastinum, displacing the esophagus and trachea anteriorly. (From Chen F, Bando T, Hanaoka N, et al.: Mediastinal thoracic duct cyst. Chest 115:584–584, 1999.)

Allen MS, Payne WS: Cystic foregut malformation in the mediastinum. Chest Surg Clin North Am 2:89–106, 1992. Azarow KS, Pearl RH, Zurcher R, et al.: Primary mediastinal masses: A comparison of adult and pediatric populations. J Thorac Cardiovasc Surg 106:67–72, 1993. Bailey PV, Tracy T Jr, Connors RH, et al.: Congenital bronchopulmonary malformations: Diagnostic and therapeutic considerations. J Thorac Cardiovasc Surg 99:597–602, 1990. Benjamin SP, McCormack LJ, Effer DB, et al.: Primary tumors of the mediastinum. Chest 62:297–303, 1972.

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Bogers AJ, Hazebroek FW, Molenaar J, et al.: Surgical treatment of congenital bronchopulmonary disease in children. Eur J Cardiothorac Surg 7:117–120, 1993. Bolton JW, Shahian DM: Asymptomatic bronchogenic cysts: What is the best management? Ann Thorac Surg 53:1134– 1137, 1992. Bower RJ, Kiesewetter WB: Mediastinal masses in infants and children. Arch Surg 112:1003–1009, 1977. Coran AG, Drongowski R: Congenital cystic disease of the tracheobronchial tree in infants and children: Experience with 44 consecutive cases. Arch Surg 129:521–527, 1994. Davis RD Jr, Oldham HN Jr, Sabiston DC Jr: Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 44:229–237, 1987. Hazelrigg SR, Landreneau RJ, Mack MJ, et al.: Thoracoscopic resection of mediastinal cysts. Ann Thorac Surg 56:659– 660, 1993. Heithoff KB, Sane SM, Williams HJ, et al.: Bronchopulmonary foregut malformations: A unifying etiological concept. Am J Roentgenol 126:46–55, 1976. Jeung MY, Gasser B, Gangi A, et al.: Imaging of cystic masses of the mediastinum. Radiographics 22 Spec No:S79–93, 2002. Karajiannis A, Krueger T, Stauffer E, et al.: Large thoracic duct cyst: A case report and review of the literature. Eur J Cardiothorac Surg 17(6):754–756, 2000. Ochsner JL, Ochsner SFL Congenital cysts of the mediastinum: 20-year experience with 42 cases. Ann Surg 163: 909–920, 1966.

Congenital Cysts of the Mediastinum

Oldham HN Jr, Sabiston DC Jr: Primary tumors and cysts of the mediastinum. Monogr Surg Sci 4:243–279, 1967. Patel SR, Meeker DP, Biscotti CV, et al.: Presentation and management of bronchogenic cysts in the adult. Chest 106:79– 85, 1994. Ponn RB. Simple mediastinal cysts: resect them all? Chest 124:4–6, 2003. Ribet ME, Copin MC, Gosselin B: Bronchogenic cysts of the mediastinum. J Thorac Cardiovasc Surg 109:1003–1010, 1995. St. Georges R, Deslauriers J, Duranceau A: Clinical spectrum of bronchogenic cysts of the mediastinum and lung in the adult. Ann Thorac Surg 52:6–13, 1991. Strollo DC, Rosado de Christenson ML, Jett JR: Primary mediastinal tumors. Part 1: tumors of the anterior mediastinum. Chest 112:511–522, 1997. Strollo DC, Rosado-de-Christenson ML, Jett JR: Primary mediastinal tumors: Part II. Tumors of the middle and posterior mediastinum. Chest 112:1344–1357, 1997. Suen HC, Mathisen DJ, Grillo HC, et al.: Surgical management and radiological characteristics of bronchogenic cysts. Ann Thorac Surg 55:476–481, 1993. Takeda S, Miyoshi S, Minami M, et al.: Clinical spectrum of mediastinal cysts. Chest 124:125–132, 2003. Weber T, Roth TC, Beshay M, et al.: Video-assisted thoracoscopic surgery of mediastinal bronchogenic cysts in adults: a single-center experience. Ann Thorac Surg 78:987–991, 2004. Whooley BP, Urschel JD, Antkowiak JG, et al.: Primary tumors of the mediastinum. J Surg Oncol 70:95–99, 1999.

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91 Acquired Lesions of the Mediastinum: Benign and Malignant John R. Roberts Larry R. Kaiser

I. SUPERIOR VENA CAVA SYNDROME II. HISTORY III. MEDIASTINAL COMPARTMENTS Anterosuperior Compartment Middle Compartment Posterior Compartment IV. EPIDEMIOLOGY AND INCIDENCE

Esophageal Lesions Pulmonary Lesions Subdiaphragmatic Lesions IX. ANTERIOR MEDIASTINAL NEOPLASMS Lesions of the Thymus Tumors of Lymph Nodes Germ Cell Tumors

VI. INVESTIGATION OF MEDIASTINAL MASSES Noninvasive Diagnostic Procedures Invasive Biopsy Procedures

X. MIDDLE MEDIASTINAL MASSES Bronchogenic Cysts Esophageal Cysts Neuroenteric Cysts Mesothelial Cysts

VII. MEDIASTINAL INFECTIONS Transsternal Esophageal Procedures Acute Descending Necrotizing Mediastinitis

XI. POSTERIOR MEDIASTINAL MASSES Neurogenic Tumors Tumors of Nerve Sheath Origin

VIII. LESIONS MASQUERADING AS MEDIASTINAL TUMORS Substernal Goiter Cystic Hygromas Lesions Originating from the Thoracic Skeleton Extramedullary Hematopoiesis Vascular Lesions

XII. ENDOCRINE TUMORS Mediastinal Pheochromocytoma Parathyroid Adenomas

V. SIGNS AND SYMPTOMS

SUPERIOR VENA CAVA SYNDROME Lesions that originate in the mediastinum are rare compared to the diverse lesions that can involve the mediastinum secondarily. Although neoplasms of the mediastinum are diverse, they have in common a single clinical manifestation: widenThis chapter has been slightly modified from the version that appeared in the third edition of Fishman’s Pulmonary Diseases and Disorders.

XIII. OTHER MEDIASTINAL TUMORS Mesenchymal Tumors Fatty Tumors XIV. SUPERIOR VENA CAVA SYNDROME

ing of the mediastinum on the chest radiograph taken in the upright position. This shared feature has not lent itself readily to differential diagnosis. In recent years, however, the advent of computed tomography (CT) and magnetic resonance imaging (MRI) has greatly enhanced the evaluation and subsequent treatment of these lesions. The mediastinum extends from the thoracic inlet to the diaphragm superoinferiorly and from pleural space to pleural space (Fig. 91-1). Contained within it are heart, aorta, brachiocephalic vein, esophagus, tracheobronchial tree, and

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Figure 91-1 Compartments of the mediastinum. A. Lateral radiograph of chest. B. Schematic representation of the contents of the three mediastinal compartments. C. Cross sections of the thorax at T4 (left) and T8 (right) to show relative positions of mediastinal structures. (Based on the data of Lyerly and Sabiston, Primary neoplasms and cysts of the mediastinum, in Fishman J (ed) Pulmonary Diseases and Disorders, 2d ed. New York, McGraw-Hill, 1988.)

elements of the autonomic nervous and lymphatic systems. Further, various endocrine organs may project into it, distant malignancies may metastasize to it, and infectious processes can manifest themselves within it. This chapter focuses on lesions that either originate in the mediastinum or represent disease processes of the mediastinum.

HISTORY The history of the diseases of the mediastinum derives mostly from the impact of study of three specific entitiesâ&#x20AC;&#x201D;substernal

goiters, ectopic parathyroid glands, and myasthenia gravis. Substernal extension of goiters into the mediastinum was first described in the middle of the eighteenth century. Billroth described resection of goiters in 1869. Kocher subsequently reported 1000 thyroidectomies and he described techniques for removing substernal goiters. Churchill first described recognition of ectopic mediastinal parathyroid glands, and Creswell and Wells subsequently reported a series of more than 6000 patients who underwent parathyroidectomy. Two percent of those patients required sternotomy for resection of a parathyroid gland in the mediastinum. Early knowledge of myasthenia gravis also developed largely from the work of German clinicians, who described

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the symptom triad of ptosis, dysarthria, and weakness in the late 1800s. Jolly unified these findings and coined the term myasthenia gravis pseudoparalytica in 1885. Laquer and Weigert connected the manifestations of myasthenia gravis to thymic disease in 1901. Not until 1974, however, were the autoimmune aspects of the disease clarified when Almon and colleagues described serum antibodies to the acetylcholine receptor. Blalock performed the first thymic resection via median sternotomy at Johns Hopkins Hospital in 1936. In 1944, Blalock reported a series of 20 patients who had undergone thymic resection and advocated thymectomy for patients with myasthenia gravis. This approach has an appreciable mortality, however, so a transcervical approach for patients with nonthymomatous myasthenia gravis is now preferred in some clinics.

MEDIASTINAL COMPARTMENTS The mediastinum has been variably described by different authors. As shown in Fig. 91-1, the simplest system divides the mediastinum into three compartments: anterosuperior, visceral (or middle), and paravertebral (or posterior).

Acquired Lesions of the Mediastinum

anterior aspect of the pericardium inferiorly and curves posteriorly to include the arch of the aorta and great vessels. Structures contained within it include the ascending aorta, superior vena cava, azygous vein, thymus gland, lymph nodes, fat, connective tissue, transverse aorta, and great vessels (Table 91-1). Common major lesions contained within the anterosuperior mediastinal compartment are thymomas, lymphomas, and germ cell tumors (Table 91-1; Fig. 91-2). Less common lesions are tumors of mesenchymal origin, vascular lesions, and displaced thyroid or parathyroid glands.

Middle Compartment The middle compartment is also called the visceral compartment (Fig. 91-1). The superior pericardial reflection defines the superior border, whereas the diaphragm defines the inferior border. The posterior border extends to the spine. Contained within this compartment are the heart and pericardium, trachea and major bronchi, pulmonary vessels, lymph nodes, fat, and connective tissue (Table 91-1). Lesions contained within the visceral compartment include cysts of the foregut, primary and secondary tumors of the lymph nodes, and, less commonly, pleural, pericardial, neuroenteric, and gastroenteric cysts (Table 91-1, Fig. 91-2).

Anterosuperior Compartment

Posterior Compartment

This compartment extends from the manubrium and the first ribs to the diaphragm. Its posterior border is defined by the

The posterior compartment is also called the paravertebral compartment. It extends from the superior aspect of the first

Table 91-1 Structures and Lesions in the Three Compartments of the Mediastinum Structures Anterosuperior compartment Ascending aorta Superior vena cava Azygous vein Thymus gland Lymph nodes Transverse and great vessels Connective tissue Middle compartment Heart and pericardium Trachea and bronchi Pulmonary vessels Connective tissue Posterior compartment Sympathetic chain Vagus nerves Esophagus Thoracic duct Lymph nodes Descending aorta

Common Lesions

Rare Lesions

Thymomas Lymphomas Germ cell tumors

Vascular lesions Mesenchymal tumors Endocrine tumors

Foregut cysts Lymphatic tumors

Pleural and pericardial cysts Neuroenteric and gastroenteric cysts

Tumars of neurogenic origin

Vascular tumors Mesenchymal tumors Lymphatic lesions

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Figure 91-2 Most common location of specific neoplasms and cysts within the subdivisions of the mediastinum.

thoracic vertebral body to the diaphragm anteriorly and then posteriorly to the posterior-most curvature of the ribs (Fig. 91-1). Contained within it are the sympathetic chain, vagus nerves, esophagus, thoracic duct, various lymph nodes, and the descending aorta. Lesions contained within it are primarily tumors of neurogenic origin. Less common is a potpourri of lesions, including vascular tumors, mesenchymal tumors, and lymphatic lesions (Table 91-1; Fig. 91-2).

EPIDEMIOLOGY AND INCIDENCE The mix of mediastinal lesions in adults has changed considerably during the past 5 decades: As may be seen in Table 91-2, significant changes have occurred in the proportions of thymoma and lymphoma, whereas the proportions of other lesions have remained relatively stable. Sabiston and Scott examined patients with 101 primary cysts and neoplasms of the mediastinum presenting at Johns Hopkins Hospital from July 1933 to July 1951. Heimberger and coworkers described 92 mediastinal lesions over a 15-year period. Benjamin and colleagues described a series of 209 patients in 1972, Davis and coworkers a series of 400 patients in 1986, Cohen and associates a series of 230 patients in 1991, and Azanowâ&#x20AC;&#x2122;s team a series of 257 patients in 1993. Results of the six series presented in Table 91-2 show a relative increase in the propor-

tion of lymphomas and relative stability in the proportion of neurogenic tumors, cysts, and thymomas. The reason for the increased incidence of lymphomas is unclear. Great differences exist between children and adults with respect to the location of mediastinal lesions. In adults, 65 percent of the lesions arise in the anterosuperior, 10 percent in the middle, and 25 percent in the posterior compartments. This distribution is reversed in children, in whom 28 percent of lesions arise in the anterosuperior, 10 percent in the middle, and 62 percent in the posterior compartments. In general, the incidence of posterior lesions is higher in children, whereas anterior lesions predominate in adults.

SIGNS AND SYMPTOMS Approximately half of all mediastinal lesions are asymptomatic and are detected on chest radiographs taken for unrelated reasons. The absence of symptoms suggests that a lesion is benign, whereas the presence of symptoms suggests malignancy. The percentage of patients with symptoms from mediastinal masses closely parallels, or equals, the percentage of malignant lesions (Table 91-2). In adults, 48 to 62 percent of lesions are symptomatic, whereas the percentage of symptomatic lesions is higher in childrenâ&#x20AC;&#x201D;58 to 78 percent. Since the incidence of symptoms parallels the incidence

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Table 91-2 Histology of Mediastinal Masses as Reported over Five Decades

Histology n

Sabiston and Scott (1952) 101

Heimberger et al. (1963) 92

Benjamin et al. (1972) 209

Davis (1987) 400

Cohen et al. (1991) 230

Frequency, % of Total Cysts

Neurogenic

Thymic

Lymphoma

Germ cell

Mesenchymal

Endocrine

Other

of malignancy, a child with a mediastinal mass is considerably more likely to have a malignancy than is an adult with a mediastinal mass. The most common symptoms are cardiorespiratory— in particular, chest pain and cough. Other manifestations are heaviness in the chest, dysphagia, dyspnea, hemoptysis, signs of superior vena caval obstruction with facial swelling, and cyanosis (Table 91-3). Recurrent respiratory infections are a common complaint. As is discussed in the following in greater detail, several mediastinal lesions are associated with other clinical syndromes—thymoma with myasthenia gravis, red-cell aplasia, hypogammaglobulinemia, and nonthymic cancers; Hodgkin’s disease with recurrent fevers; and von Recklinghausen’s disease with neurofibromas.

Table 91-3 Common Symptoms and Their Mechanisms in Patients with Mediastinal Lesions Symptom

Mechanism

Cough

Airway narrowing, compression

Chest pain

Chest wall invasion, neural invasion

Dyspnea

Airway compromise, pericardial tamponade, pleural effusions, pulmonary stenosis, congestive heart failure

Hemoptysis

Bronchogenic carcinoma, airway invasion, pulmonary stenosis, congestive heart failure

Dysphagia

Esophageal narrowing/obstruction, esophageal motor dysfunction

Hoarseness

Vocal cord paralysis

Facial swelling

Superior vena cava syndrome

INVESTIGATION OF MEDIASTINAL MASSES Mediastinal masses commonly present on routine chest radiographs obtained for other purposes. History and physical examination are occasionally useful in diagnosis, especially in patients with one of the rarer symptoms (e.g., hoarseness and Horner’s syndrome). The age of the patient can also narrow diagnostic possibilities. However, the chest radiograph remains the most important lead to diagnosis, followed by CT of the chest. The latter has revolutionized the diagnosis and evaluation of mediastinal masses and should be part of the routine workup of a mediastinal mass. In contrast to

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Figure 91-3 Mediastinal lipomatosis. A. PA radiograph of an 82-year-old woman with urinary incontinence and bladder infection. Chest radiograph shows a widened mediastinum with apparent pleural collection. B. Chest CT at level of aortic arch showing normal mediastinum except for diffuse fatty infiltration (arrow). C. Chest CT at the level of the heart demonstrating carC diomegaly and mediastinal fatty infiltration (arrow).

CT, standard tomography offers little beyond that afforded by chest radiographs and is rarely indicated.

Noninvasive Diagnostic Procedures Computed Tomography As noted, chest CT should be routine for all suspected or confirmed mediastinal masses. Although CT is poor with respect to distinguishing between cystic and solid structures, it provides excellent examination of the mediastinum. Indeed, the diagnosis of certain lesionsâ&#x20AC;&#x201D;such as aortic aneurysms, mediastinal lipomatosis, and pericardial fat padsâ&#x20AC;&#x201D;is so straightforward with CT that further search or biopsy is not necessary (Fig. 91-3). CT scanning is the most common technique used to obtain fine-needle aspiration (FNA) biopsies and provide information about invasion. Additionally, if biopsy or resection is indicated, CT can assist in the selection of the surgical approach (left chest, right chest, mediastinoscopy, or median sternotomy). Finally, chest CT may aid in the use of anesthesia. Magnetic Resonance Imaging MRI is superior to CT imaging in three specific circumstances: when preoperative determination of a tumorâ&#x20AC;&#x2122;s invasion of

vascular or neural structures is crucial, when coronal or radial body sections are necessary, and when contrast material cannot be given intravenously because of renal disease or known allergy to contrast (Fig. 91-4). Gadolinium can be used to provide additional vascular contrast with MRI but is generally unnecessary because the high inherent contrast between mediastinal masses and cardiovascular structures generally suffices to define those masses. For lesions below the aortic arch, electrocardiographic gating can improve image quality. The ability to perform T1 - and T2 -weighted images allows discrimination of mediastinal masses from mediastinal fat on T1 -weighted images and from the heart and chest wall on T2 -weighted images. The use of the combination of these sequences can usually clearly delineate mediastinal masses from surrounding soft tissues. Finally, all neoplasms have higher T1 and T2 values than inflammatory lesions, with bronchogenic carcinoma generating the greatest T1 and T2 values. The difference between T1 and T2 values for bronchogenic carcinoma and chronic inflammatory processes has been shown to be highly significant ( p < 0.001). For lesions close to the thoracic inlet, MRI is probably better than CT at identifying invasion of the brachial plexus and vertebral foramina. Similarly, MRI can clarify lesions at

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Acquired Lesions of the Mediastinum

Figure 91-4 Comparison of CT and MRI in evaluation of mediastinal masses. Nineteen-year-old man with a 1-month history of fever, heaviness in the chest, and cough. Examination revealed a tall, very thin man with dystrophic testes (habitus consistent with Klinefelterâ&#x20AC;&#x2122;s syndrome). Serum AFP was 32,000 and Î˛HCG was 25,000. A. PA radiograph of the chest reveals large mediastinal mass projecting into right hemithorax. B. CT at the level of the diaphragm demonstrates an inhomogeneous mass. Diaphragmatic invasion could not be assessed. C. Sagittal MRI view demonstrates the mass apparently contained by the diaphragm (arrows). Biopsy demonstrated embryonal cell carcinoma. This patient received high-dose cisplatin, vinblastine, and bleomycin, with resultant regression of tumor and normalization of serum markers. Subsequent resection revealed a mature teratoma.

the inferior aspect of the mediastinum that invade the diaphragm (Fig. 91-4). It is the method of choice for evaluation of neurogenic lesions, vascular anomalies, and anomalies of the aortic arch. However, MRI also has some disadvantages: longer times for acquisition of data, greater expense, and unavailability at some institutions. Also, patients are less likely to comply with MRI because of claustrophobia and difficulties inherent in lying still for longer periods. Ultrasonography Ultrasonography is used in some clinics to determine the nature of the mediastinal mass, particularly whether it is cystic or solid; in other clinics, it is used to direct fine-needle biopsies. Although the value of ultrasound in differentiating cystic and solid masses is recognized, the use of ultrasound has probably been supplanted in most institutions by CT, MRI, and ra-

dionuclide scintigraphy. It is particularly useful in evaluating masses in children because lying still is not as critical. Additionally, endoscopic ultrasound is increasingly useful in evaluating lesions of the esophagus and various periesophageal structures. Radionuclides Several radionuclide agents are useful in evaluating mediastinal masses (Table 91-4). Thyroid scintigraphy with 131 I or 123 I may be helpful in patients with obscure substernal anterosuperior compartment lesions. Although reports in the surgical literature generally find thyroid scans to be nondiagnostic for substernal thyroids, Park and colleagues found a sensitivity of 93 percent, specificity of 100 percent, and overall accuracy of 94 percent for thyroid scintigraphy when performed using current techniques. Technetium use in the mediastinum is

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Invasive Biopsy Procedures

Table 91-4 Radionuclides in the Evaluation of Mediastinal Masses Radionuclide

Mediastinal Mass

131

I or 123 I

Substernal goiter

131

I-metaiodobenzylguanine

Pheochromocytoma

Gallium 67

Lymphoma

Selenomethionin

Parathyroids

Technetium

Ectopic gastric mucosa

complicated because the salivary glands secrete technetium, which is swallowed, so the entire esophagus is invariably positive. However, technetium can help to identify rests of gastric mucosa in the esophagus if scanning is performed immediately after several glasses of liquid are swallowed to clear the esophagus. 131 I-metaiodobenzylguanine can help to identify pheochromocytomas or functioning paragangliomas anywhere in the body, including the mediastinum. Subsequent CT or MRI scanning is necessary to delineate the anatomy of “hot spots” identified in this way. Selenomethionine scans can localize parathyroid adenomas and thymic cysts. Finally, gallium 67 scanning has been used to distinguish benign from malignant anterior mediastinal masses, especially to differentiate lymphomas from benign lesions. Institutional expertise in the use of these markers and interpretation of the data they yield are at least as important as the choice of diagnostic technique. Biochemical Markers All patients with anterior mediastinal masses, particularly young men, should have determinations of levels of alphafetoprotein (AFP), beta human chorionic gonadotropin (βHCG), and carcinoembryonic antigen (CEA). Serum levels of AFP, βHCG, or both increase in the presence of nonseminomatous malignant germ cell tumors or of some teratomas and carcinomas. Pheochromocytomas are accompanied by increases in serum catecholamines and in several urinary products— e.g., catecholamines, vanillylmandelic acid, and homovanillic acid. These markers are more valuable in following patients after treatment—i.e., to detect recurrence—than in screening. The levels of these substances should be determined in patients who present with flushing, tachycardia, or headache for which there are no other explanations. Some paravertebral masses—such as paragangliomas, ganglioneromas, and some neuroblastomas—can also elaborate norepinephrine and epinephrine.

The decision to biopsy mediastinal masses is not straightforward. Biopsy before resection is not necessary in some cases and potentially harmful in others. The likelihood of a positive biopsy depends on several factors: (1) the presence or absence of local symptoms; (2) the location and extent of the lesion; (3) the presence or absence of various tumor markers; and (4) gallium uptake by the lesion. (Methods of biopsy are discussed in the following.) Locally asymptomatic lesions should not undergo biopsy before removal if they do not extend beyond the anterior compartment, show no increase in levels of tumor markers, and do not take up gallium. In particular, biopsy of a clinically suspected well-encapsulated thymoma should be avoided because it may cause spillage of tumor cells and prevent resection of an early-stage neoplasm from being curative. For patients with symptoms of locally invasive disease—such as severe chest pain, dyspnea, cough, dysphagia, pleural effusion, and superior vena caval obstruction—incisional or fineneedle aspiration biopsy (FNAB) before surgery is mandatory. These lesions are usually malignant and require chemotherapy or radiotherapy as primary or definitive therapy, rather than resection. Bulky adenopathy should always undergo biopsy, since surgical intervention is seldom the primary means for treating these lesions. Most lesions in the anterosuperior mediastinum can be easily accessed by mediastinoscopy or FNA, whereas lesions in the posterior mediastinum are amenable to FNA or thoracoscopic techniques. Lesions in the middle mediastinum (visceral), just deep to the sternum, can be sampled by way of subxyphoid mediastinoscopy, whereas other middle-mediastinal lesions require FNA or thoracoscopic techniques. It is critical to perform biopsy on patients with mediastinal masses in whom levels of AFP, βHCG, or CEA are increased. The treatment of choice for patients with these clinical features—i.e., with the features of metastatic non–small cell bronchogenic carcinoma or nonseminomatous germ cell tumors—is chemotherapy followed by surgical resection. Occasionally, chemotherapeutic treatment for oncologic emergencies may be initiated on the basis of increased levels, per se, of tumor markers. In contrast, increased concentrations of catecholamines in serum or urine contraindicate biopsy, since disturbance of a pheochromocytoma or pharmacologically active paraganglioma before preparation with alpha and beta blockade is dangerous. Gallium uptake is useful in differentiating lymphomas from thymoma. Gallium is avidly taken up by lymphomas and other inflammatory processes, whereas it is usually taken up by bronchogenic carcinomas, rarely taken up by thymomas, and unpredictably taken up by carcinoids and germ cell tumors. Method of Biopsy FNAB may fail to obtain diagnostic tissue, especially in patients with lymphoma. FNAB is diagnostic in approximately

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75 percent of mediastinal masses, although it lacks the precision to stage mediastinal and pulmonary malignancies. Heilo obtained a diagnosis in 84 percent of 62 patients undergoing ultrasound-guided core needle biopsy. It is important to emphasize that the primary benefit of FNAB in this group of patients is to prevent needless surgical intervention. Accordingly, in a candidate for surgery, a diagnosis other than lymphoma, small cell carcinoma, or stage IIIB non–small cell bronchogenic carcinoma will not obviate surgery, since all other diagnoses of solid tumor require surgical staging or resection. In a group of 35 patients in whom diagnostic tissue was obtained, ultrasound-guided needle biopsy prevented subsequent surgery in only 17 patients. Patients with potential early thymomas should not undergo FNAB, as the procedure may spread tumor cells along needle tracks, thereby preventing subsequent curative surgery. Although a core biopsy may suffice for the diagnosis of a specific lymphoma, most often more invasive and definitive approaches—such as cervical mediastinoscopy, anterior or parasternal mediastinoscopy, and videothoracoscopy—are necessary. In summary, FNAB is inconsistently useful for diagnosis of diseases of the mediastinum, and its use must be carefully assessed. However, complications of FNAB are rare. Surgical approaches to obtain tissue from mediastinal lesions include cervical mediastinoscopy, extended cervical mediastinoscopy, anterior mediastinotomy (Chamberlain procedure), subxyphoid mediastinoscopy, and videothoracoscopy. Descriptions of these specific techniques are beyond the scope of this chapter, but some generalizations may be helpful. The diagnosis of lymphoma usually requires a large tissue sample to identify the subtype, especially for nonHodgkin’s lymphomas. Also, lesions at different sites vary with respect to accessibility. Thus, cervical mediastinoscopy, performed through a small incision in the suprasternal notch, can sample masses in the anterior mediastinum or lymph nodes in the subcarinal and paratracheal location (levels 1, 2, 3, 4, 7, and 10 in the American Thoracic Society staging system). Anterior mediastinotomy performed through a small incision over the second or third rib on either side can sample lymph nodes in the para-aortic position (levels 5 and 6) or anteriormediastinal masses. These procedures can be performed in the outpatient setting, have a very low complication rate, and do not delay chemotherapy or radiotherapy. A portion of the specimen should be kept fresh for formal evaluation of T- and B-cell subpopulations and a sample of any enlarged node sent for culture. The use of mediastinoscopy to sample large masses that compromise the airway or elicit clinical signs of superior vena caval obstruction may be problematic. However, mediastinoscopy can still be useful with cautious anesthetic management (awake intubation and extubation). Mediastinoscopy poses no greater risk of bleeding for patients with superior vena caval syndrome than for normal persons undergoing mediastinoscopy. Subxyphoid mediastinoscopy, performed through an incision below the xyphoid process, is an unusual procedure.

Acquired Lesions of the Mediastinum

It is used to obtain biopsies of tissues located inferiorly in the mediastinum. Videothoracoscopic approaches to either the left or right side of the mediastinum are straightforward and obtain adequate tissue samples with minimal morbidity. However, thoracoscopic biopsies are not currently being done as outpatient procedures.

MEDIASTINAL INFECTIONS Mediastinal infections can present as mediastinal masses. The various infections that can present in this way fall into four groups: (1) mediastinitis, secondary to transsternal cardiac procedures; (2) acute perforation of the esophagus secondary to vomiting, tumor, or attempts at esophageal dilation; (3) acute descending necrotizing mediastinitis resulting from descent of oral infectious processes into the mediastinum; and (4) upward extension of a subdiaphragmatic infectious process into the mediastinum by way of the various tissue planes that connect the mediastinum with the retroperitoneum and the peritoneum. Of these categories, the first two are the most common. Diagnosis of mediastinitis after surgery on the mediastinum is uncomplicated.

Transsternal Cardiac Procedures The diagnosis of mediastinitis after surgery on the mediastinum is evident. The therapeutic approach is described in surgical texts. Esophageal Perforations Acute infections of the mediastinum caused by esophageal disease are usually due to esophageal perforation from retching or vomiting, malignancy, ingestion of a foreign body, or diagnostic or therapeutic instrumentation (Fig. 91-5). Along with clinical suspicion, two radiologic criteria are helpful in establishing the diagnosis: pneumomediastinum and pleural effusion. In distal esophageal perforations, the pleural effusion typically presents on the left side, whereas midesophageal and proximal esophageal lesions typically present with rightsided pleural effusions. Although pneumomediastinum is invariably present after an esophageal perforation, it does not localize well to the site of perforation because of dissection along tissue planes. A swallow of water-soluble contrast can confirm the diagnosis of esophageal perforation. If the swallow fails to reveal the perforation, it is repeated with a small amount of dilute barium. Although water-soluble contrast is safer from the standpoints of infection and surgery, barium affords a more detailed examination and can disclose a small perforation that is not identified by a water-soluble agent. In general, the treatment of an esophageal perforation is surgical drainage and repair of the perforation. However, appropriate timing for repair has been debated: The older surgical literature holds that a perforation more than 24 h old should be repaired only after diversion of the cervical

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Figure 91-5 Esophageal tear with communication to pleura. Sixty-three-year-old woman with multiple myeloma receiving chemotherapy in inpatient setting. After an episode of vomiting, she developed a left pleural effusion and leukopenia (WBC of 500). A. Contrast study reveals leak into left chest (arrow). B. Postoperative film after primary repair reveals normal flow of contrast.

esophagus. The more recent literature indicates that many of the late-presenting perforations can be repaired without diversion. Finally, small perforations that drain back into the gastrointestinal tract without significant soilage of the mediastinum or larger injuries that can be well drained by tube thoracostomy can be treated with antibiotics as long as the patient shows no signs of sepsis. Such fistulas that are managed without surgery may either heal spontaneously or require surgical repair at a later date.

Acute Descending Necrotizing Mediastinitis Acute descending necrotizing mediastinitis is a complication of cervical, pharyngeal, or oropharyngeal abscesses. Odontogenic diseases (molar abscesses, peritonsillar abscesses, retropharyngeal abscesses, Ludwigâ&#x20AC;&#x2122;s angina, and adult epiglottitis) and iatrogenic injury are the most common causes (Fig. 91-6). The infections are mixed, and culture may grow aerobic beta-hemolytic streptococcus, Bacteroides, peptostreptococcus, or anaerobic streptococci. Initial treatment usually entails the use of antibiotics and cervical drainage. Should these measures fail, mediastinitis can develop within 48 h. There are no pathognomonic radiographic manifestations. Mediastinal involvement is suggested by widening of the retrocervical space with an air-fluid level, anterior

displacement of the tracheal air column on lateral neck or chest radiographs, mediastinal emphysema, or the loss of the normal lordosis of the cervical spine. A CT scan of the chest and neck can verify the presence of a descending mediastinitis. The mainstays of treatment are broad-spectrum antibiotics, surgical drainage, and tracheostomy. Antibiotics should be chosen to cover gram-negative, gram-positive, and anaerobic organisms. Cervical drainage is often the definitive treatment: Careful review of the chest CT scan can indicate whether more invasive approaches are necessary. Bilateral anterior mediastinotomies may be sufficient if the infection has not progressed below the fourth thoracic vertebra. Soft, pliable drains prevent erosion into major neck vessels. Subxyphoid drainage may be necessary if the anterior space is affected. Extensive infections can be treated successfully by wide drainage of the mediastinum. The role of tracheostomy in treatment is debatable. A tracheostomy can protect the airway, especially in patients with significant cervical inflammation and edema. Despite aggressive treatment, reported mortality ranges up to 40 percent. Death can result from pulmonary sepsis, blood vessel erosion and exsanguination, and intracranial infection. A high level of suspicion that mediastinitis may be present and early surgical management are critical for successful outcome.

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C A

Figure 91-6 Acute descending necrotizing mediastinitis. Sixtynine-year-old woman developed cervical neck mass and subcutaneous emphysema 96 h after attempted esophagoscopy. A. PA radiograph reveals a widened mediastinum with pneumomediastinum and pleural effusion. B. Contrast study demonstrates leak in the proximal esophagus (arrows). C. CT scan at the thoracic inlet reveals 5-cm irregular abscess (arrows). D. CT scan of chest close to the diaphragm reveals that the abscess extends the length of the chest (arrows). E. Combined thoracoscopic and cervical drainage resulted in clearing of the abscess (arrows).

Acquired Lesions of the Mediastinum

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Figure 91-7 Chronic fibrosing mediastinitis. Thirty-year-old man with malaise and one episode of hemoptysis. Chest radiograph is normal. A. Chest CT at the level of the carina reveals paratracheal mass (arrow) surrounding the airway. B. The same process extends along the airways into inferior mediastinum. Mediastinoscopy was done to perform biopsy. Patient was treated successfully with steroids.

Subacute Mediastinitis The incidence of subacute mediastinitis is increasing in the growing population of immunocompromised patients. This diagnosis applies only to patients with mild and evanescent symptoms (e.g., substernal pain, fever, and night sweats) and with an identifiable anterior or visceral mediastinal mass. In immunocompetent patients, the most common causes are histoplasmosis and tuberculosis. Mycotic infections are rare. In immunocompromised patients, the most common causes are Mycobacterium avium-intracellulare and Mycobacterium tuberculosis. Gallium scintigraphy or indium-labeled leukocyte scintigraphy may be useful in identifying subacute infections early in their course but is less effective in more chronic infections. Chronic Mediastinitis Patients with chronic mediastinal infections often have cough, hemoptysis, fever, and dysphagia. Causes of chronic mediastinal infections are granulomatous lymphadenopathies, such as tuberculosis; fungal infections, such as histoplasmosis and coccidiomycosis; sarcoidosis; and Wegenerâ&#x20AC;&#x2122;s granulomatosis. Whereas tuberculosis was the most frequent cause in the early twentieth century, now fungal infections cause most chronic mediastinal infections. The diagnosis requires biopsy and culture. Complications of chronic mediastinal infections are uncommon. Airway compromise may require surgical relief. Seventy-five percent of all benign obstructions of the superior vena cava result from mediastinal granulomatous disease. Calcified lymph nodes may erode into airway (bronchiolithiasis) and require removal. Most symptoms resulting from benign lesions that cause obstruction of the superior vena cava resolve with time. Medical treatment consists of diuretics, anticoagulation, and observation. In contrast, ma-

lignant obstruction of the superior vena cava requires urgent nonsurgical treatment. Chronic Fibrosing Mediastinitis This entity is also referred to as chronic sclerosing mediastinitis, chronic granulomatous mediastinitis, or chronic idiopathic mediastinitis. It differs from chronic mediastinitis in its compression and obliteration of vessels, bronchi, or esophagus (Fig. 91-7). In keeping with the supposition that chronic fibrosing mediastinitis (CFM) is the result of infection, cultures of mediastinal tissue sometimes grow Histoplasma capsulatum or M. tuberculosis. Most instances of CFM involve the vicinity of the thoracic duct and its main tributaries. Most patients have strongly positive gallium scans and serum reactions to Histoplasma antigens. Patients with CFM present with a chronic smoldering inflammatory process that deposits woody, fibrous tissue throughout the visceral compartment of the mediastinum. This fibrous tissue extends beyond lymph node boundaries. A diagnosis of CFM is appropriate only if the process includes obstruction of one of the major airways, pulmonary arteries, pulmonary veins, or esophagus. Occasionally, patients have similar fibrotic processes elsewhereâ&#x20AC;&#x201D;e.g., in the retroperitoneal space, the orbit (orbital pseudotumor), or the thyroid (Riedelâ&#x20AC;&#x2122;s struma). The diffuse fibrosis, which also occurs in patients with systemic lupus erythematosus or rheumatoid disease or those who have received methysergide, suggests an immune mechanism. Clinical features are puzzling, and the disorder may be self-limiting. The highest incidence of CFM is in young adults, primarily in white women 19 to 25 years of age, who develop the disease three times more often than do men of the same age. Sixty percent of patients have symptoms that depend on the structures affected. The radiologic

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findings are variable. The superior mediastinal shadow may be abnormally wide because of an asymmetric mass that projects into either hemithorax. In some instances in which the chest radiograph is normal, a CT scan may demonstrate compression of the trachea, arterial compression, or other abnormalities. Contrast venograms, anteriograms, or MRI can document vascular obstruction even when CT scans are unrevealing. Bronchoscopy and mediastinoscopy are usually sufficient to obtain tissue for diagnosis, although thoracotomy may be necessary. Esophagoscopy can be diagnostic in patients with dysphagia. Any tissue obtained should be cultured for mycobacteria and fungus. Serum sent for complement fixation studies for histoplasmosis and coccidiomycosis can contribute to the diagnosis. Culture and histologic evaluation of material for fungal and acid-fast organisms are essential but often unrewarding: They may be negative even in patients who later respond to antibacterial treatment.

its use may obviate surgery in some patients and improve outcome in patients who require surgery. Amphotericin is of value only for acute infections. Medical treatment, using steroids, has not been effective in reversing the fibrotic process. Because major surgical resections entail high morbidity and mortality, they are worthwhile only when other measures have failed. Superior vena caval replacement by spiral vein graft may be useful for patients with localized superior vena caval obstruction and unremitting symptoms. In a series of 18 patients who underwent major surgical resections for CFM, there were four deaths, most of them in patients who required carinal pneumonectomy.

Treatment In a series of 22 patients with CFM, 13 had superior vena caval obstruction, three had dysphagia, three had stridor and dyspnea, two had pericardial involvement, and one had pulmonary artery obstruction. Ketoconazole improved outcomes in patients with high titers for histoplasmosis (greater than 1:32). It is recommended before resection because

Substernal Goiter

LESIONS MASQUERADING AS MEDIASTINAL TUMORS Substernal goiters usually present as anterosuperior mediastinal masses (Fig. 91-8), even though ectopic thyroid tissue can also be found in retrotracheal and retroesophageal locations. Essentially all substernal thyroids descend into the mediastinum from the neck; primary mediastinal thyroids are vanishingly rare. Two-thirds of patients with a substernal

Figure 91-8 Substernal goiter. A. Substernal thyroid in 33-year-old man (arrow). He underwent subsequent uncomplicated thyroidectomy by way of collar incision. B. Substernal thyroid in 67-year-old woman with diabetes and congestive heart failure (arrows). Thyroid suppression was followed by a decrease in the size of the goiter.

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goiter complain of a neck mass. Most are otherwise asymptomatic. Twenty-five percent complain of dyspnea or dysphagia. The occurrence of symptoms does not herald malignancy. CT and MRI scans are the most useful studies in the diagnosis and evaluation of these lesions. Modern radioactive 131 I scans can delineate the substernal goiter, although there is some debate about the incidence of false-negative scans. A combined analysis of available studies indicates that modern techniques of thyroid scintigraphy are diagnostic of most substernal goiters. Three recent studies, with 50 to 80 patients included in each, dealt with the evaluation and resection of substernal goiters. These reports indicate that even the most bulky lesions can be resected through cervical incisions: The lesion usually does not extend beyond the uppermost portion of the anterosuperior compartment, and ligation of the vascular supply in the neck allows delivery of the mediastinal goiter to the neck. In these series, six patients (3.3 percent) required median sternotomy or thoracotomy along with cervical incision to achieve resection. There were no deaths due to surgery in any of the series. Three patients in one series had significant intraoperative bleeding. The overall major complication rate was 1.6 percent; the rate of minor complications was 15.4 percent. The reported incidence of malignancy has ranged from 2.5 to 21 percent. These data are particularly pertinent to the decision to recommend surgery for asymptomatic substernal goiters. Everyone would support resection if 21 percent of all substernal goiters were malignant. Unfortunately, FNAB was seldom successful in identifying the lesions that ultimately proved to be malignant. Weighing in the balance the frequency of malignancy (about 2 to 20 percent), the potential danger of acute airway obstruction, and the relative safety of the surgical procedure, surgical excision seems reasonable even in asymptomatic patients. This balance in favor of surgery can obviously be tilted against it by the presence of medical complications.

Cystic Hygromas Mediastinal lymphangiomas typically extend from cervical cystic hygromas along the phrenic nerve into the chest. Cystic hygromas may be evident at birth or may not be discovered until later in life. Symptoms are caused by infection, hemorrhage, or continued growth. Resection is accomplished by combined cervicomediastinal approaches. Some of these lesions gradually regress spontaneously without surgical intervention. Sclerosis (e.g., injection of tetracycline) is possible but is generally not effective.

Lesions Originating from the Thoracic Skeleton Most skeletal lesions in the mediastinum are bony tumors that project from the thoracic spine. Chordomas of the spine are ectopic embryonic remnants of primitive notochords that may be manifest in the paravertebral sulcus. CT scanning

usually shows destruction of vertebral bodies in association with soft tissue mass. These tumors are malignant and require extensive excision and reconstruction of the spinal cord. As a rule, 5-year survival is poor. Other lesions associated with the thoracic skeleton are paravertebral abscesses caused by staphylococcal hematogenous infections of paraspinal muscles, similar to retroperitoneal abscesses. The treatment of these is the same as for all infectious lesionsâ&#x20AC;&#x201D;i.e., drainage and appropriate antibiotic treatment. An anterior meningocele may occur in the paravertebral sulcus. These are generally asymptomatic masses discovered incidentally on CT scan. They may be confused with primary neurogenic tumors. Patients with anterior meningoceles often have peripheral neurofibromatosis, skeletal abnormalities, or both. Myelography or MRI is crucial in the diagnosis of these lesions. If the diagnosis is made preoperatively, no treatment is needed unless symptoms become manifest.

Extramedullary Hematopoiesis Hematopoietic tissue can present in the mediastinum, typically in the posterior mediastinum. This process of extramedullary hematopoiesis develops as a compensatory mechanism in patients with abnormal bone marrow function. It may be manifest in several organs, such as the adrenals, liver, lymph nodes, and lungs. Large masses of extramedullary hematopoiesis are designated as erythroblastoma and myelolipoma. Consideration of this diagnosis is appropriate in patients with blood dyscrasias, especially thalassemia, who present with mediastinal masses. The tissue is pathologically characteristic, so FNAB is often diagnostic. Resection is not indicated if the diagnosis is made preoperatively.

Vascular Lesions Vascular lesions in the mediastinum may be either arterial or venous lesions and either pulmonary or systemic. Validation of lesions suspected of being vascular requires either angiography or MRI scanning to avoid dangerous biopsy. Appropriate therapy depends on the diagnosis.

Esophageal Lesions Several benign esophageal lesionsâ&#x20AC;&#x201D;such as diverticula, duplications, large leiomyomas, hiatal hernias, and achalasiaâ&#x20AC;&#x201D;may present as mediastinal masses. Esophageal carcinoma with extramural spread, bulky adenopathy, or contained perforation can manifest as bulky visceral or posterior mediastinal masses. Chest CT scan with oral contrast can differentiate most of these lesions. Formal contrast studies and esophagoscopy are reserved for puzzling circumstances.

Pulmonary Lesions Pulmonary lesions may manifest primarily as mediastinal masses, particularly as mediastinal adenopathy. Small cell

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lung cancer often presents as bulky adenopathy with either a small or an involuted primary lesion. Extralobar sequestration may also present on the chest radiograph as a paramediastinal mass in a patient with recurrent pneumonia.

Subdiaphragmatic Lesions Subdiaphragmatic lesions may present as mediastinal masses. The gastrointestinal tract (typically the stomach) may herniate through the esophageal hiatus posteriorly (to form a hiatal hernia) or through the foramen of Morgagni anteriorly. Pancreatic pseudocysts rarely present as mediastinal masses. They occur in patients with characteristic histories of previous pancreatitis or known abdominal pancreatic pseudocysts. These lesions should be drained by laparotomy rather than thoracotomy.

Table 91-6 Staging of Thymic Malignancies

Thymoma Thymomas appear benign histologically even when they are invasive. They derive from either cortical or medullary epithelial cells. They are the most common of the thymic malignancies (Table 91-5). Five histologic grades have been described, based on lymphocytic infiltration: lymphocytic, lymphoepithelial (mixed), epithelial, spindle cell, and unclassified. Thus, a lymphocytic thymoma consists of 67 to 80 percent lymphocytes. Mixed thymomas are tumors with 50 percent lymphocytes and 50 percent epithelial cells. In epithelial thymomas, 67 to 80 percent of the cells are epithelial cells. Spindle cell tumors have a characteristic appearance, and unclassified tumors are typically too undifferentiated to classify. The number of mitotic figures in these tumors is very low, so cytologic preparations always appear benign.

Table 91-5 Thymic Malignancies Thymoma Thymic carcinoma Low grade: squamous cell carcinoma, mucoepidermoid, basaloid High grade: small cell, undifferentiated, sarcomatoid, clear cell Thymic carcinoid Oat cell carcinoma of thymus Thymic hyperplasia

10-yr Survival (%)

Stage

Description

Encapsulated tumors without gross or microscopic invasion

85–100

Capsular or pleural invasion

60–84

III

Macroscopic invasion of surrounding tissuse (lung, pericardium, vena cava, or aorta)

21–77

IVA

Disseminated disease within the chest

26–47

IVB

Distant metastases

ANTERIOR MEDIASTINAL NEOPLASMS Lesions of the Thymus

Acquired Lesions of the Mediastinum

Unknown

source: Adapted from Masaoka A, Monden Y, Nakahara K, et al. Follow-up study of thymomas with special reference into their clinical stages. Cancer 48:2485–2492, 1981.

A second classification depends on the relative predominance of thymic medullary or thymic cortical cells. Medullary tumors are less aggressive, with rare recurrences, whereas cortical thymomas (and the most aggressive subtype, thymic carcinoma) tend to recur and metastasize. Differentiation between lymphomas and thymomas can be difficult without substantial tissue and often cannot be made with needle biopsy. Tumor stage at the time of treatment indicates prognosis better than tumor grade. Table 91-6 lists the most common staging mechanism applied to thymic malignancies. Stage I lesions are generally considered benign. Tumor node metastasis (TNM) staging has not been widely adopted. A peculiar characteristic of the benign histologic appearance of many of these lesions is that invasion of adjacent structures, and thus the stage of the tumor, can usually be more easily determined by the surgeon at the time of operation than by the pathologist at the time of microscopy. Thymoma is the most common primary neoplasm of the mediastinum, comprising approximately 15 percent of all thymic lesions. These tumors occur with equal frequency in men and women 40 to 60 years of age. Seventy-five percent present in the anterior mediastinum; more than 90 percent are visible on the chest radiograph. The mainstay of therapy, even for extensive lesions, is surgical resection (Figs. 91-9 and 91-10). In a series of 141 patients who underwent resection followed by routine radiotherapy (30 Gy in 3 weeks to 50 Gy in 6 weeks), those who underwent complete resections, even up to stage III, had survival rates of 100 percent at 5 years and 94.7 percent at 10 and 15 years. There was no difference between stages as long as

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A B

the resection was complete. Most surgeons, even those experienced in thoracoscopy, recommend median sternotomy for the procedure. Another study reported 5- and 10-year survivals of 74 percent and 57 percent, respectively, following a treatment regimen that included surgery and postoperative radiotherapy for all patients and postoperative chemotherapy for some patients with high-grade lesions. For patients who had total resection, the reported 5-year survival was 89 percent. Most recurrences are local, either in the pleural space or mediastinum. Distant recurrences, when they do develop,

Figure 91-9 Thymoma. Sixty-two-year-old man after successful treatment of gastric cancer and aortic aneurysm. A and B. PA and lateral radiographs demonstrate an anterior mediastinal mass projecting into left hemithorax (arrows). C. CT scan demonstrates 4-cm mass abutting thoracic aorta (arrows). No obvious invasion. D and E. Postoperative films showing remaining calcified lymph nodes but no thymoma.

are most often in bone. Recurrences are potentially curable, requiring several therapeutic methods, including repeated surgical exploration. Re-exploration and successful resection were reported for 23 patients who had recurrence of thymoma after previous complete resections. All patients in whom an invasive thymoma has been resected should receive postoperative radiotherapy, which is strongly recommended for all but stage I patients. Surgery alone yields a recurrence rate of 28 percent, whereas radiation and surgery together yield a recurrence rate of 3 percent. Whether noninvasive and encapsulated thymomas respond

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Figure 91-9 (Continued)

to irradiation is unsettled. Dosage is usually 3500 to 5000 rads over 3 to 6 weeks. A dosage of more than 5000 rads does not increase the response rate but does increase the frequency of complications. Patients with thymomas, even when the disease is unresectable, recurrent, or metastatic, often respond to treatment with cisplatin, doxorubicin, and cyclophosphamide. In an intergroup study of 22 patients with locally unresectable or metastatic disease, there were three complete and 11 partial responses, for a total response rate of 70 percent. The median survival of all patients was 59 months; three patients remained disease-free after 3 years of follow-up. Paraneoplastic Syndromes

Myasthenia gravis is the most common thymoma-associated systemic syndrome. Many other syndromes may also be related to thymoma. Table 91-7 lists the four well-established syndromes and some others that are less characteristically associated. The most commonly used clinical staging classification is shown in Table 91-8. Patients with myasthenia gravis present with muscle weakness that intensifies with repetitive activity. The pathophysiology of myasthenia gravis entails the autoimmune-mediated binding of antibodies to the acetylcholine receptor, followed by their lysis by complementmediated factors. Striking clinical improvement may occur

after thymectomy without any change in measurable immune parameters, including the absence of change in the serum levels of autoantibodies. Unfortunately, the likelihood of improvement after thymectomy is significantly less for patients with thymomas. No randomized studies have demonstrated a benefit of thymectomy for any group or subgroup of patients with myasthenia gravis, with or without thymomas. In a series of 149 patients with juvenile myasthenia gravis who were followed for a median of 17 years, half of the patients who underwent thymectomy sustained complete remission, whereas only one-third of the medically treated patients had the same response. The patients who underwent thymectomy also had slightly improved long-term survival. Because of such information, thymectomy has become standard for patients with myasthenia gravis, except for those who have only ocular symptoms. Myasthenia gravis is present in approximately onethird of patients with thymomas. This disorder may either precede or follow the development of thymoma by many years. Any type of thymic tumor may occur in patients with myasthenia gravis. Patients with thymoma and myasthenia gravis derive less neurologic benefit from resection than do those with myasthenia gravis without a thymoma. Among patients with myasthenia gravis without thymomas, remission can be expected in one-fourth to one-half:

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Figure 91-10 Benign thymoma of anterior mediastinum. A and B. Radiographic appearance of thymoma. C. Gross appearance of a benign thymoma. The tumor has a thick fibrous capsule. D to F. Varied histologic appearances of thymomas. In D, the cells are mixed epithelial (large cells with clear nuclei) and lymphocytic, ×250. In E, epithelial cells predominate, ×224. In F, the predominant cells are spindles, ×248. (Based on data of Lyerly and Sabiston, Primary neoplasms and cysts of the mediastinum, in Fishman J (ed), Pulmonary Diseases and Disorders, 2d ed. New York, McGrawHill, 1988.)

in about 20 percent, remissions are completely drug-free; in up to 30 percent, remission is maintained by drugs—i.e., a combined remission rate of 50 percent. Improvement can be expected in one-third to one-half of patients, no change is evident in 10 percent, and a rare patient gets worse after surgery. Patients with myasthenia gravis and thymoma fare more poorly after resection than do those without a thymoma. Their symptomatic improvement after surgery is poorer, with combined remission rates of only 30 percent, and there is considerable risk of recurrence of the thymoma. Combined cervical and mediastinal incisions have been recommended to accomplish a maximal thymectomy. Postoperative radiotherapy decreases the recurrence rate after resection. Radiation therapy without resection can worsen

myasthenia gravis. The dose of radiotherapy should be 3500 to 5000 rads. Red-cell aplasia occurs in 5 percent of patients with thymomas. It is a rare disorder that results in a severe normochromic normocytic anemia. Erythroid precursors in the bone marrow are decreased or absent, so reticulocytosis is markedly decreased. Thirty-three to fifty percent of patients with red-cell aplasia have thymomas. Thymectomy produces remissions in approximately 40 percent of patients. It is more likely to be effective in patients with thymoma or thymic enlargement (remissions in up to 50 percent of patients) than in patients without thymomas. Hypogammaglobulinemia occurs in 5 to 10 percent of patients with thymomas. It is more common in patients with

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Table 91-7 Paraneoplastic Syndromes Associated with Thymoma Well established (proven) Myasthenia gravis Pure red-cell aplasia Acquired hypogammaglobulinemia Nonthymic cancers Less well established (associated) Pancytopenia Lambert-Eaton Peripheral neuropathies CNS changes Multiple endocrine defects Multiple rheumatologic disorders Nephrotic syndrome

both thymoma and rheumatoid arthritis, ulcerative colitis, many cytopenias, and some extrathymic cancers. Thymectomy has not proved beneficial. Extrathymic cancers develop in up to 20 percent of patients who survive thymoma, most commonly as lymphomas, bronchogenic carcinomas, and thyroid cancers. The man-

Acquired Lesions of the Mediastinum

agement of these patients should be determined by the extrathymic malignancy and not by the previous thymoma. Thymic Carcinoma These are epithelial neoplasms of thymic origin with considerably more cytologic and architectural features of malignancy than manifested by thymomas. Several subtypes exist, with significant differences in outcomes after surgical resection. In 60 patients who underwent surgery with or without adjuvant chemoradiotherapy, the 5-year survival rate was 33 percent. As may be seen in Table 91-5, patients with low-grade lesions (squamous cell carcinoma, mucoepidermal carcinoma, and basaloid carcinoma) sustained a 95 percent cure rate. However, treatment of high-grade lesions (lymphoepithelioid lesions, small cell or neuroendocrine lesions, clear cell and sarcomatoid carcinomas, and anaplastic tumors) yielded only a 15 percent long-term survival. All high-grade lesions should be considered for resection, followed by postoperative chemotherapy, since the more malignant group of tumors may respond to cisplatin-based regimens. These malignancies often are positive for Epstein-Barr virus (EBV) or demonstrate EBV-associated nuclear antigens in carcinoma cells. However, not all thymic carcinomas demonstrate a linkage to EBV. Thymic Carcinoid These are distinctly uncommon neuroendocrine cell neoplasms that may present with a paraneoplastic syndrome. Patients in whom the tumors have a small cell appearance on histology need postoperative chemotherapy; those in whom the histology is carcinoid require resection alone.

Table 91-8 Osserman Clinical Staging Classification for Myasthenia Gravis Group 1 Ocular myasthenia gravis A Ocular symptoms, stable for 4 years B Ocular symptoms only, with history of generalized symptoms Group 2 Generalized myasthenia gravis A Mild generalized Ocular weakness gradually spreading to skeletal involvement Respiratory and bulbar muscles not affected B Moderate generalized Progression to generalized involvement of skeletal and bulbar muscles Dysarthria, dysphagia, difficult mastication C Severe generalized Skeletal and bulbar muscle weakness Respiratory muscle involvement source: Adapted from Blossman GB, Ernstoff RM, Howells GA, et al: Thymectomy for myasthenia gravis. Arch Surg 128:855â&#x20AC;&#x201C;862, 1993.

Thymolipomas These are tumors of fatty tissue within the thymus gland. They are benign tumors that masquerade as cardiomegaly. If the diagnosis is made preoperatively, they are best followed with CT scans and do not require resection. However, concern about possible malignancy usually necessitates resection. Thymic Hyperplasia True hyperplasia is a large bulky benign tumor that most commonly presents in young boys with massive thymic enlargement. This true hyperplasia occurs in children after treatment of other malignancies and recovery from other systemic disease states. It is a common form of presentation in patients who develop bulky thymus glands after treatment for Hodgkinâ&#x20AC;&#x2122;s lymphoma.

Tumors of Lymph Nodes Together, lymphomas and metastatic cancer constitute the most common mediastinal masses. The anterior mediastinum not only is the most common site of primary mediastinal lymphomas but also can be invaded by cervical or visceral disease.

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Lymphoma Lymphomas constitute 10 to 14 percent of mediastinal masses in adults. They make up 20 percent of anterosuperior mediastinal masses and 20 percent of middle mediastinal masses, ranking second in frequency in both compartments. Lymphomas are rare in the posterior mediastinum. The numerous classifications proposed for lymphoma are generally no better for determining prognosis or managing patients than is simple classification into either Hodgkin’s or non-Hodgkin’s lymphoma. Fully 20 to 30 percent of patients with lymphoma are asymptomatic, even with bulky malignant disease. Of the symptomatic patients, 60 to 70 percent have symptoms of local invasion and 30 to 35 percent have systemic symptoms, including fever, weight loss, and pruritus (so-called B type symptoms). Local symptoms include chest heaviness, discomfort, and cough. Tracheal or bronchial compression can cause associated wheezing or stridor. Dysphagia is an unusual complaint. Superior vena cava syndrome is a rare presentation. Diagnosis requires significant tissue samples. FNA biopsies are not adequate in most circumstances, although the yield improves with radiologic (ultrasound or CT) techniques that target specific areas of the mediastinal mass. The yield is relatively low, but so is the complication rate. Therefore, an attempt is reasonable, especially in patients for whom general anesthesia is problematic. Biopsies under local anesthesia of more accessible cervical nodes or of mediastinal nodes by mediastinoscopy or anterior mediastinotomy (under general anesthesia) have the greatest yield. Mediastinal Hodgkin’s Disease The age distribution of patients with mediastinal Hodgkin’s disease is bimodal—20 to 30 years of age or greater than 50 years of age. Among young adults, men and women are affected equally, although mediastinal lymphoma is more common in older men than in older women. The nodular sclerosing subtype of Hodgkin’s disease accounts for almost 90 percent of patients who present with mediastinal invasion. Of these, half have only mediastinal disease and the other half have mediastinal disease with associated neck disease. Systemic symptoms of night sweats, fever, malaise, and weight loss are common. Mild local symptoms such as pain and cough are not uncommon. Severe local symptoms, such as superior vena cava syndrome, are very uncommon. Chest radiographs reveal superior mediastinal masses that typically arise in the anterior or visceral compartment. In 108 patients with newly diagnosed Hodgkin’s disease, CT of the chest disclosed a predictable pattern of contiguous spread: The disease typically began in the anterior mediastinal/paratracheal area and spread to the other mediastinal lymph node groups and subsequently to the hila and into the lungs. So predictable was this pattern of spread that the demonstration of noncontiguous or skip disease should prompt consideration of diagnoses other than Hodgkin’s disease. Furthermore, impairment of lungs or pericardium con-

Table 91-9 Ann Arbor Staging System for Hodgkin’s Disease Stage

Characteristics

One lymph node region on either side of the diaphragm

Two or more lymph node regions on the same side of the diaphragm

III

Two or more lymph node regions on both sides of the diaphragm

Diffuse or disseminated organ involvement

sistently occurred only when the diameter of the mediastinal mass was greater than 30 percent of the thoracic diameter. This consistent progression of Hodgkin’s disease of the mediastinum correlates with the staging of the disease. Table 91-9 depicts the Ann Arbor staging system for Hodgkin’s disease. In stages IA and IIA, mediastinal irradiation alone is used. In the more advanced stages, chemotherapy is combined with radiotherapy (Fig. 91-11). Different clinics use somewhat different therapeutic approaches. Most patients (70 to 85 percent, depending on the stage of disease at presentation) respond to treatment with long-term disease-free survivals. Chemotherapy is so effective against Hodgkin’s disease that relapses can be treated effectively. Non-Hodgkin’s Lymphoma Whereas about 75 percent of patients with Hodgkin’s disease present with mediastinal disease, only 5 percent of patients with non-Hodgkin’s lymphoma present with mediastinal involvement. Abdominal lymph nodes, cervical lymph nodes, and lymphoid tissue of Waldeyer’s ring are more commonly affected than are mediastinal nodes. Large irregular anterior and superior mediastinal masses are common and are often associated with large pleural effusions, large pericardial effusions, and large pulmonary parenchymal changes. Because lymph nodes other than mediastinal nodes and body fluids are more accessible, mediastinoscopic biopsy is not usually necessary. Radiation alone is poor treatment for non-Hodgkin’s lymphoma because the disease spreads in a less predictable manner than does Hodgkin’s disease (Fig. 91-12). These malignancies may consist of T cells, B cells, diffuse large cell lymphomas, or lymphoblastic lymphomas. Because of the aggressive nature of these lymphomas, a modified staging system (Table 91-10) has been proposed for non-Hodgkin’s lymphomas (lymphocytic lymphomas). Radiation therapy is effective in treatment for patients with early-stage low-grade lymphoma. In some patients it

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may be curative (10 years disease-free survival rates of 50 to 60 percent). Chemotherapy may improve results in this group of patients. Patients with advanced low-grade lymphoma may not benefit from treatment. Indeed, no treatment has demonstrated consistent ability to induce a long-term disease-free survival or to alter the natural history of the disease in these patients. Most oncologists would treat patients with Ann Arbor stage III disease with combinations of chemotherapy and radiotherapy, anticipating a 10-year survival of 40 percent. The treatment of a localized lymphoma that appears histologically to be aggressive consists of combination chemotherapy, either with or without radiation ther-

Figure 91-11 Hodgkin’s disease. A. Bulky mediastinal mass demonstrated to be Hodgkin’s disease by mediastinoscopy. B. Chest CT demonstrates bulky mediastinal mass and pleural effusion. The mass disappeared in response to combination chemotherapy and radiotherapy. The patient is well at 18 months.

apy of the affected field. Stages I and II patients can expect 5-year disease-free survival rates of 80 to 100 percent. The benefit of radiotherapy is unclear, as comparisons between patients who receive radiotherapy and those who do not demonstrate no differences in survival. Patients with advanced aggressive disease clearly benefit from combination chemotherapy and can expect survival rates of 35 percent at 10 years.

Table 91-10 NCI Modified Staging for Intermediate and High-Grade Lymphomas

Figure 91-12 Non-Hodgkin’s lymphoma. Chest CT shows large middle and posterior mediastinal mass with distant metastasis to a rib in the contralateral chest. This skip involvement is typical of non-Hodgkin’s lymphoma.

Stage

Characteristics

Localized nodal or extranodal disease (Ann Arbor stage I or IB)

Two or more sites of disease or a localized extranodal site plus draining nodes with none of the following: Performance status <70 B sysmptoms Any mass >10 cm in diameter Serum Ldh >500 Three or more extranodal sites of desease

III

Stage II plus any poor prognostic factors

source: From DeVita VT Jr et al: Lymphatic lymphomas, in DeVita VT Jr, Hellman S, Rosenberg SA (eds), Cancer: Principles of Oncology, 3d ed. Philadelphia, Lippincott, 1989.

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Castleman’s Disease Castleman’s disease (giant lymph node hyperplasia) is characterized by mass lesions that occur most often in the anterosuperior mediastinum (52 percent) and less often (26 percent) in the neck, abdomen, and axilla. The mass is a vascular tumor often surrounded by lymphadenopathy. This arrangement makes CT useful diagnostically, since CT may reveal lymphadenopathy surrounding an encapsulated mass that enhances brightly and is distinct from the aorta. The term is applied to three lesions that are histologically distinct: hyaline vascular, plasma cell, and generalized. The first two represent localized disease, whereas the third refers to multicentric (generalized) disease (Fig. 91-13). Hyaline vascular Castleman’s disease comprises 90 percent of cases. It is a localized lesion found incidentally in asymptomatic patients. Surgical excision is the treatment of choice; radiotherapy has not been effective. The plasma cell variant, also localized, is much less common. Patients are much more likely to have symptoms and present with fever, fatigue, weight loss, and hemolytic anemia. The sedimentation rate is often high and associated with hypergammaglobulinemia, which results from the production of interleukin 6 by the hyperplastic lymph nodes. Resection is the treatment of choice to prevent malignant degeneration. Generalized, or multicentric, Castleman’s disease has the histologic features of both localized forms. The disease occurs in older patients, who typically present with severe systemic symptoms, generalized lymphadenopathy, and hepatosplenomegaly. The mortality from this disease is 50 percent, and the median survival is 27 months. Progression to lymphoma is common. The diagnosis of lymphoma is made from biopsy, and treatment is directed at managing the lymphoma. Sarcoidosis Sarcoidosis often presents with mediastinal or hilar adenopathy that is characterized histologically by noncaseating granulomas. The typical patient is in the third or fourth decade of life, is asymptomatic, and has been found to have a mediastinal mass consistent with adenopathy. Some patients present with fatigue and malaise or with complaints referable to particular organ systems. Cough and dyspnea are common; the most common sites of extrapulmonary involvement are the eyes (uveitis, conjunctivitis, and retinitis) and the skin (nodules, plaques, and erythema nodosum). The clinical and laboratory features of sarcoidosis are described elsewhere in this volume. Chest radiograph typically (in 80 percent of patients with this disease) shows bilateral hilar and mediastinal adenopathy, often accompanied by parenchymal involvement of the lungs. The diagnosis is one of exclusion but may require biopsy of skin lesions or the mediastinal nodes. Part of the tissue obtained by biopsy is smeared and cultured for acid-fast or other likely organisms. The condition of most patients improves, or remains stable, without treatment. About 20 percent suffer

progressive pulmonary impairment, with an overall mortality at 5 years of 4 percent.

Germ Cell Tumors Both benign and malignant teratomas are classified as germ cell tumors. They are the fourth most common lesion in the adult mediastinum. Most lesions in the adult (60 to 80 percent) are benign; in children, a smaller proportion (about 57 percent) are benign. Mediastinal germ cell tumors are of several types. Benign teratomas constitute 70 percent of the lesions in children and 60 percent of the lesions in adults. The predominant malignant lesions are seminomas, which constitute 50 percent of all malignant lesions. Nonseminomatous malignant lesions include a mix of tumors: malignant teratomas, malignant teratocarcinomas, yolk sac tumors, endodermal sinus tumors, choriocarcinomas, and embryonal cell carcinomas (Table 91-11). All types of germ cell tumors that have been found in the testes have been reported to occur in the mediastinum. Nonetheless, compared to testicular tumors, extragonadal germ cell tumors are uncommon. Three percent of all germ cell tumors in adults and 7 percent of germ cell tumors in children are extragonadal. An even smaller percentage (1 to 2 percent) of germ cell tumors originate in the mediastinum. Blood levels of alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) should be determined for all patients in whom malignant germ cell tumors are suspected. Mediastinal metastasis is common in testicular neoplasms. In weighing the possibility of a germ cell tumor, a primary testicular tumor should always enter into the differential diagnosis because cells responsible for mediastinal germ cell tumors may derive from germ cell rests that migrated to the mediastinum from the urogenital ridge. Metastases from the testes, however, are unlikely. Germ cell tumors usually develop along the body midline in the cranium, mediastinum, retroperitoneum, and presacral areas. Benign Germ Cell Tumors (Teratomas) These tumors are of multiple tissues that are foreign to the part of the body in which they develop. They consist of a disorganized mixture of derivatives of the three germinal layers— ectoderm, mesoderm, and endoderm. Consequently, they may contain elements of skin and its appendages, bone, cartilage, intestinal and respiratory epithelium, and neurovascular tissue. About 80 percent of these lesions are benign. A dermoid cyst (benign cystic teratoma) is a variant that contains sebaceous material within a lining of squamous epithelium. The lesions occur most often in adolescents or adults; the incidence is about equal in males and females. In one series of 86 patients in whom benign mediastinal teratomas had been resected, the mean age was 28 years. About one-third of the patients are asymptomatic, but symptoms are likely to develop if the cysts become infected and erode into the pericardial space, the pleural space, or a bronchus. Occasionally,

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Figure 91-13 Giant lymph node hyperplasia (Castlemanâ&#x20AC;&#x2122;s disease). A. Posteroanterior radiograph. Lobulated superoanterior mediastinal mass extending into the left hemithorax and containing areas of dense calcification (that were quite striking on the lateral chest radiograph). B and C. CT scans reveal enhancing mass that extends throughout the anterior mediastinum as far as the orgin of the pulmonary artery. The mass contains calcifications and is surrounded inferiorly by multiple lymph nodes. D. Excised specimen. Maximum diameter of 13.5 cm. Thick, fibrous capsule that also envelopes adjacent, anthracotic lymph nodes. E. Histologic appearance. Many lymphoid follicles with prominent germinal centers. The germinal centers are permeated by radially oriented capillaries and surrounded by concentrically arranged lymphocytes.

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Table 91-11 Mediastinal Germ Cell Tumors Histology

Primary Treatment Method

Overall 5-year Survival (%)

Benign teratomas

Surgical resection

>90

Malignant teratomas

Chemotherapy + surgical resection

∼50

Metastatic

Cisplatin-based chemotherapy

60–85

Resectable

Surgery + radiation + cisplatin chemotherapy

>90

Nonseminomatous lesions

Cisplatin-based chemotherapy

30–50

Seminomas

source: Table compiled from Parker D, Holford CP, Begent RHJ, et al: Effective treatment for malignant mediastinal teratoma. Thorax 38:897–902, 1983; Dulmet EM, Macchiarini P, Suc B, et al: Germ cell tumors of the mediastinum: A 30-year experience. Cancer 72:1894–1901, 1993; Logothetis CJ, Samuels ML, Selig DE, et al: J Clin Oncol 3:316–325, 1985; Goss PE, Schwertfeger L, Blackstein ME, et al: Cancer 73:1971–1979, 1994.

episodes of hypoglycemia occur in patients with benign mediastinal teratomas and are relieved by resection of the tumor. Approximately a third of these lesions are calcified. In the series of 86 patients, all of the surgical deaths (5 of 86) occurred before 1945. If the benign lesions were completely resected, no postoperative radiation was given and the disease-free interval averaged 10 years. In general, complete resection results in cure. Malignant Germ Cell Tumors The origin of malignant germ cell tumors is unclear. The several different types behave differently and require different therapies. Malignant Mediastinal Teratomas

Malignant teratomas typically include elements of mature (benign) teratoma, immature teratoma, choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and seminoma in various proportions. These tumors produce either AFP or HCG, the presence of either of which is diagnostic for malignant as opposed to benign tumor. In a series of eight patients, neoadjuvant chemotherapy resulted in a decrease in hormone levels. Two regimens—one with vincristine, methotrexate, bleomycin, and cisplatin and the other with etoposide, dactinomycin, and cyclophosphamide—were given. Six of the eight patients subsequently underwent resection; one patient, who had residual tumor, also received postoperative chemotherapy. One surgical patient died eight months after surgery; the others were alive and well 13 to 136 months after the start of treatment. The two patients who were treated medically died 1 and 15 months, respectively, after the operation.

Mediastinal Seminomas

The embryologic origins of mediastinal seminomas are unclear. One theory holds that they derive from somatic cells of the bronchial cleft. The other holds that they derive from extragonadal or embryonic yolk sac germ cells arrested near the developing thymus in the course of their migration along the urogenital ridge to the gonad. Pure seminomas constitute 50 percent of all germ cell tumors of the mediastinum. They occur principally in men 20 to 40 years of age (Fig. 91-14); fewer than 5 percent occur in women. Mediastinal seminomas are the most common of the malignant germ cell tumors of the mediastinum. They often present with intrathoracic metastases that preclude excision. A CT scan of the testicles is necessary to rule out a primary lesion that originates in the testicles. Serum levels of AFP and HCG rarely increase in patients with mediastinal seminomas; if their levels are increased, another diagnosis is likely. Seminomas are very radiosensitive. Radiotherapy is appropriate primary therapy for early-stage lesions, as is surgical resection. Criteria for resectability are that the patient is asymptomatic, that the mass is confined to the anterior mediastinum, and that neither intrathoracic nor distant metastases are present. Only complete resections contribute to cure or palliation. Even after complete resection, radiation (4500– 5000 rads) improves outcome. Chemotherapy benefits patients whose lesions appear histologically to be particularly malignant and therefore suggest a high risk of failure. The regimens most commonly used are vinblastine, bleomycin, and cisplatin. Chemotherapy given to patients with disseminated disease can yield 5-year disease-free survivals of 60 to 90 percent. Extensive disease and prior radiotherapy presage poorer prognosis.

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In a series of 41 patients with advanced abdominal seminoma who were re-evaluated after treatment with cisplatin-based chemotherapy, 23 were found to have a residual mass; in 14 of these patients, the mass was greater than 3 cm in diameter. Nineteen of the patients with residual lesions underwent subsequent excision or biopsy. In 6 of the 14 patients in whom the residual mass was greater than 3 cm, viable seminoma was found. These observations suggested that patients in whom the residual mass is greater than 3 cm in diameter should receive follow-up treatment with either radiotherapy or additional chemotherapy, depending on the clinical situation. Nonseminomatous Tumors

These tumors are less common than seminomatous malignant germ cell tumors. They form in the anterior mediastinal compartment. Nonseminomatous tumors present with symptoms of compression or invasion of local thoracic structures. Patients also have systemic symptoms of weight loss, fatigue, and fever. In 85 to 95 percent, there is one site of distant metastasis. Serum HCG or AFP greater than 500 mg/ml is diagnostic of nonseminomatous malignant germ cell tumors (Fig. 91-4). Nonseminomatous malignant germ cell tumors include pure and mixed embryonal carcinomas, teratocarcinomas, chorio-carcinomas, and endodermal sinus (or yolk sac) tumors. The typical patient is a young male (median age of 35 years). In all patients with these tumors, βHCG or AFP levels in serum are increased. Nonseminomatous tumors usually have a heterogeneous density on CT scan, whereas seminomas

Figure 91-14 Mediastinal seminoma. Twenty-nine-year-old man, HIV positive, with generalized malaise and 5- to 10-pound weight loss. A. Chest radiograph reveals inferior mediastinal enlargement. B . Chest CT shows homogeneous mass within thymic fat.

tend to have a homogeneous density. They can present with pleural effusions. These tumors are relatively more frequent in patients with Kleinfelter’s syndrome. Embryonal carcinomas occur in both adults and children and are clinically similar to seminomas. Choriocarcinomas typically present in young adult men, half of whom have gynecomastia. This results from production of βHCG by the tumor. Therefore, βHCG is a tumor marker in these patients and helps in following the course and recurrence of the disease. Endodermal sinus (yolk sac) tumors form in both adults and children. They occur infrequently in the mediastinum and more commonly in sacrococcygeal teratomas and in the gonads. They produce AFP no matter where they are located; the blood level of this protein helps in following therapy. Teratocarcinomas are mixed-cell lesions. They are similar to embryonal and endodermal sinus tumors in that they occur in adults and children and may present with distant metastases. Management of these tumors does not require surgery initially, since the lesions are generally unresectable at presentation. Treatment with chemotherapy and radiotherapy is the mainstay. More aggressive regimens, particularly the addition of cisplatin, improve the results of treatment of extragonadal nonseminomatous tumors. In such responders who are left with a residual mass, resection is appropriate. Testicular tumors are more chemosensitive than all extragonadal tumors, and retroperitoneal tumors are more sensitive than mediastinal tumors. The chemotherapy regimens include bleomycin, cisplatin, vinblastine, and etoposide. These regimens can yield

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complete response rates of 40 to 60 percent and 30 to 50 percent long-term survivors (Table 91-11). Patients with nonseminomatous germ cell tumors, especially those with yolk sac or embryonal cell carcinoma in combination with teratoma, are prone to develop hematologic neoplasms. The median time to development of the hematologic malignancy (usually megakaryoblastic leukemia or malignant histiocytosis) is 6 months. Thirteen of 16 reported patients developed the second hematologic malignancy within 1 year after the diagnosis of the mediastinal germ cell tumor. The course of the hematologic malignancy is particularly virulent. Although all these patients had received cisplatin, it could not be implicated as the etiologic agent because reviews of large numbers of patients who received cisplatin for other malignancies have revealed no similar hematologic malignancies. A marking isochromosome (12p) in the mediastinal germ cell tumor and in the associated leukemic blasts in one patient has suggested that these tumors may arise from a common progenitor cell. Any mass that remains after chemotherapy should be resected if two conditions are met: the patient has had a good response to the chemotherapy, and levels of tumor markers in serum fall to normal. Any tumor left behind is usually a benign teratoma or necrotic tumor mass that can degenerate and redevelop malignancy. If the tumor markers do not fall but the tumor shrinks, surgery is of no benefit. A few mediastinal germ cell tumors are composed of a single cell type. Testicular biopsy or testicular CT is necessary in patients with such mediastinal germ cell tumors to rule out a primary testicular neoplasm. Testicular biopsy is indicated if a mass is palpated, if high-resolution ultrasound is abnormal, and if CT demonstrates involvement of pelvic or retroperitoneal lymph nodes.

MIDDLE MEDIASTINAL MASSES Bronchogenic Cysts Mediastinal cysts constitute 20 percent of all mediastinal masses, and bronchogenic cysts make up 60 percent of all mediastinal cysts. Symptoms are present in two-thirds of patients, usually from compression of adjacent structures. If the diagnosis of a bronchogenic cyst is made preoperatively and patients are asymptomatic, observation is an appropriate course. If there is any question of malignancy— based on radiographic appearance, positive cytology, or evidence of enlargement or recurrence—the lesion should be resected. The presence of symptoms—especially pain, cough, or hemoptysis—suggests the advisability of resection. The presence of an air-fluid level indicates connection with the bronchopulmonary tree and the likelihood of recurrent infection and indicates that resection is in order. Symptoms tend to develop with time, and resection at an asymptomatic stage may be best in healthy subjects. Also, malignancy or infection can develop in these cysts if the decision is made to

Figure 91-15 Bronchogenic cyst. CT scan obtained to evaluate dull chest ache. The lesion was thoracoscopically excised, and the patient was discharged home 2 days after the operation.

observe instead of operating. Video-assisted techniques offer the opportunity to resect less threatening lesions with low morbidity (Fig. 91-15). In 86 patients followed for 20 years at the same institution, 20 of whom had bronchogenic cysts of the lung and 66 of the mediastinum, 33 percent were asymptomatic at the time of operation. At operation in these 86 patients, fistulization, ulceration, hemorrhage, or infection was found in 33 percent of the resected lesions. Overall, the experience indicated that 82 percent of these patients had a bronchogenic cyst that was symptomatic, complicated, or both. There were no surgical deaths, and one major complication ensued (reintubation and ultimate tracheostomy for respiratory failure). In view of these results, the authors recommended resection of all bronchogenic cysts, asymptomatic or not.

Esophageal Cysts Esophageal cysts are periesophageal lesions that are smooth and possess some form of gastroesophageal epithelial lining. Diagnosis is possible with esophageal ultrasound, chest CT scan, or contrast studies of the upper gastrointestinal tract. Resection is the therapy of choice, whether by thoracoscopic or open technique. The site of the resection should be buttressed with vascularized tissue.

Neuroenteric Cysts Neuroenteric cysts make up 5 to 10 percent of foregut lesions and are associated with vertebral anomalies. They possess not only endodermal but also ectodermal or neurogenic elements. They are usually connected by a stalk to the meninges and spinal cord. They present in infants before 1 year of age and are uncommon in adults. A CT scan showing a cystic mediastinal lesion with an associated vertebral abnormality—such as congenital scoliosis, hemivertebrae, and spina bifida—should prompt consideration of neuroenteric cysts.

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Figure 91-16 Pericardial cyst. A. Posteroanterior radiograph when patient was first seen. Arrows outline cyst. B. Three years later. C. Specimen removed at surgery.

Mesothelial Cysts Mesothelial cysts have been described as pericardial, pleuropericardial, spring water, cardiophrenic, and simple cysts. Pericardial or Pleuropericardial Cysts Pericardial cysts are commonly located in the cardiophrenic angles. They have fibrous walls and contain clear, watery fluid. Mesothelial cysts are benign, and if the diagnosis is secure, resection is not necessary. If symptoms develop or if the lesions cannot be differentiated from hernias, bronchogenic cysts, or sequestra, resection is necessary (Fig. 91-16). Thoracic Duct Cysts These cysts are rare. They may arise at any level of the thoracic duct but do not retain a communication with the thoracic duct. The lesion may distort the trachea or esophagus. Observation is appropriate if the diagnosis can be made pre-

operatively, since there is no malignant potential. Ligation of the thoracic duct may be necessary to resect a thoracic duct cyst.

POSTERIOR MEDIASTINAL MASSES Neurogenic Tumors The most common masses in both children and adults used to be neurogenic tumors. In recent decades, although these tumors continue to be the most common malignancy in children, in adults they have become less common than either thymomas or lymphomas. They now represent approximately 15 percent of all mediastinal masses in adults. Furthermore, in adults, the malignancy rate of neurogenic tumors is less than 10 percent (and probably only 1 to 2 percent). In children, fully 50 percent of these lesions are malignant. Neurogenic tumors develop from the embryonic neural crest cells around the spinal ganglia and from either

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sympathetic or parasympathetic components. Almost all these lesions form in the paravertebral sulci in association with intercostal nerves. Lesions can also develop from vagus and phrenic nerves. Most of the lesions are asymptomatic, although some patients manifest symptoms of spinal cord compression or have cough, dyspnea, chest wall pain, and hoarseness. Horner’s syndrome is an unusual presentation. Most patients with neurogenic tumors are asymptomatic, so the initial diagnosis is usually made on chest radiographs obtained for other reasons. A rare patient may present with a pheochromocytoma or a chemically active neuroblastoma or neuroganglia. In all symptomatic patients, serum catecholamine levels and 24-h urine levels of homovanillic acid and vanillylmandelic acid should be determined. CT scanning is necessary to rule out intraspinal extension along the vertebral nerve roots (so-called dumbbell tumors). These patients often present with symptoms of spinal cord compression. About 10 percent of patients with mediastinal neurogenic tumors have extension through a vertebral foramen. Although the vast majority of these lesions are benign, approximately 1 to 2 percent are malignant. The CT scan typically shows a smoothly rounded homogeneous density abutting the vertebral column. For patients with dumbbell extensions through the intravertebral foramina or lesions abutting on the thoracic vessels, MRI may be useful in demonstrating involvement of the vertebral column and extension into the spinal cord. Nerve sheath tumors account for 65 percent of all mediastinal neurogenic tumors. Widening of the intervertebral foramen calls for myelography to determine

Figure 91-17 Schwannoma. PA radiograph of 67-year-old man with chronic cough who had undergone a total thyroidectomy 20 years earlier. A. Chest radiograph demonstrates superior mediastinal mass projecting into the right hemithorax. B. Lesion high in thoracic inlet abutting anterior and posterior chest walls.

whether there is involvement of the spinal cord. Combined laminectomy and thoracic resection at the same site has been popularized by Grillo’s team.

Tumors of Nerve Sheath Origin Benign lesions are classified as either neurilemoma (schwannoma) or neurofibromas (Fig. 91-17). Neurilemomas are more common than neurofibromas. Twenty-five to 40 percent of patients with nerve sheath tumors have multiple neurofibromatosis (von Recklinghausen’s disease). Malignant tumors (neurogenic sarcomas or malignant schwannomas) are unusual. The incidence of malignancy is greater in tumors that are part of von Recklinghausen’s disease (10–20 percent). Neurilemomas are well encapsulated, firm, and grayish tan. Melanotic schwannomas are grossly pigmented, and most of them extend into the spinal cord. In general, the prognosis with any malignant tumor of nerve sheath origin is poor. Neurogenic sarcomas occur at the extremes of age—in the first and second decades of life and in the sixth and seventh decades. They represent less than 10 percent of all thoracic neurogenic tumors. The primary method of treatment is resection, by either thoracotomy or video-assisted thoracic resection. CT scanning is necessary to identify any intraspinal extension. If intraspinal extension is present, it should be resected at the same time with neurosurgical assistance. Postoperative radiation is always given.

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So-called dumbbell tumors are neurogenic tumors that extend through the intravertebral foramen into the spinal column. Akwari and associates found that 9.8 percent of patients with mediastinal neurogenic tumors had extension through an intervertebral foramen. These patients present with symptoms of spinal cord compression. MRI is useful to delineate vertebral column impairment and intraspinal extension. Tumors of Autonomic Nervous System

Neuroblastomas and ganglioneuroblastomas typically occur in children and are rare in adults. They are malignant and should be resected if identified.

ENDOCRINE TUMORS

Acquired Lesions of the Mediastinum

neck exploration for hyperparathyroidism. After a negative exploration of the neck, further search using MRI, technetium scanning, thallium scanning, single photon emission computed tomography (SPECT) scanning, and venous sampling for parathyroid hormone can help to localize the lesion.

OTHER MEDIASTINAL TUMORS Mesenchymal Tumors These tumors constitute approximately 2 percent of all tumors that occur in the mediastinum. More than half of these mesenchymal lesions are malignant, however, and they run the entire gamut of soft tissue tumors. Their management resembles that of soft tissue tumors in the rest of the body; resection is indicated if possible.

Mediastinal Pheochromocytoma These tumors usually cause no symptoms. Occasionally, however, they do present with varying degrees of hypertension, diabetes, and hypermetabolism. The tumors produce epinephrine, norepinephrine, or both. Vanillylmandelic acid and homovanillic acid are the chief urinary excretion products, but epinephrine and norepinephrine may also be secreted in the urine. Normal levels of vanillylmandelic acid in the urine are 2 to 9 mg/24 h. Normal levels of epinephrine in the urine should be less than 50 µg/24 h; normal norepinephrine levels in urine should be less than 150 µg/24 h. Large masses may be visible on the chest radiograph, but in most patients CT scans are necessary to visualize the tumors. On MRI, a nonhomogeneous mass with a flow void will be visualized. 131 I-metaiodobenzylguanidine scintigraphy is particularly useful for mediastinal lesions: It can be used to localize lesions not seen on other scans. The tumors may produce functioning peptides that can cause Cushing’s syndrome, secretory diarrheas, and polycythemia vera. In the thorax, they probably derive from neuroendocrine cells and typically develop in the paravertebral sulci. Treatment requires surgical excision. However, the patient should first undergo alpha blockade with phenoxybenzamine for 1 week and then beta blockade with metoprolol or propranolol. Typically, the fluid volume of these patients is contracted and will normalize during the period of alpha blockade. For emergency surgery, simultaneous alpha and beta blockade and fluid restoration are necessary.

Parathyroid Adenomas Normal parathyroid glands occur in abnormal positions in 20 percent of the population—in the lower part of the neck, thymic capsule, or anterior mediastinum. Approximately 20 percent of parathyroid adenomas localize to the mediastinum: 80 percent in the anterior mediastinum and 20 percent in the visceral compartment. It is unusual to be able to identify these lesions either by chest radiography or CT scan. Usually, a search in the mediastinum begins only after a negative

Fatty Tumors Some fatty tumors, if they can be reliably identified before surgery, do not require resection. Lipomatosis is overgrowth of mature fat seen as a widening of the mediastinum (Fig. 913). It results from exogenous obesity, steroids, or Cushing’s disease and should not be resected. Lipomas can form in the mediastinum and do not require resection unless they appear to be growing rapidly. Large lipomas can cause respiratory embarrassment and may require resection for symptomatic reasons. Lipomoblastomatosis is an unusual benign lesion seen principally in children. It is associated with fatty overgrowth in the mediastinum and compression of structures. It should be resected. Liposarcomas of the mediastinum are rare. On CT scanning, the density of these masses is midway between that of fat and water. The lesions are large and ill defined. They cause local symptoms, including superior vena caval obstruction and tracheobronchial compression. They should be resected.

SUPERIOR VENA CAVA SYNDROME In the first part of the twentieth century, the most common causes of superior vena cava (SVC) syndrome were benign mediastinal diseases, specifically syphilitic aneurysms. Currently, malignant tumors, such as lymphoma, bronchopulmonary cancers, thymic malignancies, and germ cell tumors of the mediastinum, account for more than 90 percent of all SVC obstructions. Lung cancer is most common, especially small cell cancer, although lymphoma is also common. Other malignancies are rare. Five to 10 percent of cases of SVC obstruction are due to benign causes. Most result from invasive monitoring techniques, such as the placement of central venous lines, Swan-Ganz catheters, and interventional techniques, such as the placement of pacemakers and central venous catheters for chemotherapy.

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Diseases of the Mediastinum

Congestion of venous outflow from the head, neck, and upper extremities results in swelling of the face, neck, arms, and upper chest. Patients may have headaches, dizziness, tinnitus, and a bursting sensation. In addition, the face may appear cyanotic even though capillary refill is normal. Venous hypertension in SVC syndrome may lead to serious consequences (e.g., jugular venous and cerebrovascular thrombosis). Therefore, this syndrome requires urgent treatment. Chest radiography may show mediastinal widening but is nonspecific. CT scanning, using intravenous contrast, can document the SVC syndrome but must show opacification of the SVC above the mass and nonopacification below to establish the diagnosis. Thrombosis, compression, and invasion of the SVC are common causes. If the CT scan is nondiagnostic, bilateral phlebography using arm veins may demonstrate caval obstruction, especially for the SVC syndrome that is secondary to chronic fibrosing mediastinitis or indwelling intravenous catheters or pacemaker leads. Radioactive iodine scans may be useful for SVC obstruction secondary to goiter. In order to obtain tissue for diagnosis, FNAB may be diagnostic. Experienced surgeons and anesthesiologists can perform mediastinoscopy safely in this group of patients. Intraoperative complications, including bleeding, are rare, but the airway management is complicated. Patients with the SVC syndrome, or any large anterior mediastinal mass, often must be intubated and extubated while awake so that airway obstruction can be prevented during the surgical procedure. If the underlying disease is malignant, it is important to obtain tissue from the mediastinal neoplasm causing the SVC syndrome in order to direct therapy. Because the SVC syndrome may cause cerebral venous thrombosis, it is an oncologic emergency. In patients with respiratory or neurologic symptoms, treatment without tissue diagnosis may be necessary. The treatment of choice is very high-dose radiation therapy: 3000 to 4000 rads for 4 days. Additional medical measures include salt restriction, diuretic treatment, steroid administration, and anticoagulation. Although radiotherapy is the mainstay of treatment, patients with small cell carcinoma, lymphoma, and undifferentiated carcinoma may benefit from the addition of chemotherapy. Intravascular stenting with expandable venous stents (Gianturco or Palmaz) has been successful in many patients and is appropriate therapy for poor-risk patients who do not respond to radiotherapy. Surgical resection is aggressive therapy but is appropriate in good-risk patients. In a series of 22 patients who underwent resection of lung cancers (n = 6) and malignant mediastinal tumors (n = 16), combined with resection of the SVC and subsequent reconstruction, the mortality was modest (4.5 percent) and the survival rates surprisingly good: the overall actuarial survival rate was 48 percent at 5 years. The survival rate of patients with mediastinal tumors was 60 percent at 5 years. For benign causes of SVC syndrome, treatment must be tailored to the specific origin. Substernal goiters should

be resected. Aneurysmal disease causing SVC syndrome requires cardiopulmonary bypass and repair. Anticoagulation and antibiotic administration are the best initial treatments of idiopathic thrombophlebitis or septic thrombophlebitis and iatrogenic thrombosis of the SVC. Failure of these approaches calls for the use of fibrinolytic agents such as urokinase and streptokinase. The treatment of SVC syndrome in patients with chronic fibrosing mediastinitis is controversial. Replacement of the SVC with vein or ringed polytetrafluoroethylene (PTFE) grafts is possible, but the technique is reserved for severe symptoms recalcitrant to medical treatment. The best approach in this case is median sternotomy. Unless the benign process continues to progress, however, most symptoms will resolve without surgery as collaterals develop.

SUGGESTED READING Akwari OE, Payne WS, Onofrio BM, et al: Dumbbell neurogenic tumors of the mediastinum. Mayo Clin Proc 53:353– 358, 1978. Allo MD, Thompson NW: Rationale for the operative management of substernal goiters. Surgery 94:969–977, 1983. Almon RR, Andrew CG, Appel SH: Serum globulin in myasthenia gravis: Inhibition of α-bungarotoxin binding to acetylcholine receptors. Science 186:55–57, 1974. Azanow KS, Pearl RH, Zurcher R, et al: Primary mediastinal masses: A comparison of adult and pediatric populations. J Thorac Cardiovasc Surg 106:67–72, 1993. Benjamin SP, McCormack LJ, Effler DB: Primary lymphatic tumors of the mediastinum. Cancer 30:708–712, 1972. Billroth T: Geschwulster der Schiddr use. Chir Klin Zurich 67–89, 1869. Blalock A: Thymectomy in the treatment of myasthenia gravis: Report of 20 cases. J Thorac Surg 13:316–339, 1944. Blalock A, Mason MF, Morgan HJ, et al: Myasthenia gravis and tumors of the thymic region. Ann Surg 110:544–561, 1939. Blalock A, Mason MF, Morgan HJ, et al: Myasthenia gravis and tumors of the thymic regions: Report of a case in which the tumor was removed. Ann Surg 110:544–561 1939. Blossmon GB, Ernstoff RM, Howells GA, et al: Thymectomy for myasthenia gravis. Arch Surg 128:855–862, 1993. Cantinella FP, Boyd AD, Spencer FRC: Intrathoracic extramedullary hematopoiesis simulating anterior mediastinal tumor. J Thorac Cardiovasc Surg 89:580–584, 1985. Cohen AJ, Thompson L, Edwards FH, et al: Primary cysts and tumors of the mediastinum. Ann Thorac Surg 51:378–386, 1991. Creswell LL, Wells SA: Mediastinal masses originating in the neck. Chest Surg Clin North Am 2:23–78, 1992. Crucitti F, Doglietto GB, Bellantone R, et al: Effects of surgical treatment in thymoma with myasthenia gravis: Our experience in 103 patients. J Surg Oncol 50:43–46, 1992.

1613 Chapter 91

Dartevelle PG, Chapelier AR, Pastorino U, et al: Long-term follow-up after prosthetic replacement of the superior vena cava combined with resection of mediastinal-pulmonary malignant tumors. J Thorac Cardiovasc Surg 102:259–265, 1991. Davis RD, Oldham HN, Sabiston DC: Primary cysts and neoplasms of the mediastinum: Recent changes in clinical presentation, methods of diagnosis, management and results. Ann Thorac Surg 44:229–237, 1987. DeFilippi VJ, Richman DP, Ferguson MK: Transcervical thymectomy for myasthenia gravis. Ann Thorac Surg 57:194–197, 1994. Diehl LF, Hopper KD, Giguere J, et al: The pattern of intrathoracic Hodgkin’s disease assessed by computed tomography. J Clin Oncol 9:438–443, 1991. Doty DB, Doty JR, Jones KW: Bypass of superior vena cava: Fifteen years’ experience with spiral vein graft for obstruction of superior vena cava caused by benign disease. J Thorac Cardiovasc Surg 99:889–896, 1990. Dulmet EM, Macchiarini P, Suc B, et al: Germ cell tumors of the mediastinum: A 30-year experience. Cancer 72:1894– 1901, 1993. Ferguson MK, Lee E, Skinner DB, et al: Selective operative approach for diagnosis and treatment of anterior mediastinal masses. Ann Thorac Surg 44:583–586, 1987. Fossa SD, Borge L, Aass N, et al: The treatment of advanced metastatic seminoma: Experience in 55 cases. J Clin Oncol 5:1071–1077, 1987. Frist WH, Thirumalai S, Doehring CB, et al: Thymectomy for the myasthenia gravis patient: Factors influencing outcome. Ann Thorac Surg 57:334–338, 1994. Grillo HC, Ojemann RG, Scannell JG, et al: Combined approach to “dumbbell” intrathoracic and intraspinal neurogenic tumors. Ann Thorac Surg 36:402–407, 1983. Heilo A: Tumors in the mediastinum: US-guided histologic core-needle biopsy. Radiology 189:143–146, 1993. Heimberger IL, Battersby JS, Vellios F: Primary neoplasms of the mediastinum: A 15-year experience. Arch Surg 86:978– 985, 1963. Hoppe RT, Coleman CN, Cox RS, et al: The management of stage I–II Hodgkin’s disease with irradiation alone or combined modality therapy: The standard experience. Blood 59:455–465, 1982. Jaretzki IIIA, Wolff M, Jaretzki A: “Maximal” thymectomy for myasthenia gravis. Surgical anatomy and operative technique. J Thorac Cardiovasc Surg 96:711–716, 1988. ¨ Jolly F: Uber myasthenia gravis pseudoparalytica. Berl Klin Wochenschr 32:1–7, 1885. Kelley MJ, Mannes EJ, Rawin CE: Mediastinal masses of vascular origin. A review. J Thorac Cardiovasc Surg 76:559–572, 1978. Katlic MR, Grillo HC, Wang C: Substernal goiter: Analysis of 80 patients from Massachusetts General Hospital. Am J Surg 149:283–287, 1985. Kirchner T, Muller-Hermelink HK: New approaches to the diagnosis of thymic epithelial tumors. Prog Surg Pathol 70:167–189, 1989.

Acquired Lesions of the Mediastinum

Kirschner PA: Reoperation for thymoma: Report of 23 cases. Ann Thorac Surg 49:550–555, 1990. Kirschner PA: Myasthenia gravis, in Shields TW (ed), Mediastinal Surgery. Philadelphia, Lea & Febiger, 1991, pp 339–369. Kocher T: Bericht u¨ ber ein zweites tousend Kropfexcisionen. Arch Klin Chir 64:454–471, 1901. Laquer L, Weigert C: Beitrage zur Lehyre von de Erbschen Krankheit. I: Uber de Erbschen Krankheit (myasthenia gravis) (Laquer). II: Pathologisch-anatomischer Beitrag zur Erbschen Krankheit (myasthenia gravis) (Weigert). Zentralbl Neurochir 20:594–612, 1901. Lewis BD, Hurt RD, Payne WS, et al: Benign teratomas of the mediastinum. J Thorac Cardiovasc Surg 86:727–731, 1983. Lewis RJ, Sisler GE, MacKenzie JW: Mediastinoscopy in advanced superior vena cava obstruction. Ann Thorac Surg 32:458–462, 1981. Loehrer PJ, Birch R, Williams SD, et al: Chemotherapy of metastatic seminoma: The Southeastern Cancer Study Group experience. J Clin Oncol 5:1212–1220, 1987. Loehrer PJ, Perez CA, Roth LM, et al: Chemotherapy for advanced thymoma: Preliminary results of an intergroup study. Ann Intern Med 113:520–524, 1990. Longo DL, Mauch P, Devita VT, et al: Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia, Lippincott, 1993. Marino M, M¨uller-Hermelink HK: Thymoma and thymic carcinoma: Relation of thymoma epithelial cells to the cortical and medullary differentiation of the thymus. Virchows Arch [A] 407:119–149, 1985. Masaoka A, Monden Y, Nakahara K, Tanioka T: Follow-up study of thymomas with special reference into their clinical stages. Cancer 48:2485–2492, 1981. Mathisen DJ, Grillo HC: Clinical manifestation of mediastinal fibrosis and histoplasmosis. Ann Thorac Surg 54:1053– 1058, 1992. Motzer R, Bosl G, Heelan R, et al: Residual mass: An indication or further in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 5:1064–1070, 1987. Nakahare K, Ohno K, Hashimoto J, et al: Thymoma: Results with complete resection and adjuvant postoperative irradiation in 141 consecutive patients. J Thorac Cardiovasc Surg 95:1041–1047, 1988. Nichols CR, Roth BJ, Heerema N, et al: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322:1425–1429, 1990. Park H-M, Tarver RD, Siddiqui AR, et al: Efficacy of thyroid scintigraphy in the diagnosis of intrathoracic goiter. Am J Roentgenol 148:527–529, 1987. Parker D, Holford CP, Begent RHJ, et al: Effective treatment for malignant mediastinal teratoma. Thorax 38:897–902, 1983. Pugatch RD, Faling LJ, Robbins AH, et al: CT diagnosis of benign mediastinal abnormalities. Am J Roentgenol 134:685– 694, 1980. Rodriguez M, Gomez MR, Howard FM Jr, et al: Myasthenia gravis in children: Long-term follow-up. Ann Neurol 13:504–510, 1983.

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Diseases of the Mediastinum

Rosai J, Levine GD: Tumors of the thymus, in Atlas of Tumor Pathology, 2nd series, fascicle 13. Washington, DC, Armed Forces Institute of Pathology, 1976, pp 55–99. Sabiston DC, Scott HW: Primary neoplasms and cysts of the mediastinum. Ann Surg 136:777–797, 1951. Sanders LE, Rossi RL, Shahian DM, et al: Mediastinal goiters: The need for an aggressive approach. Arch Surg 127:609– 613, 1992. Saunders DB, Scoppetta C: The treatment of patients with myasthenia gravis. Neurol Clin North Am 12:343–369, 1994. Shamberger RC, Holzma RS, Griscow NT, et al: CT quantitation of tracheal cross-sectional areas as a guide to the surgical and anesthetic management of children with anterior mediastinal masses. J Pediatr Surg 26:138–143, 1991. Shapiro B, Sisson J, Kalff V, et al: The location of middle mediastinal pheochromocytomas. J Thorac Cardiovasc Surg 87:814–820, 1994. St. Georges R, Deslauriers J, Duranceau A, et al: Clinical spectrum of bronchogenic cysts of the mediastinum and lung in the adult. Ann Thorac Surg 52:6–13, 1991.

Sugarbaker DJ: Thoracoscopy in the management of anterior mediastinal masses. Ann Thorac Surg 56:653–656, 1993. Suster S, Rosai J: Thymic carcinoma: A clinicopathologic study of 60 cases. Cancer 67:1025–1032, 1991. Urschel HC, Razzuk MA, Netto GJ, et al: Sclerosing mediastinitis: Improved management and histoplasmosis titer and ketoconazole. Ann Thorac Surg 50:215–221, 1990. Van Dam J, Rice TW, Sivak MV: Endoscopic ultrasonography and endoscopically guided needle aspiration for the diagnosis of upper gastrointestinal tract foregut cysts. Am J Gastroenterol 87:762–765, 1991. Von Schulthess GK, McMurdo K, Tscholakoff D, et al: Mediastinal masses: MR imaging. Radiology 158:289–296, 1986. Weide LG, Ulbright TM, Loehrer PJ, Williams SD: Thymic carcinoma: A distinct clinical entity responsive to chemotherapy. Cancer 71:1219–1223, 1993. Wheatley MJ, Stirling MC, Kirsh MM, et al: Descending necrotizing mediastinitis: transcervical drainage is not enough. Ann Thorac Surg 49:780–784, 1990.

PART

XII Disorders of the Chest Wall, Diaphragm, and Spine

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92 Nonmuscular Diseases of the Chest Wall George E. Tzelepis F. Dennis McCool

I. KYPHOSCOLIOSIS Diagnosis and Etiology Respiratory Mechanics and Pulmonary Function Tests Exercise Capacity Control of Breathing Sleep Disordered Breathing Gas Exchange Clinical Course Treatment II. THORACOPLASTY III. PECTUS EXCAVATUM Respiratory Mechanics and Exercise Capacity Treatment

Gas Exchange and Exercise Capacity Pleuropulmonary Abnormalities Treatment V. OBESITY Chest Wall Mechanics and Pulmonary Function Control of Breathing Gas Exchange Treatment VI. FLAIL CHEST Pulmonary Function and Respiratory Mechanics Treatment

IV. ANKYLOSING SPONDYLITIS Etiology and Clinical Features Respiratory Mechanics and Pulmonary Function Tests

The chest wall, an integral part of the respiratory pump, consists of the rib cage, rib cage muscles, diaphragm, and abdomen. Like the respiratory muscles, the nonmuscular structures of the chest wall (i.e., thoracic spine, ribs) are also essential for normal respiratory function. Disorders primarily affecting these structures, by themselves or in combination with other disease processes, may impose elastic and resistive loads on the inspiratory muscles, weaken them and ultimately lead to respiratory failure and death. In some disorders, such as kyphoscoliosis and obesity, the load on the respiratory muscles is chronic and progressive. In contrast, with flail chest, the load on the respiratory muscles is acute. The respiratory muscles have little time to adapt and respiratory failure may quickly ensue. Other disorders, such as ankylosing spondylitis and pectus excavatum, have minimal impact on respiratory function. Diseases directly affecting the respiratory muscles are discussed in Chapter 93.

KYPHOSCOLIOSIS Diagnosis and Etiology Kyphoscoliosis refers to a group of spinal disorders characterized by curvature of the spine in the lateral direction (scoliosis), sagittal plane (kyphosis) as well as rotation of the spine itself (Fig. 92-1). Kyphoscoliosis may be: (a) congenital; (b) secondary to other disorders; or (c) idiopathic (Table 92-1). Congenital kyphoscoliosis is usually present at birth. Not necessarily familial, congenital kyphoscoliosis may be related to isolated malformations of the vertebrae during prenatal development or may be a manifestation of a more generalized disorder such as muscular dystrophy, Ehlers-Danlos syndrome, or neurofibromatosis. Secondary kyphoscoliosis is usually associated with diseases that primarily affect the neuromuscular system. Kyphoscoliosis associated with

1618 Part XII

Disorders of the Chest Wall, Diaphragm, and Spine

Table 92-1 Causes of Kyphoscoliosis Congenital Paralytic or secondary Neuromuscular Poliomyelitis Muscular dystrophy Cerebral palsy Friedreich’s ataxia Charcot-Marie-Tooth disease Disorders of connective tissue Marfan’s syndrome Ehlers-Danlos syndrome Morquio’s syndrome Vertebral disease Osteoporosis Osteomalacia Vitamin D-resistant rickets Tuberculous spondylitis Spina bifida Post-thoracoplasty Idiopathic

Figure 92-1 Schematic representation of the rotation of the spine and the rib cage seen with scoliosis. (Based on data of Bergofsky EH, Torino GM, Fishman AP: Cardiorespiratory Failure in Kyphoscoliosis. Medicine (Baltimore) 38:263–317, 1959.)

neuromuscular disease is sometimes referred to as “paralytic” kyphoscoliosis. The most common causes of paralytic kyphoscoliosis are polio, muscular dystrophy, cerebral palsy, and spina bifida. Idiopathic kyphoscoliosis, the most common cause of all forms of kyphoscoliosis, usually begins in late childhood or early adolescence and involves females more often than males with a ratio of 4:1. In severe kyphoscoliosis, the deformity is readily apparent on physical examination. The dorsal hump seen on examination is due to the angulated ribs rather than to the spine. The shoulders and hips are also rotated and on different planes because of the spinal rotation. In children and adolescents with idiopathic kyphoscoliosis, the initial changes in spinal curvature may be very subtle and require careful inspection to detect them. However, as the degree of kyphosis progresses the spinal deformity becomes easily recognized. The true degree of spinal rotation and flexion is not apparent on physical examination, especially in mild cases

of kyphoscoliosis. The severity of the defect is more accurately assessed by radiographically measuring the Cobb angle, which is the angle formed by the intersection of two lines, each of which is parallel to the top and bottom vertebrae of the scoliotic or kyphotic curves (Fig. 92-2). The greater the Cobb angle, the more severe is the deformity. Cobb angles of greater than 100 degrees are more likely to be associated with respiratory symptomatology. Typically, symptoms consist of dyspnea on exertion that progress with age and the degree of spinal deformity.

Respiratory Mechanics and Pulmonary Function Tests The combined effects of kyphosis, scoliosis, and rotation of the spine reduce the compliance of the chest wall and increase the recoil pressures of the chest wall and the respiratory system at any given lung volume, with the recoil pressures being greatest as one approaches total lung capacity (TLC) (Fig. 92-3). The most pronounced reductions in respiratory system and chest wall compliance are usually seen in individuals with severe kyphoscoliosis and Cobb angles greater than 100 degrees. These individuals may exhibit the most severe reductions in chest wall and respiratory system compliances when compared with other diseases of the chest wall (Table 92-2). Those with scoliotic angles of less than 50 degrees usually have minimal changes in respiratory system compliance. However, children with congenital kyphoscoliosis may have

1619 Chapter 92

Nonmuscular Diseases of the Chest Wall

Table 92-2 Respiratory Mechanics in Diseases of the Chest Wall

Figure 92-2 Schematic of the posteroanterior radiograph depicting the lines constructed to measure the Cobb angle of scoliosis and the lines drawn on the lateral radiograph to measure the Cobb angle of kyphosis. (Based on data of Rochester DF, Findley LJ: The lungs and neuromuscular and chest wall disorder in Murray and Nadel (eds), Textbook of Respiratory Medicine. Philadelphia, WB Saunders, 1988, p 1942.)

normal chest wall compliance despite pronounced chest wall deformity. This may reflect a very compliant rib cage in newborns and young children. The lung also becomes less distensible, but its compliance is not as severely affected as that of the chest wall. It is thought that the reduced lung compliance results from microatelectasis due to breathing with low tidal volumes rather than from intrinsic lung disease. Respiratory muscle strength, assessed by measurements of maximal static inspiratory and expiratory pressures (PImax and PEmax , respectively), may be normal or reduced in patients with kyphoscoliosis. Individuals with kyphoscoliosis secondary to neuromuscular diseases have the most pronounced inspiratory muscle weakness, whereas respiratory muscle strength is typically normal in young patients with idiopathic scoliosis and Cobb angles of less than 50 degrees. When the Cobb angle is greater than 50 degrees, there may be mild to moderate reductions in PImax and PEmax . In the

Post-THOR

CRS (% predicted)

â&#x20AC;&#x201D;

CCW (% predicted)

â&#x20AC;&#x201D;

CL (% predicted)

Pimax (cm H2 O)

MVV (L/min)

107

Notes: Abbreviations: KS = kyphoscoliosis; Post-THOR = postthoracoplasty; PE = pectus excavatum; AS = ankylosing spondylitis; CRS = compliance of respiratory system; CCW = compliance of chest wall; CL = compliance of lungs; PImax = maximum inspiratory pressure; MVV = maximum voluntary ventilation.

absence of neuromuscular disease, the reduced strength may be related to altered geometry of the chest wall, which in turn affects the mechanical advantage of the respiratory muscles. In patients with secondary kyphoscoliosis due to neuromuscular diseases, the reduced respiratory system compliance in conjunction with respiratory muscle weakness may result in a profound restrictive process. These individuals are at extreme risk for developing respiratory failure. Kyphoscoliosis can lead to one of the most profound restrictive patterns of any of the chest wall diseases (Table 92-3). TLC and vital capacity (VC) may be reduced to 30 percent of predicted with severe deformities of the spine. Residual volume (RV) may be normal or slightly increased. Since the RV is not as severely affected as TLC, the RV/TLC ratio may be high. Individuals with mild and moderate degrees of

Figure 92-3 Schema showing the volume-pressure relationships of the chest wall (dashed line), lung (dot and dashed line), and respiratory system (solid line) for (A) healthy individuals, (B ) individuals with chest wall restriction, and (C ) individuals with chest wall restriction complicated by inspiratory muscle (IM) weakness. C . Maximal inspiratory muscle pressures (Pmus ) are reduced by about half in this panel. B . The reduction of chest wall compliance lowers respiratory system compliance, FRC, and TLC. C . The restriction is amplified by the presence of IM weakness.

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Disorders of the Chest Wall, Diaphragm, and Spine

velocities of shortening that the muscles can develop. Since respiratory muscle fatigue is, in part, a function of the balance between the loads placed upon the respiratory muscles and their reserve to overcome these loads, it is clear that individuals with severe kyphoscoliosis are at high risk for developing respiratory failure.

Table 92-3 Pulmonary Function in Diseases of the Chest Wall KS

Post-THOR

TLC (% predicted)

VC (% predicted)

RV (% predicted)

100

FEV1 (% predicted)

FEV1 /FVC

Note: Abbreviations: KS = kyphoscoliosis; Post-THOR = postthoracoplasty; PE = pectus excavatum; AS = ankylosing spondylitis; TLC = total lung capacity; VC = vital capacity; RV = residual volume; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity.

kyphosis and scoliosis (Cobb angles less than 60 degrees) may only have mild reductions in VC and TLC. Individuals with Cobb angles greater than 90 degrees, however, invariably have restricted lung volumes. Other factors contributing to the degree of restriction include: (a) the number of vertebrae involved; (b) the location of the curve; (c) the patientâ&#x20AC;&#x2122;s age; (d) the presence of kyphosis; and (e) the degree of rotation of the spine. Although indices of forced expiratory flow are typically reduced, i.e. a low FEV1 , the ratio of FEV1 /FVC remains normal, thereby indicating no concomitant obstructive process. Although the degree of spinal curvature is associated with the extent of pulmonary restriction, inspiratory muscle strength is another factor that importantly determines severity of the restrictive pattern. In patients with paralytic kyphoscoliosis (spinal deformity secondary to neuromuscular disease), the neuromuscular weakness itself seems to be the predominant factor promoting restriction and the association between the degree of spinal curvature and extent of restrictive dysfunction is not as strong. Individuals with paralytic kyphoscoliosis are thus likely to have greater pulmonary function impairment for a similar degree of spinal deformity than patients with idiopathic scoliosis. Similarly, individuals with congenital scoliosis have a greater loss in VC for a given degree of spinal deformity than patients with idiopathic scoliosis. Coexisting rib deformities or underlying lung abnormalities amplify the restrictive process in individuals with congenital scoliosis. The combination of reduced chest wall and lung compliance increases the elastic work of breathing. Since the oxygen cost of breathing increases with increasing loads placed on the respiratory system, it is not surprising that the resting oxygen cost of breathing is three to five times that seen in healthy subjects. Inspiratory muscle weakness diminishes respiratory muscle reserve by reducing maximal forces and

Exercise Capacity Individuals with combined restrictive defect and inspiratory muscle weakness have impaired exercise tolerance. Maximum oxygen consumption may be reduced to about 60 to 80 percent of predicted. Because these individuals exhibit a restrictive pattern on pulmonary function testing, the breathing pattern response to exercise in patients with severe kyphoscoliosis differs from that seen in normal subjects. Specifically, the ratio of tidal volume to vital capacity (VT/VC) is greater than 0.5 and the ratio of maximum exercise ventilation to maximum voluntary ventilation (VEmax /MVV) can reach 70 percent. Deconditioning and lack of regular aerobic exercise may be contributing to the poor exercise tolerance in individuals with moderate to severe scoliosis. Supplemental oxygen may improve oxygenation during exercise but usually does not affect walk distance.

Control of Breathing When an elastic load is imposed on the respiratory muscles in a healthy individual, the neural drive to breathe is increased. Accordingly, one may predict that the added elastic load of the stiffened chest wall would provide a greater stimulus to breath in individuals with kyphoscoliosis. Thus, during quiet breathing or breathing stimulated by carbon dioxide or exercise, indirect measures of neural drive to the respiratory muscles, such as the mouth occlusion pressure at 100 ms (P0.1), may be elevated in these individuals. The mouth occlusion pressure (P0.1) has been shown to correlate positively with the degree of scoliotic deformity. Increased drive may not be seen as an increase in ventilatory response to CO2 as the stiffened chest wall has reduced mobility and cannot increase ventilation in response to increased respiratory muscle drive or activity. Thus, the drive to breathe may be normal in these individuals, but compensatory increases in minute ventilation are limited by mechanical factors of the rib cage. The effects of aging and its influence on the control of breathing require further clarification in this population as any blunting of respiratory drive increase the risk of CO2 retention. Another means of compensating for heightened elastic loads is to alter breathing pattern (i.e., raise respiratory frequency and lower tidal volume). Patients with severe kyphoscoliosis may adopt a rapid shallow breathing pattern consisting of low tidal volumes and shortened inspiratory time. Both of these factors are found to correlate negatively with the angle of scoliosis. The advantages of adopting such a breathing pattern include: (a) a reduction in the work per breath, but not necessarily the cumulative work per minute; and (b) the reduction of the ratio of pressure needed to inhale

1621 Chapter 92

(P breath) to PImax . In theory, reducing this ratio would lessen the likelihood of developing inspiratory muscle fatigue. However, the disadvantages of adopting this breathing pattern include worsening microatelectasis leading to further reduction of lung compliance.

Sleep Disordered Breathing Patients with kyphoscoliosis may be predisposed to hypoventilation during sleep. The increased elastic load due to stiffened chest wall heightens respiratory drive so that diaphragm activation increases and there is greater recruitment of the inspiratory muscles of the rib cage. Since neural drive to the intercostal muscles is diminished during non-rapid eye movement (non-REM) sleep and may be absent during REM sleep, the burden of expanding the nondistensible chest wall falls more on the diaphragm. If there is any degree of diaphragm weakness, this can result in hypoventilation, especially during REM sleep. Consequently, the degree of oxyhemoglobin desaturation during sleep is more severe in individuals with severe kyphoscoliosis than that seen during sleep in patients with other respiratory diseases, such as chronic obstructive pulmonary disease or interstitial lung disease. The magnitude of hypoxia may not correlate with the degree of thoracic deformity. Persistent nocturnal desaturation during sleep may further exacerbate respiratory muscle dysfunction, lead to cor pulmonale, and predispose these individuals to cardiorespiratory failure. Obstructive sleep apnea, which has a prevalence similar to that seen in the general population, may further complicate nocturnal hypoventilation in these patients. Because sleep-related disorders represent a potentially treatable cause of respiratory failure, they should always be evaluated in kyphoscoliotic patients with carbon dioxide retention.

Gas Exchange Persistent nocturnal desaturation may eventually be associated with daytime hypoxemia and hypercapnia. The cause of hypoxemia may be multifactorial; ventilation/perfusion (V/Q) mismatching is commonly present and is worse in patients with Cobb angles greater than 65 degrees. In addition to V/Q mismatch, intrapulmonary shunt related to underlying atelectasis as well as alveolar hypoventilation may also account for the hypoxemia in some individuals. Hypercapnia initially appears during sleep and with exercise; eventually, as the disease progresses, hypercapnia is seen during the day. Prolonged hypoxemia may result in pulmonary hypertension. The degree of hypoxemia is positively associated with the degree of kyphosis, but not with the etiology of kyphoscoliosis, or age of onset of scoliosis. Individuals with severe kyphoscoliosis may have oxyhemoglobin desaturation with minimal activity.

Clinical Course Congenital kyphoscoliosis may exhibit a rapidly progressive course with spinal cord compression further compromising

Nonmuscular Diseases of the Chest Wall

the respiratory system. Similarly, individuals with neuromuscular disease who develop secondary kyphoscoliosis may also have pronounced respiratory disability. Those at greater risk for developing respiratory complications are individuals who have an onset of the spinal deformity at an early age, rapid progression of the deformity during growth, and continued progression after skeletal maturity. By contrast, individuals with idiopathic kyphoscoliosis typically have a more benign course. If the thoracic deformity is mild, they have an excellent prognosis with little impairment in breathing or overall lifestyle. Individuals with mild idiopathic kyphoscoliosis are no more likely to develop ventilatory failure or have any greater loss of lung volume with aging than the general population. However, those with moderate or severe idiopathic kyphoscoliosis may be at higher risk for respiratory compromise. In general, individuals with thoracic deformities greater than 50 degrees at skeletal maturity are at risk for a progressive increase in the spinal angulation at a rate of about 1 degree annually. Although individuals with severe idiopathic kyphoscoliosis younger than 35 years of age are usually asymptomatic, those who are older need to be closely monitored for respiratory compromise. These individuals may have an insidious onset of shortness of breath, initially with exertion and then at rest. As the spinal deformity progresses during aging, respiratory failure may ensue. Once cor pulmonale develops, the prognosis is generally poor and, without treatment, death may occur within 1 year. This risk depends on the degree of deformity. Factors such as inspiratory muscle weakness, underlying neuromuscular disease, sleep disordered breathing, and airway compression should be entertained. Concomitant obstructive dysfunction heightens the risk for respiratory failure. In contrast, pregnancy poses no added risk for respiratory complications; however, patients with severe degrees of kyphoscoliosis and reductions in VC to less than 1 L may have respiratory difficulties during pregnancy. The observation that patients with Cobb angles of greater than 100 degrees may survive into their seventh decade with minimal or mild cardio-respiratory impairment supports the notion that factors other than the spinal deformity also importantly influence outcome.

Treatment General supportive care for adults with kyphoscoliosis includes immunization against influenza and pneumococci, prompt care of respiratory infections, use of supplemental oxygen, smoking cessation, and maintenance of body weight within a desirable level. Preventive measures include interventions such as chest physiotherapy, use of bronchodilators, diuretics, and physical activity to improve exercise capacity and minimize deconditioning. Supplemental oxygen may be needed with activity or exercise and can be beneficial in improving exercise tolerance. Specific treatment of nocturnal hypoventilation can be accomplished with noninvasive positive pressure ventilation, which is typically delivered by a nasal or full-face mask.

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Disorders of the Chest Wall, Diaphragm, and Spine

Indications for initiating noninvasive nocturnal ventilation include symptoms suggestive of nocturnal hypoventilation (i.e., fatigue, morning headache, dyspnea) or signs of cor pulmonale with either an elevated daytime arterial Pco2 or nocturnal oxygen saturation less than 88 percent for 5 consecutive minutes. The advent of this method of ventilatory support has provided an alternative to the clinician for treating respiratory failure. Treatment of respiratory failure with these devices may avert or delay the need for tracheotomy. Both negative and positive pressure devices have been used to ventilate individuals with kyphoscoliosis noninvasively. Initially, negative pressure ventilators such as cuirass, body wrap ventilators, or tank ventilators were used. However, drawbacks of using such devices included induction of upper airway obstruction during sleep, the bulky nature of the equipment, and the need to custom fit devices such as a cuirass ventilator to the chest wall. In contrast, noninvasive positive pressure ventilation has become a more accepted therapy because the equipment is compact and more portable than negative pressure devices. Furthermore, if there is associated sleep apnea, positive pressure devices are well suited to minimize the apneic episodes. When prescribing a positive pressure device, either a pressure- or volume-preset ventilator can be recommended. Apart from a greater leakage with the pressure modality, these two modalities have equivalent effects on physiological and clinical parameters and overall health status. The rapid shallow breathing pattern that is usually adopted by these patients highlights the importance of having a ventilator that has a short response time and minimizes patient-ventilator asynchrony. Contraindications to noninvasive ventilation include the inability to protect the upper airway due to impaired cough or excessive airway secretions. The benefits of noninvasive nocturnal ventilation in patients with kyphoscoliosis have been well documented and include improvements in quality of life, gas exchange, sleep architecture, and pulmonary hemodynamics (Table 92-4). It has much less of an impact on measurements of VC and respiratory muscle strength, including twitch trans-diaphragmatic pressure or endurance. The likely mechanism of improvement in respiratory failure is increased ventilatory response to carbon dioxide rather than improvement in respiratory muscle contractility. Long-term noninvasive ventilation significantly reduces the number of days spent in the hospital as well as number of hospitalizations for respiratory failure. It is also likely that there is a survival benefit in patients with kyphoscoliosis who have had an episode of respiratory failure (Fig. 92-4). In uncontrolled studies at 1 and 5 years, survival of patients with kyphoscoliosis and respiratory failure who were treated with noninvasive ventilation was 90 and 80 percent, respectively. The role of noninvasive ventilation in acute respiratory failure is not as well documented. In this instance, volume cycle ventilation via an endotracheal tube would be the treatment of choice. Operative treatment traditionally consists of spinal fusion and/or insertion of Harrington rods. These approaches

Table 92-4 Therapeutic Benefits of Noninvasive Mechanical Ventilation in Patients with Kyphoscoliosis Gas exchange indices Pao2 Paco2 Bicarbonate

Increase Decrease Decrease

Pulmonary Function Tests FVC FEV1 TLC FRC

No change No change No change No change

Respiratory mechanics MIP, MEP Twitch Pdi Chest wall compliance Lung compliance Hemodynamic parameters PAP Ventilatory control Hypercapnic ventilatory response

No change or slight increase No change No change No change

Decrease

Increase

Sleep Epworth sleepiness score

Decrease

Quality of life Survival

Improvement Increase

Efficacy data derived from mostly nonrandomized, noncontrolled studies. Notes: Abbreviations: MIP = maximal inspiratory pressure; MEP = maximal expiratory pressure; Pdi = transdiaphragmatic pressure; PAP = pulmonary artery pressure.

have been used for many years to correct the spinal deformity and stabilize the spine. However, these interventions are often accompanied by complications later in life, such as chronic back pain or further spinal deformation. Spinal fusion and Harrington rod placement may not significantly improve the VC or gas exchange in patients over the age of 20. Typically, immediately following surgery, there is a reduction in the compliance of the chest wall and respiratory system as well as in VC, although improvements in pulmonary function may occur in some individuals. In children and adolescents, the results are more promising. In the short term (11/2 to 3 years following surgery) lung function may improve. The role of surgery may be most important in patients with

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Nonmuscular Diseases of the Chest Wall

Figure 92-4 Survival curves of kyphoscoliotic patients treated with long-term oxygen therapy (LTO) or LTO and nocturnal nasal intermittent positive pressure ventilation (nNIPPV). (From Buyse B, Meersseman W, Demedts M: Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation? Eur Respir J 22:525â&#x20AC;&#x201C;528, 2003, with permission.)

kyphoscoliosis secondary to neurological disorders. In these individuals, early stabilization of the spine may help prevent progressive myelopathy. Surgery has recently evolved to include less invasive procedures such as titanium rib implantation with rib cage expansion. Initial results are promising in individuals with congenital kyphoscoliosis. In summary, severe kyphoscoliosis alters the mechanics of the chest wall, imposes an elastic load on the respiratory muscles, increases the work of breathing, and ultimately leads to hypercapnic respiratory failure and cor pulmonale. The degree and onset of respiratory impairment depend to a large extent on the underlying cause of kyphoscoliosis, rate of progression of deformity, onset in relation to skeletal maturity, coexisting respiratory muscle weakness, and sleep disordered breathing. Noninvasive positive pressure ventilation is highly effective in improving gas exchange, overall clinical status, and prognosis in patients with respiratory failure.

disease, previous lung resection, or phrenic nerve damage. Often, surgery on the rib cage was followed by progressive scoliosis with aging and further deterioration of respiratory function. The severity of restriction and stiffening of the chest wall was similar to that seen with kyphoscoliosis leading to an increase in the oxygen cost of breathing, limited exercise tolerance, and impairment in gas exchange. In general, hypoxemia was common in these patients and cor pulmonale often developed as a harbinger of a poor prognosis. As with severe kyphoscoliosis, treatment consisted of domiciliary oxygen, antibiotics when appropriate, and noninvasive nocturnal ventilation. Although it is unlikely that one may encounter post-thoracoplasty patients, knowledge of the natural history and progressive impairment of respiratory function following aggressive surgery on the rib cage may be useful in understanding and anticipating complications due to similar chest wall surgery for other reasons, such as postinfectious empyema or aggressive treatment of lung cancer.

THORACOPLASTY Prior to the advent of antituberculous chemotherapy, surgery involving the lung and/or rib cage was one approach to treat tuberculosis. The varied surgical procedures are referred to as thoracoplasty and were intended to compress the underlying lung (Fig. 92-5). Thoracoplasty consists of different combinations of rib removal, rib fractures, phrenic nerve resection, or compression of underlying lung by filling the pleural space with foreign material (i.e., ping pong balls). Since this procedure was performed in the 1940s and 1950s, very few people, who are alive today, have had these procedures. However, much can be learned from the natural history of patients who have undergone thoracoplasty. These individuals commonly developed dyspnea, severe restrictive dysfunction, and chronic respiratory failure as they aged. The severity of the restrictive pattern was related to a number of factors including the number of ribs removed, the presence of fibrothorax, progressive lung fibrosis due to underlying granulomatous

Figure 92-5 Chest radiograph of a patient with a history of M. tuberculosis, demonstrating marked deformity of the left hemithorax consistent with prior thoracoplasty.

1624 Part XII

Disorders of the Chest Wall, Diaphragm, and Spine

PECTUS EXCAVATUM Pectus excavatum is a chest wall deformity characterized by excessive depression of the sternum which affects between 0.5 and 2 percent of the population. It occurs once in every 1000 children and is the most common chest wall deformity seen by pediatricians. The deformity occurs more frequently in males than females (3:1 ratio). The sternal depression can be minimal or extreme. In extreme cases it is readily apparent at birth and progresses as the child grows, especially during the teenage years. The etiology of pectus excavatum is unknown. It is possible that a defect in the connective tissues surrounding the sternum may be present. Connective tissue disorders such as Marfanâ&#x20AC;&#x2122;s syndrome have a higher incidence of pectus deformity. A family history may or may not be present and other factors such as scoliosis, congenital heart disease, and functional heart murmurs occur in patients with pectus excavatum. The most frequent complaints of patients with pectus excavatum are cosmetic and usually become most troublesome between the ages of 15 and 20 years. Dyspnea with activity and exercise intolerance occurs in 30 to 70 percent of patients. These symptoms are usually out of proportion to what one would expect from the mild restrictive pattern or normal echocardiography. Although rare, respiratory failure can occur in adults with severe pectus deformity. The degree of deformity is assessed radiographically, most often with chest computed tomography (CT), by measuring the ratio of the transverse to anterior-posterior (AP) diameters of the rib cage at the level of the deepest sternal depression (Fig. 92-6). If the ratio is greater than 3.25, the pectus deformity is considered significant.

Respiratory Mechanics and Exercise Capacity Impairment in pulmonary function is usually minimal, with TLC and VC being normal or mildly reduced. In most cases, there is no underlying lung disease and lung compliance is

Figure 92-6 Chest computed tomography of a patient with pectus excavatum. The distance between the anterior aspect of the vertebral body and the posterior aspect of the sternum is decreased.

normal. If restriction is apparent on pulmonary function testing, it may be related to the presence of concomitant scoliosis. In contrast to individuals with ankylosing spondylitis, the mobility of the rib cage is not impaired during quiet breathing or exercise. Cardiopulmonary exercise testing is often normal in these individuals. Indices such as maximal work rate, maximal oxygen consumption, and maximal heart rate, as well as the oxygen pulse, are similar among patients with pectus excavatum and controls. Only the most severe deformities may be associated with reductions in maximal work rate or a decrease in oxygen consumption at a given work rate. In these instances, the reduction in exercise capacity is out of proportion to what one would expect from the mild restrictive process. Therefore, other factors leading to decreased exercise tolerance may be operant. Among postulated mechanisms is a reduction in venous return to the heart associated with right ventricular compression due to sternal deformation. In keeping with this postulated mechanism, cardiac anomalies such as compression of the right ventricle, narrowing of the right ventricular outflow track and sacculations of the right ventricular wall have been observed using two-dimensional echocardiography.

Treatment Medical therapy for pectus excavatum is generally supportive. However, certain individuals with severe deformities have undergone surgical repair of the rib cage. Some individuals selected for surgical repair have had a chest CT scan demonstrating a transverse to AP diameter ratio of greater than 3.25 at the level of the greatest sternal depression. Others with lesser degrees of deformity (transverse to AP diameter ratio less than 3.25) also have undergone repair. Although surgery is most often performed for cosmetic purposes, occasionally it is indicated to relieve pulmonary restriction. The surgical approaches may be invasive or minimally invasive. Earlier operations, such as the Ravitch repair, include resection of costal cartilage and a sternal osteotomy with or without fixation of the sternum with external or internal supports. This procedure may be complicated by sternal necrosis, infection, or recurrence of the deformity especially in younger children in whom sternal supports are not used. Surgery at an age less than 4 may be further complicated by arrest in growth of the rib cage and worsening of the restrictive process. A less invasive approach has been developed over the last decade. The Nuss procedure provides a minimally invasive alternative to the traditional approach to correcting pectus deformity. The Nuss procedure consists of placing a curved metal bar under the sternum at the point of its deepest depression through small incisions made on each side of the rib cage (Fig. 92-7). Coastal cartilage is not resected and the sternum is pushed forward and stabilized by the metal bar. The bar generally is in place for 2 to 4 years, resulting in permanent chest wall remodeling. The approach leads to immediate cosmetic improvement. Complications

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Nonmuscular Diseases of the Chest Wall

appearance but are not always associated with improvements in pulmonary function or exercise capacity.

ANKYLOSING SPONDYLITIS Etiology and Clinical Features

Figure 92-7 Schema depicting the Nuss procedure in a patient with pectus excavatum. A curved bar is inserted behind the sternum and then rotated to displace the depressed sternum ventrally.

of the minimally invasive approach include bar displacement or rotation that would require reoperation, as well as pneumothorax, pericarditis, and infection. Both procedures afford a positive effect on the psychosocial well-being of the patient. Physiological benefits of either invasive or minimally invasive procedures remain controversial. Pulmonary function may actually deteriorate and exercise capacity and dyspnea may improve slightly. Because most studies of pulmonary function were performed in patients undergoing the more invasive Ravitch operation, the deterioration in pulmonary function seen early or several years after surgical repair has been attributed to disordered chest wall mechanics as a result of structural changes in the sternal and parasternal areas. In theory, the minimally invasive procedure should have fewer adverse effects on pulmonary function. The effects of surgery on exercise tolerance are controversial. Improvements in exË&#x2122; 2max after surgical corercise tolerance, cardiac output and VO rection have been reported in some but not in all studies. Discrepancies among studies may be due to differences in patient selection, surgical techniques, interval after the operation, or the effects of growth on pulmonary function. In summary, pectus deformities apart from their aesthetic effects may also be accompanied by slight decreases in exercise capacity, TLC, and VC. Selection of patients for surgical correction is based on radiographic measurements of the transverse and AP diameter of the chest wall. The minimally invasive correction techniques may cosmetically restore chest

Ankylosing spondylitis (AS), a chronic inflammatory disease of unknown etiology, is the prototype of a group of related disorders known as the spondyloarthritides, the main characteristic of which is inflammation of the axial skeleton. The spinal involvement in AS can be more severe than that seen in other spondyloarthritides. In particular, the chronic inflammation of the spinal structures and sacroiliac joints may lead to fibrosis and ossification of these structures, thereby limiting spinal mobility. Bony ankylosis of the costovertebral and sternoclavicular joints causes considerable limitation in rib cage expansion. The annual incidence of AS is 6.6 per 100,000 Caucasian Americans, afflicting men more commonly than women. There is a genetic predisposition for AS, as 95 percent of Caucasian with AS have the HLA-B27 antigen. Clinically, AS patients typically complain of low back pain and stiffness beginning in late adolescence or early adulthood; onset of the disease after the age of 45 is rare. Symptoms are worse in the morning or after rest. Chest pain due to inflammation of manubriosternal junction and/or the sternoclavicular joints and inability to fully expand the chest on inspiration are infrequent complaints. On physical examination, there may be tenderness of the anterior chest wall, or over the costochondral region or the manubriosternal junction. Exercise intolerance and dyspnea are uncommon, unless the patient has parenchymal lung disease, diaphragmatic dysfunction, or cardiac disease. Frequently, sleep interruption due to back pain and stiffness may lead to daytime somnolence and fatigue. Upper airway obstruction due to cricoarytenoid cartilage involvement is a rare complication. In late stages, the limited rib cage expansion may be obvious on inspection while the individual is in the seated position. The change in rib cage circumference at the level of the fourth intercostal space can be measured between a full inspiration and full expiration. If not explained by another condition, rib cage expansion less than 2.5 cm is abnormal and should raise the possibility of AS in young patients with chronic low back pain.

Respiratory Mechanics and Pulmonary Function Tests Limited expansion of the rib cage is the hallmark of respiratory involvement in AS. This limitation results from fusion of the costovertebral and sternoclavicular joints and possibly intercostal muscle atrophy. The direction of rib cage motion is similar to that in healthy individuals, but the extent of movement is diminished (Fig. 92-8). As with kyphoscoliosis, chest wall and total respiratory system compliance is reduced

1626 Part XII

Disorders of the Chest Wall, Diaphragm, and Spine

Figure 92-8 Changes in anteroposterior dimensions of the rib cage (RC) and abdomen (Abd) in a healthy individual and one with ankylosing spondylitis (AS). There is limited mobility of the rib cage in all positions resulting in greater motion of the abdomen relative to the rib cage.

in AS, while chest wall resistance is increased. In general, lung compliance is normal unless there is fibrobullous lung disease. Since expansion of the rib cage is severely limited, displacement of the abdomen by diaphragm displacement is the primary pathway for inflating the chest wall, as rib cage expansion is severely limited. Accordingly, most of the volume change during quiet breathing or exercise can be attributed to caudal displacement of the diaphragm and abdominal wall expansion. For example, in healthy individuals, transdiaphragmatic pressure increases by 1.4-fold during stimulated CO2 rebreathing. In contrast, transdiaphragmatic pressure in AS increases 2.2-fold for a given amount of minute ventilation during stimulated CO2 rebreathing. The combination of increased diaphragm shortening and decreased chest wall compliance increases the work performed by the diaphragm and may potentially provide a training stimulus to the diaphragm. Measurements of pulmonary function usually reveal only mild reductions in VC and TLC. VC is generally reduced to 70 percent of predicted; the reduction is positively correlated with lack of rib cage expansion, disease activity and duration, and spinal mobility. TLC is reduced on average to 80 percent of predicted, and its reduction is proportional to the radiographic severity of spinal ankylosis. Because the rib cage is often fixed in an inspiratory position, both FRC and RV may be increased above predicted normal levels; consequently, the RV/TLC ratio may also be higher. In this setting, the increased RV/TLC ratio should not be interpreted as related to obstructive airway disease. Osteoporosis of the thoracic spine, which is frequently found in AS, especially in late stages, may lead to kyphosis, modest spinal deformity, and worsening of the restrictive defect. However, the kyphosis angle does not correlate with VC in AS because the effects of posterior fusion of the ribs play a greater role in limiting rib expansion and VC than the degree of kyphosis. Because the rigid osteoporotic spine is excessively fragile, spinal fractures can occur even with minimal trauma. These fractures may also lead to kyphosis and further compromise of respiratory function. Cervical spine

fractures, usually at the C6 or C7 level, can result in tetraplegia and respiratory failure. They are associated with a high mortality. Modest decrements in indices of respiratory muscle strength, especially PImax and PEmax , have been described in patients with AS. Because these maximal pressures are limited by the rib cage and accessory muscles, the reduction in these pressures may be related to possible intercostal muscle atrophy secondary to decreased rib cage mobility rather than to diaphragmatic dysfunction. The ability of diaphragm to generate pressure appears to be intact in these patients.

Gas Exchange and Exercise Capacity Gas exchange is usually normal, with Pao2 either within the normal range or slightly reduced. Modest hypoxemia may be due to concomitant apical fibrobullous lung disease. Exercise capacity may be mildly decreased in patients with AS, especially in those with marked chest wall restriction. The mechanism of exercise limitation does not appear to be due to ventilatory impairment, as patients usually attain adequate minute ventilation during exercise. Instead, peripheral deconditioning or cardiac limitation may be responsible for the decreased exercise capacity. In support of a cardiac etiology are recent studies showing a decreased stroke volume during exercise in normal individuals with chest wall restriction caused by strapping the rib cage.

Pleuropulmonary Abnormalities A small percentage (1 to 4 percent) of AS patients develops upper lobe fibrobullous disease. Although the causes are not entirely known, they may include decreased upper lobe ventilation, mechanical stress due to rib cage rigidity, and recurrent lung infections due to impaired cough. Fibrobullous disease is more common in male patients with long-standing disease and may manifest as interstitial infiltrates, fibrosis with honeycombing, or cavitation that mimics tuberculosis. Patients with AS manifest an increased propensity for spontaneous

1627 Chapter 92

pneumothorax and infections with Aspergillus or atypical mycobacteria. The course of fibrobullous disease is usually progressive and not affected by steroid therapy. Because resection of the lung with fibrobullous disease is complicated by bronchopleural fistula in 50 to 60 percent of patients, surgery should be reserved for the treatment of major hemoptysis. Additional pleuropulmonary abnormalities may be detected only by high resolution CT in patients with AS. These abnormalities include interstitial lung disease, pleural thickening, parenchymal bands, or mild bronchial wall thickening. These changes are subtle and do not correlate with clinical or functional impairment.

Treatment Medical treatment in patients with AS should focus on relief of symptoms and maintenance of posture and movements, including chest wall expansion. Physiotherapy is regarded as an essential element of the overall management in AS, and should incorporate chest wall expansion and breathing exercises. The exercises are preferably taught to patients by a respiratory physiotherapist. Smoking should be avoided and baseline chest radiographs and spirometry should be obtained. These interventions improve the likelihood of maintaining full employment. The recent introduction of antagonists of tumor necrosis factor (TNF) in the treatment of AS has revolutionized the overall management of the disease. Recent studies have shown remarkable improvements in all aspects of the disease, including rib cage expansion and quality of life. The extent to which these drugs will affect the natural history of the disease and prevent or delay spinal ankylosis will require long-term studies. An adverse effect of the anti-TNF therapy may be reactivation of tuberculosis. Therefore, AS patients who are candidates for anti-TNF treatment should be screened with a tuberculin skin test and receive prophylactic treatment with isoniazid prior to starting treatment. In summary, ankylosing spondylitis, through chronic inflammation that primarily affects the axial skeleton, limits spinal flexion, reduces rib cage compliance, and restricts chest wall expansion. These mechanical alterations are associated with only mild reductions in VC, TLC, and exercise capacity. The diaphragm/abdomen pathway compensates for the reduced rib cage distensibility by an increased contribution to ventilation during quiet breathing and exercise. Apical fibrobullous disease, which is occasionally found in advanced cases, may require special attention.

OBESITY Obesity is a major health problem, with more than half of the adults in the United States being either overweight or obese. This epidemic is not confined to the United States. Indeed, the prevalence of obesity is increasing throughout the world. The most commonly used index to assess the severity of obesity

Nonmuscular Diseases of the Chest Wall

is the body mass index (BMI). This is calculated as the body weight (BW) in kilograms divided by the square of the height (Ht) in meters (BW/Ht2 ). The body mass index is positively associated with morbidity and mortality. An individual with a BMI between 18.5 and 24.9 kg/m2 is normal; a BMI between 25 and 29.9 kg/m2 is overweight, and a BMI greater than 30 kg/m2 is considered obese. Those with a BMI greater than 40 kg/m2 are especially predisposed to develop restrictive lung disease. Obesity-associated respiratory morbidity can be considered in the context of its effects on: (a) chest wall mechanics and pulmonary function; and (b) the control of breathing. Obesity may or may not be associated with hypoventilation. Individuals in whom there is carbon dioxide retention during wakefulness are considered to have the obesity hypoventilation syndrome (OHS); whereas individuals who are eucapnic are considered to have simple obesity (SO). Individuals with OHS are more likely to have disordered chest wall mechanics and individuals with SO usually exhibit minimal or no pulmonary compromise. Obese, eucapnic individuals with compromised pulmonary function are considered to be morbidly obese.

Chest Wall Mechanics and Pulmonary Function In individuals with SO, the most common abnormalities in pulmonary function tests are a decrease in expiratory reserve volume (ERV) and FRC with preservation or mild reduction in TLC (Table 92-5). The lower than predicted FRC is a consequence of decreased chest wall compliance by fat in the rib cage and abdomen. The stiffened chest wall changes the slope of the chest wall volume-pressure (V-P) relationship (Fig. 92-3). This shift in the V-P characteristics of the chest wall alters the balance between the recoil of the chest wall and lung so that the FRC occurs at a lower lung volume. In contrast, RV may be normal or even slightly increased in SO. As a result, the difference between the two volumes (ERV) is markedly reduced. In patients with OHS, the reductions in FRC, RV, and TLC are more pronounced. Since similar degrees of obesity in SO and OHS may result in different degrees of lung restriction, the adverse effects of obesity on pulmonary function cannot be entirely explained by the absolute load of adipose tissue on the chest wall. One factor that may account for this difference is the distribution of body fat. Upper body or central fat distribution has a greater effect on pulmonary function than lower body fat distribution, whereas lower fat distribution is more often associated with sleep disordered breathing. Diverse methods have been used to assess the distribution of body fat. These include measurement of waist/hip circumference ratio, abdominal girth/hip breadth ratio, and the thickness of skin folds at multiple sites. CT or MRI imaging has also been used to assess the cross-sectional area of the visceral fat/subcutaneous fat ratio. Expiratory flow rates are generally normal in SO except for modest reductions in forced vital capacity (FVC) when the

1628 Part XII

Disorders of the Chest Wall, Diaphragm, and Spine

Table 92-5 Respiratory Mechanics in Simple Obesity (SO) and Obesity Hypoventilation Syndrome (OHS) Normal

OHS

BW (% ideal)

105

195

201

BW/Ht (kg/cm)

0.42

0.75

0.78

BMI (kg/m2 )

TLC (% predicted)

100

CRS (L/cm H2 O)

0.11

0.05

0.06

RRS (cm H2 O L1 sec1 )

1.2

4.0

7.8

Work (J/L)

0.43

0.74

1.64

MVV (L/min)

159

129

PImax (cm H2 O)

100

Note: Abbreviations: BW = body weight; BMI = body mass index; TLC = total lung capacity; CRS = compliance of the respiratory system; RRS = respiratory system resistance; PImax = maximal inspiratory pressure; MVV = maximum voluntary ventilation.

BMI exceeds 45 kg/m2 . Although the FEV1 /FVC ratio may be normal, airways resistance is often increased. The increase in resistance may be due in part to the reduction in lung volume. However, even after correcting for lung volumes, specific airways conductance may be reduced to up to 50 to 70 percent of normal. This may be especially evident in the supine position. When supine, further increases in intraabdominal pressure may reduce lung volume and increase

respiratory resistance. The same mechanisms, especially in the supine position, can promote expiratory flow limitation during tidal breathing and in morbidly obese individuals may lead to the development of intrinsic positive end-expiratory pressure (PEEP) and/or orthopnea. The reduction in the compliance of the entire respiratory system and increase in its resistance increase the elastic and resistive loads on the respiratory muscles. The work of breathing and oxygen cost of breathing may be 60 percent higher in SO and as much as 250 percent higher in OHS. A two- to threefold increase in intra-abdominal pressure at FRC further impedes breathing by constituting a threshold load that the inspiratory muscles need to overcome to initiate inspiration. This threshold load, in combination with the increased elastic and resistive loads imposed by the lung and chest wall, increases the oxygen cost of breathing at rest in SO by about fivefold and in OHS by nearly tenfold. It is critical that the inspiratory muscles maintain their strength in order to overcome the heightened loads imposed by obesity. In patients with SO, inspiratory and expiratory muscle strength are generally well preserved. In contrast, individuals with OHS often have weakened respiratory muscles, with strength diminished to approximately 40 percent of predicted. In these individuals, respiratory muscle weakness may be related to deconditioning, fatty infiltration of muscle, or other factors related to chronic disease. Regardless of mechanism, inspiratory muscle weakness may be one of the mechanisms underlying CO2 retention in individuals with OHS. Another factor may be related to disordered respiratory control (Fig. 92-9).

Control of Breathing In nonobese individuals, added elastic or resistive loads alter the control of breathing so that neural drive to the respiratory muscles increases. Similarly, one may expect that the increased elastic load due to excess chest wall adipose tissue would increase neural drive to the respiratory muscles in obese individuals. Indeed, respiratory drive in SO is either normal or increased when compared with those of

Figure 92-9 Factors involved in the pathophysiology of obesity hypoventilation syndrome.

1629 Chapter 92

nonobese subjects during resting ventilation as well as during ventilation stimulated by hypoxia or hypercapnia. The increased chemosensitivity in SO may correlate with BMI and can decrease following weight loss. In contrast, patients with OHS have blunted respiratory drive. In these individuals, there may be significant depression of the ventilatory responses to hypercapnia and hypoxemia, with the response to hypoxia blunted to a greater extent than the ventilatory response to hypercapnia. Peripheral or central factors may underlie the reduced ventilatory drive. Peripheral limits to ventilation due to the stiff chest wall could limit the level of ventilation that can be achieved despite a normal respiratory drive. However, other indices of central respiratory drive, such as the mouth occlusion pressure (P0.1 ) and a reduced diaphragmatic EMG in OHS suggest that a central rather than a peripheral mechanism is responsible for the decreased ventilatory responses to hypercapnia and hypoxemia. Possible explanations for the diminished respiratory drive include either a genetic predetermination or an acquired cause, such as persistent hypoxemia or sleep apnea. Mediators such as leptin have also been implicated as a cause of the reduced ventilatory drive. Obese individuals also may adapt to the added elastic and resistive loads by changing breathing pattern. Lowering tidal volume and raising the breathing frequency reduces the elastic and resistive work per breath. Individuals with SO have about a 40 percent higher respiratory frequency than nonobese individuals. The increase in breathing frequency is accomplished by shortening both inspiratory and expiratory times. Thus, the ratio of inspiration to total breath time (Ti/Ttot) remains normal. Since tidal volume during quiet breathing is generally not reduced in SO, resting ventilation may be higher. This may reflect an increase in basal metabolism. Those with OHS have a breathing frequency that is higher and a tidal volume that is about 25 percent lower than those with SO. Exercise capacity is near normal in individuals with SO. Minute ventilation, respiratory rate, heart rate, and oxygen consumption during treadmill exercise are higher in obese subjects than in normal weight individuals; however, the anaerobic threshold is lower than in normal weight individuals. With weight loss, the metabolic demands are reduced and carbon dioxide production and alveolar ventilation during exercise fall by approximately 20 percent.

Gas Exchange Hypoxemia may either be mild or absent in individuals with SO, whereas it is generally present in individuals with OHS. The mechanism is due in part to hypoventilation, which lowers the partial pressure of oxygen in the alveoli. In addition venous admixture due to ventilation-perfusion mismatch may widen the alveolar-arterial oxygen gradient, thereby worsening hypoxemia. The mismatch of ventilation and perfusion is likely to occur at the lung bases, which are generally well perfused in obesity but poorly ventilated because of airway

Nonmuscular Diseases of the Chest Wall

closure or frank alveolar collapse. These alternations in gas exchange are amplified when obese individuals assume the supine position. Practical consequences of these changes relate to anesthesia and sleep. In both SO and OHS, hypoxemia becomes more pronounced in the supine position; this can be a major concern during induction of anesthesia. During sleep, the increase in metabolic rate with obesity, coupled with the worsening of ventilation perfusion mismatch, produces a more rapid decrease in arterial oxygen saturation during apnea than in nonobese subjects.

Treatment Weight loss is the optimal treatment for obesity. However, it is not only difficult for individuals to lose weight but even more so to maintain weight loss. One difficulty is that weight loss decreases total energy expenditure in both normal and obese subjects, whereas the opposite is true with weight gain. In patients with OHS and acute or chronic respiratory failure, nasal intermittent noninvasive ventilation may improve gas exchange, daytime somnolence, and overall clinical status. The effects of weight loss induced by diet or surgery on pulmonary function in SO have been well documented. A weight loss of 40 kg may have little effect on VC and TLC in SO, but a pronounced effect on increasing ERV and lesser effects on increasing FRC. There is generally better ventilation to the lung bases resulting in an increase in arterial PO2 of about 4 to 8 mmHg. With OHS, the effects of weight loss on ERV and FRC are even more pronounced and vital capacity increases as well. These changes are positively associated with weight loss. The oxygen consumption required for a given level of exercise is also diminished. In contrast, respiratory control remains essentially unaltered after weight loss. The effects of laparoscopic gastroplasty on pulmonary function need further clarification; however, this has become a more accepted means of inducing and maintaining weight loss in subjects with SO and OHS. In summary, respiratory impairment due to obesity may manifest as a sole mechanical impairment (simple obesity) or may be combined with disordered ventilatory control (obesity hypoventilation syndrome). In SO, the VC, TLC, and respiratory compliance are mildly decreased, whereas respiratory muscle strength, ventilatory drive, and eucapnia are well preserved. By contrast, in OHS, all measurements of respiratory mechanics are decreased to a greater extent than in simple obesity; in addition, hypoventilation with hypoxemia and hypercapnia, which results from complex interactions between impaired respiratory mechanics and abnormal ventilatory control, may lead to respiratory failure and cor pulmonale. Obstructive sleep apnea may coexist with either entity. Noninvasive positive-pressure ventilation can efficiently improve gas exchange and overall clinical status in OHS. Weight loss may reverse the impaired pulmonary function and gas exchange due to obesity.

1630 Part XII

Disorders of the Chest Wall, Diaphragm, and Spine

FLAIL CHEST Flail chest can occur in up to 25 percent of adults who have blunt chest wall trauma. It is a condition in which fractures of the ribs produce a segment of the rib cage that deforms markedly during breathing. Generally, double fractures of three or more contiguous ribs or the combination of sternal and rib fractures are required to create a flail segment of the rib cage. During inspiration, the flail segment is displaced inward rather than expanding outward in concert with the remainder of the rib cage. The most common cause of flail chest is trauma related to automobile accidents or falls. It may also be seen following aggressive cardiopulmonary resuscitation. Rarely, flail chest is due to pathological fractures of ribs, as may occur with multiple myeloma or congenital rib defects. In spontaneously breathing patients with a history of blunt trauma to the chest wall, the diagnosis of flail chest can be made at the bedside by observing the paradoxical motion of the flail segment of the chest wall. Chest radiographs demonstrating multiple rib fractures support the diagnosis. A CT scan yields more information than a chest radiograph with respect to the extent of the injuries of the pleura and pulmonary parenchyma, including pulmonary contusion. Pulmonary complications such as pulmonary contusion, hemothorax, and pneumothorax can occur in up to 60 percent of patients with flail chest. Thus, the mortality from flail chest may be high. With chest wall trauma alone, mortality ranges between 7 and 14 percent; when chest wall trauma is complicated by flail chest, the mortality rate increases further. Trauma sufficient to cause flail chest is often accompanied by other injuries, such as fractures of the long bones and vertebrae, head trauma, rupture of the aortic arch or other arteries, or laceration of the liver or spleen. Patients with multiple trauma and lung contusion complicating flail chest have a mortality rate as great as 56 percent. This high mortality is not solely attributed to respiratory complications. If the patient survives the initial injury, long-term disability after flail chest is relatively common. Symptoms consist of chest tightness, chest pain, dyspnea, and limitation of ability to exercise.

Figure 92-10 During inspiration, pleural pressure becomes more negative causing the flail segment to move paradoxically inward as the remainder of the chest wall is moving outward. During expiration, pleural pressure increases, causing the flail segment to move outward as the remainder of the chest wall becomes smaller.

rib cage from the remainder of the chest wall, the deflationary effect of intrapleural subatmospheric pressure is unchecked by the factors that promote rib cage expansion. Consequently, unopposed subatmospheric intrapleural pressure causes the flail segment to move inward during inspiration. During expiration, pleural pressure becomes more positive and the flail segment moves outward. This paradoxical motion of the flail segment is amplified by anything that further lowers pleural pressure, such as pulmonary contusion, which reduces lung compliance or an increase in airway secretions, which increases airways resistance. Fractures involving the lateral rib cage provide the most common location for flail chest (Fig. 92-11). Anterior flail chest occurs when there is separation of the sternum from the ribs; and posterior flail chest is associated with less severe clinical derangement because of splinting provided by the back muscles. The pattern of paradoxical rib cage and abdomen motion is not unique to the location of the flail segment. Flail patterns may occur within the rib cage itself (i.e., between the upper and lower rib cage), or between the rib cage and abdomen (i.e., lower rib cage and anterior abdominal wall). These different patterns of motion of flail chest may reflect differences in the patterns of recruitment of the respiratory muscles. The observation that external intercostal

Pulmonary Function and Respiratory Mechanics The disordered movement of the flail segment is related to changes in pleural pressure during the breathing cycle (Fig. 92-10). During inspiration, pleural pressure becomes subatmospheric; this is inflationary to the lung but deflationary to the rib cage. Normally, rib cage expansion is due to several factors, including: (a) diaphragm insertional forces on the lower rib cage; (b) the actions of the intercostal muscles on the upper rib cage; (c) positive intra-abdominal pressure in the zone of apposition of the diaphragm to the rib cage; and (d) the passive outward recoil of the rib cage at high lung volumes. Once multiple rib fractures uncouple a segment of the

Figure 92-11 Schema of the rib cage depicting different locations of rib fractures producing flail segments in varied locations.

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EMG activity increases more than threefold in the flail area supports this mechanism. Flail chest may severely reduce VC and FRC to as much as 50 percent of predicted. The reductions in lung volume can be attributed to both paradoxical movements of the flail segment and, in certain patients, to underlying pulmonary contusion. In those individuals who have flail chest uncomplicated by pulmonary contusion and survive the initial injury, VC and FRC return to baseline values within 6 months or remain mildly reduced. In contrast, patients with pulmonary contusion complicating flail chest can have persistent reductions in lung volumes for up to 4 years. These changes have been attributed to fibrous changes in the contused area. Although it is easy to ascribe respiratory failure to paradoxical motion of the rib cage in patients with flail chest, the pathogenesis of respiratory failure is complex; contributing factors include hypoventilation and flail-induced changes in lung and respiratory muscle function. Flail chest in itself is accompanied by considerable pain, which in turn impairs cough effectiveness, causes regional atelectasis, rib cage muscle spasm, and alters patterns of respiratory muscle activation and recruitment. Flail chest may increase elastic loads presented to the respiratory muscles by promoting regional atelectasis near the flail segment, generalized microatelectasis due to splinting and pain, or pulmonary contusion. Flail chest further increases the work of breathing by causing the inspiratory muscles to shorten more for a given tidal volume. The excessive muscle shortening represents extra work (force X distance) that is not measured using standard calculations of work per breath (pressure X volume). The added inspiratory muscle shortening due to the flail segment causes the inspiratory muscles to operate over shorter lengths. This reduces inspiratory muscle efficiency, thereby adding to the oxygen cost of breathing. Thus, the added work of breathing, respiratory muscle inefficiency, hypoxemia due to atelectasis, and contusion all combine to predispose these patients to respiratory muscle fatigue and respiratory failure (Fig. 92-12).

Figure 92-12 Factors involved in the pathophysiology of flail chest.

Nonmuscular Diseases of the Chest Wall

Treatment The mainstay of treatment is to control pain because of its central role in the development of atelectasis and promoting ineffective cough. Pain control also reduces splinting, improves tidal volume, and minimizes areas of atelectasis. It can be accomplished by use of oral or intravenous narcotics, intercostal nerve blocks, or epidural anesthesia. Pain relief in combination with supplemental oxygen, improving tracheal bronchial toilet, and cautious fluid replacement often results in successful treatment of flail chest with avoidance of respiratory failure. Attempts to stabilize the flail segment by applying tape, strappings, or other external devices to the chest wall have met with limited success. However, stability of the flail segment may be accomplished with the use of positive pressure mechanical ventilation or surgical fixation in selected individuals. Mechanical ventilation with positive pressure breathing has been shown to stabilize the flail segment by eliminating subatmospheric changes of pleural pressure during inspiration. This â&#x20AC;&#x153;internal pneumatic stabilizationâ&#x20AC;? was initially accomplished by tracheostomy combined with prolonged mechanical ventilation. However, complications of mechanical ventilation often supervened and increased morbidity and mortality. Consequently, mechanical ventilation is no longer recommended as a primary means of stabilizing the chest wall; instead, it is recommended when there is respiratory failure, concomitant central nervous system or intra-abdominal injuries, shock, or need to operate for other injuries. If mechanical ventilation delivered via an endotracheal tube is instituted, ventilator modes that minimize patient effort and the generation of subatmospheric pleural pressure should be employed. For example, low impedance modes of mechanical ventilation, such as high flow continuous positive airway pressure, are accompanied by less chest wall distortion during inspiration. Positive pressure ventilation delivered by noninvasive techniques may provide an alternative means of stabilizing the flail segment by preventing subatmospheric changes in pleural pressure during inspiration. Noninvasive ventilation to selected patients who are breathing spontaneously in conjunction with regional anesthesia can improve gas exchange and enable physiotherapy and early patient mobilization. In selected patients with flail chest, noninvasive ventilation may significantly reduce morbidity and length of hospitalizations. A randomized control trial comparing patients with mask CPAP vs. assist control ventilation found that patients treated with mask CPAP had fewer complications, fewer days in hospital and intensive care unit, and less ventilator time than patients with similar degrees of blunt thoracic trauma treated with assist control ventilation. This technique has not been fully evaluated in patients with flail chest. The chest wall can also be stabilized by a variety of surgical procedures. In selected individuals, external fixation of the chest wall with wires, steel plates, and staples to approximate the fractures improves respiratory mechanics and reduces the duration of mechanical ventilation as well

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Figure 92-13 Chest radiograph depicting osteosynthesis plates in an individual who has undergone operative chest wall fixation. (From Engel C, Krieg JC, Madey SM, et al: Operative chest wall fixation with osteosynthesis plates. J Trauma 58:181–186, 2005, with permission.)

as hospital stay (Fig. 92-13). The proper selection of candidates for operative stabilization is uncertain; however, it is likely to benefit individuals who are ventilator dependent and unable to protect their upper airways. Individuals with concurrent problems, such as those undergoing thoracotomy for intrathoracic injuries, young patients with severe chest wall deformation, or patients with large unstable segments and borderline pulmonary function may also be potential candidates. To summarize, flail chest is associated with acute respiratory failure most often in the setting of trauma in which, in addition to a mechanically inefficient rib cage, there is concomitant lung contusion. Pain and respiratory muscle dysfunction also contribute to the pathogenesis of respiratory failure. The essential components of nonsurgical treatment include pain control and mechanical ventilation for respiratory failure. Surgical fixation of the flail segment may be needed in some patients and may reduce the duration of mechanical ventilation and decrease the incidence of pulmonary infections and barotrauma. However, the indications for external fixation are not fully defined.

SUGGESTED READING Baraliakos X, Davis J, Tsuji W, et al: Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 52:1216–23, 2005. Buyse B, Meersseman W, Demedts M: Treatment of chronic respiratory failure in kyphoscoliosis: oxygen or ventilation? Eur Respir J 22:525–528, 2003.

Cappello M, Yuehua C, DeTroyer A: Respiratory muscle response to flail chest. Am J Respir Crit Care Med 153:1897– 1901, 1996. Croitoru DP, Kelly RE Jr, Goretsky MJ, et al: The minimally invasive Nuss technique for recurrent or failed pectus excavatum repair in 50 patients. Pediatr Surg 40:181–186, 2005 Engel C, Krieg JC, Madey SM, et al: Operative chest wall fixation with osteosynthesis plates. J Trauma 58:181–186, 2005. Fisher LR, Cawley MI, Holgate S: Relation between chest expansion, pulmonary function, and exercise tolerance in patients with ankylosing spondylitis. Ann Rheum Dis 49:921–925, 1990. Foster GD: Principles and practice in the management of obesity. Am J Respir Crit Care Med 168:274–280, 2003. Gorman JD, Sack KE, Davis JC Jr: Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 346:1349–1356, 2002. Jackson M, Smith I, King M, et al: Long term non-invasive domiciliary assisted ventilation for respiratory failure following thoracoplasty. Thorax 49:915–919, 1994. Lawson ML, Mellins RB, Tabangin M, et al: Impact of pectus excavatum on pulmonary function before and after repair with the Nuss procedure. J Pediatr Surg 40:174–180, 2005. Lin MC, Liaw MY, Chen WJ, et al: Pulmonary function and spinal characteristics: Their relationships in persons with idiopathic and postpoliomyelitic scoliosis. Arch Phys Med Rehabil 82:335–341, 2001. Nauffal D, Domenech R, Martizez Garcia MA, et al: Noninvasive positive pressure home ventilation in restrictive disorders: Outcome and impact on health-related quality of life. Respir Med 96:777–783, 2002. Nickol AH, Hart N, Hopkinson NS, et al: Mechanisms of improvement of respiratory failure in patients with restrictive thoracic disease treated with non-invasive ventilation. Thorax 60:754–760, 2005. Olson AL, Zwillich C: The obesity hypoventilation syndrome. Am J Med 118:948–956, 2005. Pelosi P, Croci M, Ravagnan I, et al: Respiratory system mechanics in sedated, paralyzed, morbidly obese patients. J Appl Physiol 82:811–818, 1997. Perez de Llano LA, Golpe R, Ortiz Piquer M, et al: Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 128:587–594, 2005. Rochester DF: Obesity and pulmonary function, in Alpert MA, Alexander JK (eds), The Heart and Lung in Obesity, 1st ed. Armonk, NY, Futura, 1998, pp 109–131. Schonhofer B, Barchfeld T, Wenzel M, et al: Long term effects of non-invasive mechanical ventilation on pulmonary hemodynamics in patients with chronic respiratory failure. Thorax 56:524–528, 2001. Shimura R, Tatsumi K, Nakamura A, et al: Fat accumulation, leptin, and hypercapnia in obstructive sleep apneahypopnea syndrome. Chest 127:543–549, 2005.

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Tanaka H, Yukioka T, Yamaguti Y, et al: Surgical stabilization or internal pneumatic stabilization? A prospective randomized study of management of severe flail chest patients. J Trauma 52:727–732, 2002. Tuggey GM, Elliott MW: Randomised crossover study of pressure and volume non-invasive ventilation in chest wall deformity. Thorax 60:859–864, 2005 Tzelepis GE, McCool FD, Hoppin FG Jr: Chest wall distortion in patients with flail chest. Am Rev Respir Dis 140:31–37, 1989.

Nonmuscular Diseases of the Chest Wall

VanNoord JA, Caubergs M, Van de Woestigne KP, et al: Total respiratory system resistance and reactance in ankylosing spondylitis and kyphoscoliosis. Eur Respir J 4:945–951, 1991. Weistein SL, Dolan LA, Spratt KF, et al: Health and function of patients with untreated idiopathic scoliosis. A 50-year natural history study. JAMA 289:559–567, 2003. Zhao L, Feinberg MS, Gaides M, et al: Why is exercise capacity reduced in subjects with pectus excavatum? J Pediatr 136:163–67, 2000.

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93 Effects of Neuromuscular Diseases on Ventilation Gerard Joseph Criner

Nathaniel Marchetti

I. RESPIRATORY PATHOPHYSIOLOGY II. CONTROL OF BREATHING Respiratory Muscle Function Lung and Chest Wall Mechanics Sleep-Related Breathing Disturbances III. ASSESSMENT OF RESPIRATORY FUNCTION Clinical History Physical Examination Radiographic Assessment Arterial Blood Gas Analysis IV. RESPIRATORY MUSCLE STRENGTH Maximum Mouth Pressures Spirometry Flow-Volume Loop

Neuromuscular diseases comprise a diverse group of disorders that vary markedly in etiology, rate of progression, pattern of respiratory involvement, prognosis, and therapy. Neuromuscular disorders impair the respiratory system as a vital pump; however, depending on the particular disease, the respiratory pump may be impaired at the level of the central nervous system (e.g., cerebral cortex or brain stem), spinal cord, peripheral nerve, neuromuscular junction, or respiratory muscle (Table 93-1). The pattern of ventilatory impairment among these disorders is highly dependent on the specific neuromuscular disease. For example, some disorders may impair ventilation at only one level (e.g., isolated diaphragm paralysis) or simultaneously affect it at different levels (e.g., multiple sclerosis). Additionally, the severity of impairment may be minimal and totally resolve with time and proper treatment (e.g., Guillain-BarrÂ´e syndrome) or is characterized by relentless progression to eventual respiratory death (e.g., amy-

Lung Volumes Maximum Voluntary Ventilation V. SELECTED NEUROMUSCULAR DISEASES Upper Motoneuron Lesions Lower Motor Neuron Lesions Disorders of Peripheral Nerves Disorders of the Neuromuscular Junction Muscular Dystrophies and Acquired Myopathies Inherited Myopathies Acquired Myopathies VI. TREATMENT Principles of Management Preventive Therapies Other Forms of Ventilatory Assistance

otrophic lateral sclerosis). Moreover, some neuromuscular diseases concomitantly affect several structures (e.g., swallowing dysfunction in poliomyelitis, interstitial lung disease in polymyositis), increasing ventilatory workload in patients who already have diminished ventilatory reserve. This chapter describes the etiology, pathophysiology, and treatment of ventilatory dysfunction in neuromuscular diseases.

RESPIRATORY PATHOPHYSIOLOGY Substantial information exists concerning the ventilatory function of patients with neuromuscular disease at rest and during sleep, as well as the effects on maximum static inspiratory and expiratory efforts and responses associated with these disorders to hypoxic and hypercapnic challenges. In

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Table 93-1 Levels of Respiratory System Dysfunction Induced by Neuromuscular Diseases and Conditions Level Upper motoneuron Cerebral

Spinal cord

Lower motoneuron Anterior horn cells

Motor nerves

Neuromuscular junction

Muscle

Disease or Condition

Vascular accidents Cerebellar atrophy Trauma Trauma Tumor Syringomyelia Multiple sclerosis

Poliomyelitis Spinal muscle atrophy Amyotrophic lateral sclerosis Cardiac surgery Charcot-Marie-Tooth disease Diabetes Polyneuropathy Toxins Guillain-BarrÂ´e syndrome Neuralgia amyotrophy Critical illness polyneuropathy Myasthenia gravis Eaton-Lambert syndrome Botulism Organophosphate poisoning Drugs Dystrophy Acid maltase deficiency Malnutrition Corticosteroids Polymyositis

general, the response of the respiratory system to moderate or severe neuromuscular disease is relatively stereotyped. The typical features are a reduced forced vital capacity, reduced respiratory muscle strength, and in some cases, malfunction of the neurons that control breathing.

CONTROL OF BREATHING The breathing pattern is often abnormal in patients with neuromuscular disease. In comparison with healthy subjects, patients with respiratory muscle weakness have a low tidal volume and a high respiratory rate that persists in response even

to hypoxic or hypercapnic challenge. Moreover, this rapid, shallow breathing pattern is not due to abnormalities in gas exchange (i.e., hypoxemia or hypercapnia) but is more likely to be due to severe muscle weakness and/or disordered afferent and efferent output in motoneurons impaired by the underlying neuromuscular disease. Changes in ventilation can be used to evaluate ventilatory drive in subjects with normal lung and respiratory muscle mechanics. However, ventilation is not a good index of respiratory motor activity in subjects with significant respiratory muscle weakness because the thoracic bellows cannot perform increased work of breathing. Decreased ventilatory response to hypoxic or hypercapnic challenge in these patients could indicate abnormalities in afferent information from diseased respiratory muscles, abnormal lung or chest wall mechanics, or upper motoneuron dysfunction rather than an abnormality in the central control of breathing. In some neuromuscular diseases, degenerative changes in the muscle spindle, impaired afferent stimulation from abnormal stretch reflexes in the muscle spindles, or decreased mechanoreceptor output from tendons may explain the altered breathing pattern. Measurement of mouth occlusion pressure generated during the first 100 ms of inspiration (P0.1 ) is relatively independent of inspiratory effort and therefore is a more reliable estimate of central ventilatory drive independent of respiratory muscle mechanics. P0.1 is maintained or increased in patients with neuromuscular disease despite substantial muscle weakness. The relationship between respiratory mechanics, respiratory muscle strength, and control of ventilation has been examined in patients with neuromuscular diseases in comparison with healthy control subjects. Although patients had 37 and 52 percent reductions in maximum inspiratory and expiratory mouth pressures, respectively, their P0.1 was 66 percent greater than that of controls. Similar findings were encountered when normal subjects had acute muscle weakness induced by curarization. After severe muscle weakness was induced, significant increases in P0.1 were observed during hypercapnic challenge. Partial curarization of spontaneously breathing cats also produced a marked increase in phrenic nerve discharge despite a substantial decrease in minute ventilation. These studies indicate that under conditions of substantial respiratory muscle weakness, ventilation is not a reliable measure of central respiratory drive, and that central respiratory drive, at least when measured by P0.1 , is usually well preserved.

Respiratory Muscle Function Patients with neuromuscular disease who develop significant respiratory muscle weakness may demonstrate fatigue, dyspnea, and impaired control of secretions, recurrent lower respiratory tract infections, acute or chronic presentations of respiratory failure, pulmonary hypertension, and cor pulmonale. The pattern, prognosis, and degree of respiratory muscle weakness attributable to a neuromuscular disorder are

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varied. They depend on the level of neuromuscular system impairment, the prognosis of the underlying disorder, and whether therapy is available. Patients with neuropathy, such as Guillain-BarrÂ´e syndrome, tend to have less severe respiratory muscle weakness than patients with lower motoneuron lesions or neuromuscular junction disorders, such as myasthenia gravis. Even when respiratory muscle dysfunction is observed, not all respiratory muscles are equally impaired, and the course of the underlying neuromuscular disease and degree of respiratory and nonrespiratory muscle impairment can be very different among patients with the same disease. In some neuromuscular disorders, respiratory muscle weakness is the only presentation of an underlying disease (i.e., neuralgia amyotrophy of the diaphragm); in the case of muscular dystrophy, significant respiratory muscle weakness may occur only late in the disease course. Severe, relentless, progressive dysfunction of the respiratory muscles may occur, as in amyotrophic lateral sclerosis, or be characterized by exacerbations and relapses (e.g., multiple sclerosis). Finally, respiratory muscle weakness may completely reverse with time (phrenic nerve injury after open-heart surgery) or therapy (plasmapheresis in myasthenia gravis). A significant number of patients with severe respiratory muscle weakness were also found in 50 percent of 30 asymptomatic patients with stable chronic neuromuscular disease. Reductions in inspiratory and expiratory mouth pressures did not correlate with general muscle strength assessment; however, both the type of neuromuscular disease and distribution of general muscle weakness correlated with respiratory muscle impairment. Patients with myopathy, rather than polyneuropathy, whose involvement produced proximal rather than distal limb muscle weakness, were more likely to have significant respiratory muscle weakness. Pulmonary symptoms correlated poorly with evidence of respiratory muscle weakness. Explanations for the lack of pulmonary complaints in these two studies despite significant muscle weakness are not clear. Patients with chronic and severe neuromuscular disease are usually sedentary and incapable of exertion and, therefore, seldom stress the respiratory system, which may explain their lack of symptoms. The rapid, shallow breathing pattern found in patients with respiratory muscle weakness may be due to decreased respiratory muscle force generation, but it also may be due to changes in lung and chest wall elastic recoil. A decrease in inspiratory muscle tone may lead to unopposed lung elastic recoil, which reduces lung volume and produces chronic changes in chest wall tone and distensibility. Once inspiratory muscle strength decreases to approximately 30 percent of normal, abnormalities in gas exchange (manifested primarily by hypercapnia) commonly occur. Expiratory muscle weakness is also commonly observed in patients with neuromuscular disease. It causes ineffectual cough and impaired secretion clearance, which in some patients leads to recurrent lower respiratory tract infections. In normal persons, dynamic compression of the central intrathoracic airways by large changes in pleural pressure gener-

Effects of Neuromuscular Diseases on Ventilation

ated by forceful contraction of the expiratory muscles acts to propel secretions proximally, where they can be expectorated. As expiratory muscle weakness progresses, pleural pressures generated during coughing efforts are reduced and airway clearance is impaired.

Lung and Chest Wall Mechanics A characteristic hallmark of chronic neuromuscular disease is a decreased vital capacity (VC). The VC is reduced because of respiratory muscle weakness, and the decrease in VC parallels the progression of the underlying disease, but the magnitude of the reduction in VC is greater than expected solely based on the reduction in respiratory muscle force. The sigmoidal shape of the pressure-volume curve suggests that large reductions in pressure initially produce only small reductions in lung volume. In 25 patients with a variety of neuromuscular diseases, De Troyer found that reductions in VC were much greater than expected, solely based on the reductions in inspiratory muscle strength (Fig. 93-1). Similar results were observed in studies on the effect of curare on maximum static pressure-volume relationships in normal volunteers. It appears that in addition to muscle weakness, alterations in the mechanical properties of the lung and chest wall contribute to the reduced VC. Using the mean deflationary pressure-volume curve of the lung in 25 patients with moderate to severe neuromuscular disease, De Troyer and colleagues found, on average, a 40 percent decrease in lung compliance (Fig. 93-2). Because of the hysteresis of the pressure-volume curve obtained by static expiratory

Figure 93-1 The solid curve represents the theoretic effect of respiratory muscle weakness on vital capacity (VC) on the assumption that the relaxation pressure-volume characteristic of the lung and chest wall are normal and that the inspiratory and expiratory muscles are uniformly involved. Dashed curve is the logarithmic regression calculated in 25 patients with neuromuscular disease (closed circles). Data suggest that loss of lung volume is out of proportion to the degree of inspiratory muscle weakness. (Based on data of De Troyer A, Borenstein S, Cordier R. Analysis of lung volume restriction in patients with respiratory muscle weakness. Thorax 35:603â&#x20AC;&#x201C;610, 1980, with permission.)

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Figure 93-2 Static expiratory pressure-volume curve in patients with neuromuscular disease and respiratory muscle weakness. Open circles represent average data in 25 patients. Volume is displayed on the Y axis as a percentage of predicted total lung capacity (TLC). Closed circles represent mean predicted values. In patients, absolute lung volume was decreased for any given transpulmonary pressure. (Based on data of De Troyer A, Borenstein S, Cordier R. Analysis of lung volume restriction in patients with respiratory muscle weakness. Thorax 35:603–610, 1980, with permission.)

maneuvers, a reduction in static compliance achieved on full inspiration alters the position of the expiratory curve and tends to underestimate measured static expiratory compliance. However, this effect is small, and does not account for the significant reductions in expiratory pulmonary compliance observed in their study. Furthermore, measurements of static lung compliance measured during inspiration in patients with neuromuscular diseases also show marked reductions, suggesting that chronic respiratory muscle weakness changes the elastic properties of the lung itself. The cause of reduced lung distensibility in patients with neuromuscular disease is unknown. Several causes—such as failed maturation of normal lung tissue in the presence of childhood or congenital neuromuscular diseases, the presence of microatelectasis or macroatelectasis, increased alveolar surface tension caused by breathing chronically at low tidal volumes, and alteration in lung tissue elasticity—all have been proposed. Impaired lung maturation is unlikely, since patients who develop neuromuscular disease in adulthood also have a reduction in VC that is disproportionate to the magnitude of respiratory muscle weakness. The presence of microatelectasis and macroatelectasis also appears untenable, because most patients who have significant reductions in VC do not have alveolar collapse on chest radiograph or chest computed tomography. In the minority of patients who have atelectasis on radiographic examination, the areas of atelectasis are usually insufficient to account for the reductions in lung compliance. Studies in rats and dogs demonstrate that breathing at small tidal volumes is associated with reductions in lung compliance and may promote increased alveolar surface tension. In

experimental models of increased alveolar surface tension, a few deep inspirations rapidly restored lung distensibility. Although rapid and shallow breathing patterns are encountered in patients with chronic severe neuromuscular disease, mechanical hyperinflation of the lung does not restore lung distensibility. Therefore, increased alveolar surface tension is not considered the principal cause of reduced lung compliance in patients with chronic neuromuscular disease. Theoretically, a reduction in lung tissue elasticity may also contribute to a reduction in lung compliance in patients with neuromuscular disease, but there is no evidence that lung collagen, elastin, and other matrix proteins change in these diseases. Currently, the reason for the reduction in lung compliance in patients with chronic neuromuscular disease is unknown and awaits further study. Many studies indicate that chest wall compliance is decreased by approximately 30 percent in patients with chronic neuromuscular disorder. In 16 patients with chronic neuromuscular diseases (e.g., spinal cord injury, Duchenne muscular dystrophy, and myasthenia gravis), the weighted spirometer technique was used to examine chest wall compliance in comparison with that of 20 healthy control subjects. The weighted spirometer technique delivers an airway pressure that causes an increment in thoracic volumes so as to construct the pressure-volume relationship. In 12 of these patients, chest wall compliance was reduced (Fig. 93-3). Based on the contour of the pressure-volume curve of the normal relaxed chest wall at lower lung volumes, a reduction in functional residual capacity (FRC), as seen in patients with chronic neuromuscular diseases, may in itself reduce static chest wall

Figure 93-3 Relationships between total respiratory system compliance and VC and TLC (upper panels) and between chest wall compliance and VC and TLC (lower panels) in 16 patients with chronic neuromuscular diseases (open symbols) compared with 20 healthy controls (closed circles). Triangles symbolize patients who are quadriplegic, squares symbolize patients who are paraplegic, and circles symbolize four patients who had generalized neuromuscular diseases. In patients, total respiratory system and chest wall compliance were significantly reduced. (Based on data from Estenne A, Heliporn A, Dellez L, et al. Chest wall stiffness in patients with chronic respiratory muscle weakness. Am Rev Respir Dis 128:1002–1007, 1983.)

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compliance. However, in other disorders in which FRC is decreased owing to parenchymal lung disease (i.e., pulmonary fibrosis), a reduction in chest wall compliance has not been demonstrated. The mechanism for the reduction in chest wall compliance in patients with chronic neuromuscular disease has not been definitely established, but limitations in respiratory excursions have been proposed to lead to increased rib cage stiffness by decreasing the viscoelasticity of chest wall structures (i.e., tendons, ligaments, and costovertebral and costosternal articulations). Regardless of the mechanism, it appears that a reduction in chest wall compliance, along with a decrease in lung compliance, contributes to the marked decrease in VC observation in patients with neuromuscular disease. Although reductions in VC appear to be clearly established in patients with chronic neuromuscular disease, data examination of the effect of chronic neuromuscular disease on FRC and residual volume (RV) are contradictory. FRC has been reported to be unchanged, decreased, or mildly increased. Similarly various results have been reported for RV. Discrepancies among these studies could be explained by differences in the type of, severity, and stages of neuromuscular diseases studied or body positions in which testing was performed. However, in two separate studies, patients with a wide variety of chronic neuromuscular diseases, all studied in a similar seated position, were found to have approximately 20 percent reductions in FRC but normally predicted values of RV. Furthermore, confirmation of these findings was demonstrated in eight patients with myasthenia gravis given pyridostigmine, which acutely decreased FRC by approximately 15 percent without any significant change of RV. Further corroboration of the maintenance of RV and reduction in FRC in states of respiratory muscle weakness was again demonstrated when normal subjects partially curarized were found to have a reduction in FRC and no change in RV. On the basis of the preceding data, it appears that patients with chronic neuromuscular disease have moderate reductions in VC and total lung capacity (TLC) that are associated with a moderate decrease in FRC and a normal RV. The decrease in VC not only is due to respiratory muscle weakness but also appears to result from decreased lung and chest wall compliance. Table 93-2 summarizes the effect of neuromuscular diseases on both lung volumes and central respiratory drive.

Effects of Neuromuscular Diseases on Ventilation

Table 93-2 Characteristic Changes in Respiratory Mechanics in Patients with Neuromuscular Disease Central drive

Rapid shallow breathing pattern Decreased ventilatory response to hypoxic or hypercapnic challenge Normal or increased P0.1 to hypoxic or hypercapnic challenge

Lung volumes

Decreased vital capacity (VC) Decreased inspiratory capacity (1C) Decreased functional residual capacity (FRC) Decreased expiratory reserve volume (ERV) Maintained residual volume (RV)

saturation during REM sleep and approximately 35 percent reductions in minute ventilation compared with their baseline awake values. Furthermore, the severity of diaphragmatic dysfunction was related to the degree of oxygen desaturation. Several hypotheses have been proposed to explain nocturnal desaturation. Patients with chronic neuromuscular diseases develop an even more rapid and shallow breathing pattern during REM sleep. A rapid and shallow breathing pattern leads to increased dead-space ventilation, which promotes hypercapnia and worsened oxygenation. Reductions in ventilatory drive may be accentuated during sleep in patients with underlying neuromuscular disease, especially in those who have preexisting abnormalities of ventilatory control, which may further contribute to worsened nocturnal hypoventilation.

Sleep-Related Breathing Disturbances Breathing during sleep is often abnormal in patients with neuromuscular disease. Impaired sleep quality and hypopnea and hypercapnia related to rapid eye movement (REM) sleep are frequent. Patients with chronic neuromuscular disease of various causes have significant and numerous episodes of nocturnal desaturation, which are most prevalent during REM sleep and are characterized by hypoventilation rather than upper-airway obstruction (Fig. 93-4). Of six patients, 16 to 22 years of age, with advanced Duchenne muscular dystrophy, randomized to breathing either air or oxygen on two consecutive nights, five demonstrated significant oxygen de-

Figure 93-4 Oxygen desaturation and hypercapnia in rapid eye movement sleep shown from a recording of an all-night sleep study. Transcutaneous carbon dioxide (TccO2 ) is shown in the smooth solid line; arterial hemoglobin oxygen saturation (SaO2 ) is shown in the line with sharp deflections. (Taken from the data of Bye PT, Ellis ER, Issa FG, et al. Respiratory failure and sleep in neuromuscular disease. Thorax 45:241â&#x20AC;&#x201C;247, 1990.)

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It has been hypothesized that patients with neuromuscular disease, especially with diaphragmatic dysfunction, may be more prone to nocturnal desaturation during REM sleep. Intercostal muscle and accessory respiratory muscle activity during REM sleep are depressed, with a greater contribution of the diaphragm required for maintenance of eucapnia and oxygenation. Support for this hypothesis comes from studies that have found diaphragm dysfunction to be highly correlated with the presence and magnitude of REM-related oxygen desaturation. A direct relation has been found between the lowest SaO2 value measured during REM sleep and the percentage fall in VC measured between the erect and supine positions, using the latter measurements as an index of diaphragm weakness. Similarly, among patients who have paradoxical abdominal movement, signifying a decrease in diaphragmatic contribution to ventilation, a greater oxygen desaturation in both REM and non-REM sleep is observed. In contrast, patients with isolated diaphragmatic dysfunction with intact accessory muscle function are not predisposed to severe nocturnal hypoventilation. Accordingly, severe hypoventilation may become evident only when diaphragmatic weakness is found in the background of global accessory and intercostals muscle weakness, or when ventilatory reserve is severely reduced for other reasons, such as asthma or chronic obstructive pulmonary disease (COPD). Abnormalities in nocturnal gas exchange are harbingers of problems in daytime gas exchange. Hypoventilation during sleep precedes the appearance of daytime hypercapnia, and patients with the most impaired gas exchange during REM sleep have the greatest degree of daytime hypercapnia. Moreover, patients with normal nocturnal gas exchange are unlikely to have abnormal daytime values. Noninvasive (e.g., nasal positive-pressure ventilation, external negativepressure ventilation) or invasive (e.g., positive-pressure ventilation by tracheostomy) mechanical ventilation improves nocturnal gas exchange and sleep quality, with simultaneous improvement in daytime gas exchange. Two theories have been proposed to explain the sustained improvements in gas exchange during daytime spontaneous breathing in patients with chronic neuromuscular disease who receive nocturnal ventilatory support. One theory states that nocturnal ventilation rests chronically fatigued respiratory muscles, thereby permitting improved spontaneous ventilation and gas exchange. In keeping with this theory, several studies have demonstrated that noninvasive ventilation relieves inspiratory muscle fatigue in patients with neuromuscular disease, or that mechanical ventilation consistently increases respiratory muscle strength. An alternative hypothesis suggests that nocturnal ventilatory support lowers the CO2 set point of the central respiratory center, thereby setting the central controller to maintain a lower spontaneous daytime CO2 level. This hypothesis is supported by studies showing that after several weeks of chronic nocturnal ventilation, hypoventilation was less severe in nocturnal studies without ventilation than it had been on baseline nights before chronic intermittent ventilation. Moreover, interruption of

successful nocturnal noninvasive ventilation in patients with neuromuscular disease and chronic respiratory failure results in a return of nocturnal hypoventilation and symptoms of impaired gas exchange without evidence of respiratory muscle dysfunction. To date, neither of the preceding theories has been established conclusively, and further investigation is warranted, as one or the other, or both, may be valid in different patients.

ASSESSMENT OF RESPIRATORY FUNCTION Patients with significant respiratory muscle impairment may range from being totally asymptomatic to having moderate dyspnea at rest or, in some cases, overt respiratory failure. Some patients with neuromuscular disease may have significant weakness of the respiratory muscles and be asymptomatic, whereas others may present with ventilatory failure without an established history of a neuromuscular disease. In the latter patients, the diagnosis of neuromuscular disease may initially be entertained only after difficulty is encountered in weaning the patient from mechanical ventilation. A detailed history and physical examination, coupled with appropriate diagnostic tests, enable the physician to diagnose the presence and type of neuromuscular disease and its effect on the respiratory system. The following section reviews features of the history and physical examination and the diagnostic studies considered useful in the assessment of respiratory function in patients with neuromuscular disease. In order to provide an organized approach to direct the clinical history taking and physical examination of patients with neuromuscular disease, Table 93-1 characterizes the types of neuromuscular diseases that present at different levels of the neuromuscular system, and Table 93-3 describes the innervation of the different groups of respiratory muscles.

Clinical History The signs and symptoms of respiratory muscle weakness due to a neuromuscular disease are usually nonspecific and of limited value. Moreover, the clinical manifestations of respiratory muscle dysfunction depend on the specific muscle or muscles affected and the extent of their impairment. In conditions of mild weakness, or in the early stages of neuromuscular disease, the patient may be totally asymptomatic. As respiratory muscle weakness progresses, however, dyspnea on exertion followed by dyspnea at rest occurs. Disturbances in sleep and daytime hypersomnolence resulting from nocturnal hypoventilation may occur, and if the expiratory muscles are affected, patients may have impaired cough and repeated lower respiratory tract infections. As respiratory muscle weakness becomes more severe, hypercapnia or hypoxemia becomes evident and respiratory failure may ensue, requiring ventilatory support. The clinical history is invaluable in that it may be the first clue that a neuromuscular disease is the cause of the patientâ&#x20AC;&#x2122;s pulmonary dysfunction. A history is also useful

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Effects of Neuromuscular Diseases on Ventilation

Table 93-3 Innervation of the Respiratory Muscles Innervation Muscle Group

Level

Nerve

Upper airway Palate, pharynx Genioglossus

IX, X, XI XII

Glossopharyngeal, vagus, spinal accessory Hypoglossal

Inspiratory Diaphragm Scalenes Parasternal intercostals Stenocleidomastoid Lateral external intercostals

C3-5 C4-8 T1-7 X1 . C1 .C2 T1-12

Phrenic Intercostal Spinal accessory Intercostal

Expiratory Abdominal Internal intercostals

T7 -L1 T1-12

Lumbar Intercostal

in characterizing the type of neuromuscular disease that is present. Dyspnea and impaired cough with or without recurrent lower respiratory tract infections may be the first clinical clues that a neuromuscular disease is present. Impaired swallowing due to bulbar symptoms and the presence of peripheral limb muscle weakness are indications that one is dealing with disseminated neuromuscular disease.

Physical Examination Although the physical examination may yield normal results in patients with early or mild impairment of the respiratory system, patients with more established disease often demonstrate tachypnea at rest. Further clinical information on the nature of the underlying disease and the extent of underlying muscle impairment can be gleaned from the pattern of respiratory muscle contraction in both seated and supine positions. Respiratory rate should be recorded along with any evidence of nasal flaring, intercostals muscle retraction, or palpable evidence of contraction of the sternocleidomastoid and scalene muscles. Furthermore, inward paradoxical motion of the rib cage or abdomen should be sought, as its presence may indicate a respiratory workload that is greater than the patientâ&#x20AC;&#x2122;s respiratory muscle strength, or evidence of severe weakness of the diaphragm as a result of the underlying neuromuscular disease. Besides gross paradoxical movement of the rib cage or abdominal compartments, asynchronous compartmental movements (e.g., one compartment moving faster than the other) may be early evidence of impaired respiratory pump performance. The hallmark of severe diaphragm weakness or paralysis is paradoxical inward movement of the abdomen with inspiration. In the presence of severe diaphragm weakness,

the upper abdomen moves inward when the upper rib cage moves outward, in stark contrast to the normal pattern of synchronized outward movements of the rib cage and abdominal compartments. Besides paradoxical movement of the upper abdomen, a marked increase in respiratory rate, accompanied by progressive accessory muscle use and increased dyspnea occur when patients assume the recumbent position due to hypoxemia, hypercapnia, and placing the accessory inspiratory muscles at mechanical disadvantage. Upon reassuming the upright posture, patients may have palpable phasic contractions of the abdominal expiratory muscles. Physiologically, this inward movement of the abdomen on expiration enables passive outward movement of the upper abdomen and diaphragm descent during expiratory muscle relaxation in early inspiration. Besides a detailed examination of the respiratory musculature and breathing pattern, the physical examination should include a complete neuromuscular examination to exclude systemic involvement. Inspection for atrophy or fasciculations of respiratory and nonrespiratory muscles may point to a lower motoneuron disease. The presence of scoliosis may contribute to the development of restrictive ventilatory pattern.

Radiographic Assessment In patients with severe inspiratory muscle weakness or bilateral diaphragm paralysis, maximum inspiration is limited and lung volume appears reduced on the chest radiograph. Unilateral hemidiaphragm paralysis produces an elevated hemidiaphragm on the affected side. Fluoroscopy is often used in the assessment of diaphragm paralysis while the patient makes a forceful sniff

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Table 93-4 Respiratory Muscle Testing Name of Test

Information Provided

Diagnostic Purposes

How to Perform

Diaphragm Dome ultrasound A

Movement of right (or left) dome

Unilateral or bilateral diaphragm paralysis

Ultrasound probes with sufficient penetration (3 or 3.5 MHz) placed over abdomen (A) or over lateral rib cage (B). M-mode

Thickness at different lung volumes, relaxed or contracted

Detect contraction during tidal breathing or inspiratory efforts Effects of pulmonary or neuromuscular disease, training, and disuse Placement of intramuscular electrodes

Length at different lung volumes

Estimates of diaphragm length and swept volume

High-resolution probe with less penetration (7.5 MHz) over intercostal space, usually in anterior axillary line. B- or M-mode (C) Linear probe in craniocaudal plane over lateral rib cage. B-mode (D) Both measurements are usually made on the right side

Zone of apposition ultrasound

Dome

Zone Aoo

Taken from the ATS/ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 166:518–624, 2002.

in the supine position. In unilateral diaphragm paralysis, a positive “sniff ” test may demonstrate paradoxical upward movement of the affected hemidiaphragm. However, “sniff ” tests have a false-positive rate as high as 6 percent in normal persons. The use of the “sniff ” test to diagnose bilateral diaphragm paralysis is limited by compensatory abdominal muscle contraction. With abrupt cessation of abdominal muscle contraction during early inspiration, the abdominal contents descend caudally. The abdominal wall moves outward and the diaphragm will then appear to descend caudally, at least radiographically. Besides the fact that passive diaphragm descent due to active abdominal muscle contraction is a limitation during fluoroscopy, the fluoroscopic observational field used to examine the diaphragm is limited because of the small visual band that encompasses only the diaphragmatic dome and adjacent ribs. If rib cage rostral movement exceeds diaphragm ascent, the diaphragm will appear to descend lower than the thorax thereby falsely, suggesting shortening of the diaphragm. Although the diaphragm itself is poorly echogenic, ultrasound can be used to assess its function because the parietal pleura and peritoneal membranes lining the diaphragm are brightly echogenic. The two approaches used are the visualization of the dome or measurement of the muscle thickness at the zone of apposition. Craniocaudal movement of the

dome of the diaphragm can be measured by placing an ultrasound probe on the upper abdomen or on the lateral chest, as shown in Table 93-4. This technique has compared favorably to the traditional fluoroscopic procedures used to assess diaphragm movement. Because the costal portion of the diaphragm is close to the skin, the zone of apposition (Table 93-4) is an ideal area to use ultrasound for assessment of the diaphragm thickness and estimation of length. The thickness of the diaphragm increases with increasing lung volumes and is inversely proportional to its length. Measurement of the zone of apposition permits the detection of diaphragm contraction during inspiratory efforts when trying to diagnose diaphragm paralysis. As the subject with diaphragm paralysis makes an inspiratory effort there will not be thickening of the diaphragm at the zone of apposition. Measurement of the thickness also allows for the assessment of atrophy or the effect of neuromuscular diseases.

Arterial Blood Gas Analysis Arterial blood gas abnormalities usually occur only in patients with severe respiratory muscle weakness. Hypoxemia is usually mild and may occur as a result of macroatelectasis and subsequent intrapulmonary shunting or ventilationperfusion mismatch. In addition, patients with impaired muscle strength have impaired cough and may retain

1643 Chapter 93

secretions that further contribute to the development of hypoxemia. Measurement of arterial oxyhemoglobin saturation by pulse oximetry, which has become an extremely common laboratory test for oxygenation, is an insensitive indicator of hypoventilation. In patients with mild to moderate respiratory muscle weakness, the value of solely measuring the level of oxygenation is limited and may be misleading. Hypercarbia is an insensitive measure of respiratory muscle strength. The PaCO2 does not increase until respiratory muscle strength (measured by maximum inspiratory and expiratory mouth pressures) is less than 50 percent of predicted. In patients with severe respiratory muscle weakness, however, an increase in PaCO2 may occur. Examination of the bicarbonate and pH values may help to determine whether an acute or chronic respiratory acidosis is present. Because daytime hypercapnia is usually followed by nocturnal hypoventilation, the presence of daytime hypercapnia should prompt investigation of the breathing pattern and gas exchange during sleep, so that appropriate therapy (e.g., nocturnal supplemental oxygen or noninvasive ventilation) can be implemented.

RESPIRATORY MUSCLE STRENGTH Maximum Mouth Pressures Maximum static inspiratory and expiratory mouth pressures, measured at the airway opening during a voluntary contraction against an occluded airway, are the simplest and most commonly performed tests of respiratory muscle strength. Although several methods exist, the technique of Black and Hyatt is still the most widely used. In this technique, mouth

Effects of Neuromuscular Diseases on Ventilation

pressures are measured using a hand-held manometer with the patient seated upright and wearing a nose clip. During these maneuvers, the patient purses the lips inside a circular wide-bore rubber mouthpiece, which prevents perioral air leakage. This small orifice (2 mm in diameter, 15 mm in length) is placed in the circuit to minimize the contribution of the facial muscles to airway pressure and keep the glottis open. Maximum inspiratory pressures (PImax ) are measured near residual volume after maximal expiration, while maximal expiratory pressures (PEmax ) are measured at or near total lung capacity. In each case, efforts are maintained for at least 1 second. Maximum inspiratory and expiratory mouth pressures in normal males and females are listed in Table 93-5. Reported values in normal subjects vary widely and may be due to differences in techniques between different studies or a learning effect in subjects who perform these maneuvers. A major factor affecting PImax is lung volume. PImax is greatest at residual volume, so that the inspiratory muscles are at greatest mechanical advantage and the outward elastic recoil of the respiratory system is maximal. On the other hand, measurement of PEmax is greatest at total lung capacity because expiratory muscles are at greatest mechanical advantage and inward elastic recoil of the respiratory system is greatest (Fig. 93-5). Only at functional residual capacity, in which the respiratory system recoil pressures measured at the airway opening are zero, are maximum inspiratory and expiratory mouth pressures solely a function of the pressure generated by actively contracting respiratory muscles (PMOS ). Changes in lung volume due to chest wall or lung pathology may have important effects on the generation of maximum respiratory pressures in patients. For example,

Table 93-5 Reported Values for Maximum Static Airway Pressures in Normal Adults Study

Sex

Black and Hyatt, 1969

Males Females

Rinqvist, 1966

Age Range (Years)

PImax (cmH2 O)

PEmax (cmH2 O)

60 60

20–54 20–54

124±22 87±16

233±42 152±27

Males Females

100 100

18–83 18–83

130±32 98±25

237±46 165±30

Leech et al., 1983

Males Females

325 480

17–35 15–35

114±36 71±27

154±82 94±33

Rochester and Arora, 1983

Males Females

80 121

19–49 19–49

127±28 91±25

216±41 138±39

Vincken et al., 1987

Males Females

46 60

16–79 16–79

105±25 71±23

140±38 89±24

Cook et al., 1964

Males Females

17 9

18–47 18–32

133±39 100±19

237±45 146±34

Wilson et al., 1984

Males Females

48 87

19–65 18–65

106±31 73±22

148±34 93±17

Values are mean ± standard deviation.

No. of Subjects

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during cough (PGA cough) in a group of normal subjects and in those with suspected respiratory muscle weakness from pulmonary and neuromuscular disease. The measurement of PGA cough is theoretically better because it takes into account the abdominal musculature, eliminates the problem of leak around the mouth piece, and a cough maneuver is easier to perform than the PEmax maneuver. In 122 patients with a normal PEmax , more than 95 percent also had a normal PGA cough, but in 171 patients with a low PEmax 72 had a normal PGA cough suggesting a high false-positive rate of a low PEmax . Conversely, in 105 patients with a low PGA cough only six had a normal PEmax , suggesting a low false positive rate for a low PGA cough.

Figure 93-5 The effect of lung volume on maximum respiratory pressures (PImax and PEmax ) measured at the airway opening displayed by solid lines. Both PImax and PEmax are made up of two components: The pressure generated by the respiratory muscles (Pmus , dashed lines) and the recoil pressure of the respiratory system. At functional residual capacity, both PEmax and PImax are equal to Pmus .

patients with COPD and significant hyperinflation have a larger FRC and residual volume than normal subjects; therefore, PImax performed at FRC or RV usually results in lower values than in age- and sex-matched normal subjects. Likewise, a reduction in total lung capacity due to restrictive ventilatory diseases may result in a reduction in measured values for PEmax . Therefore, it is important to realize that in patients with pathologically altered lung volumes, all or part of the reduction in mouth pressures may be due to inspiratory muscle mechanical disadvantage. Maximum inspiratory and expiratory mouth pressures in patients with neuromuscular diseases range from normal to severely reduced. Patients may have significant respiratory muscle weakness without any pulmonary complaints, and no correlation exists between respiratory muscle strength and the presence of generalized nonrespiratory muscle weakness. When PImax falls below 30 cm H2 O, ventilatory failure commonly ensues. The assessment of a patient’s ability to generate an effective cough is extremely important when managing the pulmonary effects of neuromuscular diseases. Nearly all of these disorders result in weak cough, which puts the individual at risk for aspiration and pneumonia. While a normal PEmax ensures that the patient has adequate cough, a low PEmax could result from poor effort, bulbar weakness not allowing a tight seal around the mouthpiece, or true expiratory muscle weakness. Therefore, there is interest in developing a test that will allow the assessment of cough strength in a nonvolitional manner. Measurement of positive pleural pressures during a forceful cough (Pes cough) has also been proposed as a measure of expiratory muscle strength. Pes cough has been shown to decrease in parallel with PEmax when expiratory muscle weakness is induced by progressive curarization. A study examined the use of measurement of gastric pressures

Transdiaphragmatic Pressure Measurement While maximum static airway pressures are useful measures of global respiratory muscle strength, they fail to assess individual respiratory muscle function. Since the diaphragm is the primary muscle of inspiration, and may be susceptible to isolated disease (e.g., phrenic nerve paralysis after open heart surgery or idiopathic diaphragm paralysis), specific testing of diaphragm strength is desirable in some patients. Assessment of diaphragm strength is made by measuring gastric (Pga) and endoesophageal (Pes) pressures with balloon-tipped catheters placed in the stomach and midesophagus, respectively. Transdiaphragmatic pressure (Pdi) is then calculated as the algebraic subtraction of Pes from Pga (Pdi = Pga − Pes). Maneuvers to elicit maximum transdiaphragmatic pressures (Pdimax ) have been the subject of intensive study. Earlier studies measured Pdi during maximum static inspiratory efforts against a closed airway (e.g., Mueller’s maneuver) at FRC or RV. However, this maneuver results in submaximal diaphragm activation, with the degree of activation varying widely from subject to subject. Several studies have demonstrated significant intraindividual variability, with a coefficient of variation as high as 40 percent in measurement of Pdimax during Mueller’s maneuver. When five maneuvers to measure Pdimax in 35 subjects (10 normal, 13 with restrictive lung disease, and 12 with COPD) were compared, a combined maneuver of active expulsion with superimposed Mueller’s maneuver yielded the most reproducible and maximal transdiaphragmatic pressure. Phrenic Nerve Stimulation A crucial factor in the measurement of diaphragm strength is the ability to consistently obtain maximal activation of the diaphragm during volitional efforts. Electrophrenic stimulation is a method that has been recently utilized to consistently activate the diaphragm. Although phrenic nerve stimulation as a means of providing artificial respiration in patients has been known since the 1950s, its application in assessing diaphragm contractile function was not studied until the past decade. Besides assessing diaphragm strength, this technique has the added advantage of assessing phrenic nerve conduction and excluding the possibility of phrenic nerve injury in patients with diaphragm weakness of unknown origin.

1645 Chapter 93 100 Pdi (% Pdi max)

The phrenic nerve is stimulated in the neck near the posterior border of the sternocleidomastoid muscle, at the level of the cricoid cartilage, where the phrenic nerves are most superficial. Stimulation may be performed either transcutaneously with surface electrodes (electrical stimulation electrodes), magnetic coil, or percutaneously with needle or wire electrodes. The percutaneous method is rarely used now. Stimulation of the phrenic nerves must be supramaximal with regard to voltage and current. Supramaximal conditions are ensured by increasing the stimulus intensity until maximum diaphragm muscle action potential (DMAP) or Pdi is achieved. The DMAP is measured by surface EMG electrodes, and the Pdi is measured by measuring the esophageal and gastric pressures via two pressure transducers as described above. The DMAP is then checked periodically throughout the study to ensure that consistent stimulation is maintained. The most commonly used technique of electrophrenic stimulation now employs a frequency of one pulse per second to measure Pdi during a single unfused twitch contraction (e.g., Pditwitch ). Pditwitch has also been used to assess maximal static Pdi indirectly by the twitch occlusion technique. In this method, single twitches are superimposed on progressively stronger voluntary Pdi contractions. As voluntary effort and Pdi increase, the increment in Pdi produced during the twitch (the twitch deflection superimposed on the Pdi) decreases (Fig. 93-6A). When there is no discernible Pditwitch deflection, it is assumed that the diaphragm is maximally activated. An inverse linear relationship exists between the amplitude of the superimposed twitch and Pdi measured during volitional effort. The extrapolation of the line of this relationship to the X-axis has been interpreted as representing maximum static Pdi (Fig. 93-6B). An alternate way to perform phrenic nerve stimulation is via magnetic stimulation. In this technique, an electric current is run through a coil, thereby producing a magnetic field. The coil is placed over the spinous process of the seventh cervical vertebral body (cervical magnetic stimulation) stimulating the C3 -C5 cervical roots of the phrenic nerve causing the diaphragm to contract. Magnetic stimulation of this area also stimulates contraction of neck and upper rib cage muscles as well. The advantages of this technique are that it is less painful than the electrical stimulation method, and it is easier to evoke diaphragm contractions. Also it is possible to perform magnetic stimulation of the phrenic nerve while the patient is in the supine position by placing the magnetic coil anterior to the sternum. This allows for hospitalized bed-bound patients to be evaluated for diaphragm weakness via phrenic nerve stimulation. One of the disadvantages of magnetic stimulation is that it lacks the specificity that electrophrenic stimulation has for the diaphragm and obtaining an EMGdi signal can be more difficult with magnetic stimulation. When comparing magnetic stimulation Pditwitch to electrophrenic Pditwitch , the Pditwitch tends to be 20 to 25 percent higher with magnetic stimulation. In addition to assessing diaphragm strength, phrenic nerve stimulation can be used to assess phrenic nerve func-

Effects of Neuromuscular Diseases on Ventilation

80 60 40 20

Figure 93-6 A. Illustration of a typical Pdi tracing during twitch occlusion study. As the Pdi increases during volitional efforts, the superimposed Pdi deflection during phrenic nerve 1-Hz stimulation (twitch) decreases. At 100 percent of Pdimax , the diaphragm is maximally activated and no superimposed twitch is seen. Arrows on the horizontal axis mark indicate the phrenic nerve twitches. B . Data from A plotted as Pditwitch amplitude versus voluntary Pdi. Using linear regression, Pdimax can be extrapolated from results obtained during submaximal efforts. It has been suggested that extrapolation performed from Pdi values below 70 percent of maximum may underestimate Pdimax by approximately 10 percent (dashed line).

tion. The EMGdi is measured via surface or esophageal electrodes during electric or magnetic phrenic nerve stimulation and the phrenic nerve conduction time can be measured. This measurement is useful when assessing possible injury to the phrenic nerve from thoracic surgery, trauma, or neuropathies (i.e., critical illness polyneuropathy or GuillainBarrÂ´e syndrome). The normal conduction time via electrical stimulation is 7.5 to 9 ms, but the normal conduction time via magnetic stimulation has not been well defined because activation of the brachial plexus affects the phrenic nerve conduction time. However, a recent paper has shown that if the magnetic coil was placed anteriorly to the cricoid cartilage, then the phrenic nerve conduction time was very similar to that obtained by electric stimulation. If the magnetic coil was lowered to just above the clavicle, the conduction time slowed significantly. The authors believe that this occurred because there was more brachial plexus activation in the lower position compared with the higher position.

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Because of the relative invasiveness of electrophrenic stimulation of the diaphragm, and the large coefficient of variation in some studies in which Pdi was measured during maximal volitional efforts, some investigators prefer measuring maximum inspiratory pressures during a sniff maneuver. In this technique, the subject performs a vigorous sniff against an unoccluded airway. During such an effort, the nose acts as a Starling resistor, thereby generating intrathoracic pressures against an occluded airway. Some investigators argue that this maneuver approaches a more natural respiratory effort than other types of maneuvers used to measure maximum inspiratory pressures and thus should be easily mastered by patients and more reproducibly performed by technicians. Analysis of Rib Cage and Abdominal Motion During normal tidal breathing, the chest and abdominal compartments move synchronously in an outward direction, owing to diaphragm contraction, decreasing pleural pressure, and increasing abdominal pressure. In situations in which the diaphragm is severely paretic or paralyzed, however, the flaccid diaphragm cannot counterbalance the negative changes in pleural pressure generated by contraction of the inspiratory muscles of the neck and rib cage. Instead of moving normally in a caudad direction the flaccid diaphragm moves paradoxically cephalad into the thorax. This change in diaphragm motion gives rise to a paradoxical inward motion of the upper abdomen indicative of severe diaphragm weakness or paralysis. Changes in rib cage and abdominal pressure, or volume displacement during respiration, can provide important information about diaphragm strength. Partitioning of respiration can be examined from changes in abdominal and pleural pressures, as proposed by Macklem and colleagues. Changes in abdominal and pleural pressures during inspiration, expressed as the ratio of delta Pab : Delta PPL are normally negative as pleural pressure becomes more negative and abdominal pressure becomes more positive. This ratio has a maximum value of +1 when the diaphragm does not contribute to inspiration and is valid only if the expiratory muscles do not contribute significantly to the pressures being generated. Alternatively, the partitioning of ventilation can be noninvasively measured by compartmental changes in rib cage and abdominal volume by respiratory inductance plethysmography or magnetometry.

Figure 93-7 Two representative patients with myasthenia gravis and respiratory muscle weakness illustrating the effect of anticholinesterase therapy on maximum expiratory and inspiratory flow-volume curves. Solid curves represent pretreatment data; dashed curves were obtained following the injection of pyridostigmine. (From DeTroyer A and Borenstien S. Acute changes in respiratory mechanics after pyridostigmine injection in patients with myasthenia gravis: Am Rev Respir Dis 121:629–638, 1980, with permission.)

as a sign of diaphragmatic weakness and a greater likelihood of sleep-related hypoventilation. Forced expiratory volume in 1 s (FEV1 ) and measurements of midexpiratory flow rates (FEF25–75 or FEF50 ) are often greater than normal predicted values in patients with neuromuscular disease. The supranormal increases in midexpiratory flow rates appear to be due to the fact that maximum expiratory flow can be achieved over most of the vital capacity with low driving pressures. Further increases in expiratory flow may occur in patients with neuromuscular disease due to increased lung recoil. Two independent studies have shown that partial curarization in normal subjects produces a decrease in peak expiratory flow with an increase in midexpiratory flow rates compared with baseline. Moreover, in patients with myasthenia gravis who are in their baseline state of weakness before the administration of pyridostigmine, midexpiratory flow rates are increased over the range of vital capacity when referenced to absolute lung volume (Fig. 93-7).

Flow-Volume Loops Spirometry Respiratory muscle weakness induced by neuromuscular disease produces a restrictive pattern on spirometric testing with a reduction in VC. As mentioned, the reduced VC is commonly out of proportion to the reduction in maximal respiratory muscle force. Reductions in lung and chest wall compliance also probably contribute. Moreover, because of the contour of the pressure-volume curve, large reductions in the respiratory muscle forces have to occur before VC is significantly reduced. A decrease in VC greater than 25 percent on moving from the upright to supine postures has been used

Changes in the configuration of the flow-volume loop occur in various neuromuscular diseases. These changes reflect respiratory muscle weakness or malfunction of upper-airway muscles. “Saw toothing” of the flow contour is seen in extrapyramidal disorders affecting upper-airway muscles. Similarly, plateauing of the inspiratory flow wave form, indicative of extrathoracic airway obstruction, has been described in vocal cord paralysis caused by extrapyramidal neuromuscular disorders. An abnormal flow-volume curve is significantly more common in patients with clinically apparent bulbar muscle involvement (90 versus 15 percent, respectively), and the presence of an abnormal, flow-volume loop

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Effects of Neuromuscular Diseases on Ventilation

Figure 93-8 Flow-volume loop in a patient with motor neuron disease, showing inspiratory flow oscillation and inspiratory flow limitation. Subdivisions on volume and flow axis represents 1L, flow axis 1 L/s. (Based on data of Vincken W, Elleker MG, Cosio MG: Determinants of respiratory muscle weakness in stable chronic neuromuscular disorders. Am J Med 82:53–58, 1987, with permission.)

predicted bulbar and upper muscle involvement by a neuromuscular disease with a high sensitivity and specificity. A characteristic flow-volume contour showing involvement of the upper-airway muscles by motor neuron disease is shown in Fig. 93-8. Among patients with stable, chronic neuromuscular disease, the flow-volume loop is significantly more disturbed in those with respiratory muscle weakness, and these abnormalities correlate with reduced mouth pressures. Several features of flow-volume loop configuration correlate with reduced maximum static inspiratory and expiratory mouth pressures; a reduced peak expiratory flow, decreased slope of the ascending limb of the maximum expiratory curve, a drop-off of forced expiratory flow near residual volume, and a reduction in forced inspiratory flow at 50 percent of vital capacity (Fig. 93-9). A flow-volume loop score composed of the above parameters has a high degree of specificity and 90 percent sensitivity in predicting respiratory muscle weakness.

Lung Volumes A restrictive ventilatory pattern is demonstrated in patients with neuromuscular disease. A reduced TLC and a normal or reduced FRC are common. The RV is usually elevated and is a sign of expiratory muscle weakness.

Maximum Voluntary Ventilation Maximum voluntary ventilation (MVV) is an index of respiratory muscle endurance in the presence of normal expiratory flow rates. This appears to be appropriate in patients with neuromuscular disease, since airway resistance and FRC are usually within the normal range. Values for MVV correlate with respiratory muscle strength and may be even more sensitive than VC in detecting respiratory muscle weakness.

Figure 93-9 Representative flow-volume loop of a patient with chronic neuromuscular disease, showing different volume loop parameters indicative of respiratory muscle weakness. These parameters quantify the effects of respiratory muscle strength on the effort-dependent portions of the flow-volume loop. These four parameters are peak expiratory flow (PEF); ratio of PEF to the exhaled volume at which PEF was achieved, rapid vertical drop of forced expiratory flow at residual volume, and forced midinspiratory flow. (Based on data of Vincken W, Elleker MG, Cosio MG: Determinants of respiratory muscle weakness in stable chronic neuromuscular disorders. Am J Med 82:53–58, 1987, with permission.)

SELECTED NEUROMUSCULAR DISEASES A helpful approach toward understanding how specific neuromuscular diseases affect the respiratory system is to localize the anatomic involvement of the respiratory system. A detailed description of the neuroanatomy of respiration is outside the scope of this chapter (see Chapter 10). In general, however, neuromuscular disorders can be broken down into disorders that involve the upper motoneuron, lower motoneuron, or muscle itself. Lesions that arise in the cerebral cortex, brain stem, or spinal cord are classified as upper motoneuron lesions and are characterized by an increase in muscle tone or spasticity, the presence of an extensor plantar response, and increased reflex activity. Lesions in the lower motoneuron system demonstrate flaccidity, depressed reflexes, muscular fasciculations, and atrophy. The location and character of the patient’s weakness may enable one to identify the exact site of the lesion in the

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lower motoneuron system (i.e., the anterior horn cell, peripheral nerve, neuromuscular junction, or muscle itself). The following describes the effect of specific neuromuscular disease on the respiratory system and makes recommendations for treatment.

Upper Motoneuron Lesions Stroke Hemispheric ischemic strokes reduce chest wall and diaphragm movement on the side contralateral to the cerebral insult. Decreased diaphragm excursion with stroke correlates with diaphragmatic cortical representation identified by transcranial magnetic stimulation. Bilateral hemispheric strokes are also associated with Cheyne-Stokes respiration, which is progressive hyperventilation alternating with hypoventilation and ending in apnea (see Chapter 10). This breathing pattern may result from increased responsiveness to carbon dioxide as a result of interruption of normal cortical inhibition. The significance of Cheyne-Stokes respiration to stroke remains unclear but appears to be more common with bilateral than unilateral insults. Besides it effects on an alteration of breathing pattern, up to 50 percent of patients with strokes may have signs of pulmonary aspiration due to dysfunction of upper-airway muscles that protect the airway. Spinal Cord Injury The degree of respiratory impairment depends on the level and extent of the spinal cord injury. High cervical cord lesions (C1 to C3 ) cause paralysis of the diaphragmatic, intercostal, scalene, and abdominal muscles. Because all respiratory muscle activity is lost except for accessory and bulbar muscle function, high cervical cord injuries almost always require ventilatory assistance. In some patients, spontaneous breathing can be accomplished by glossopharyngeal breathing or diaphragmatic pacing because the phrenic nerve motoneurons (C3 to C5 ) remain intact. Middle cervical cord (C3 to C5 ) lesions destroy the phrenic motoneurons and prohibit the use of phrenic nerve pacing. Patients with more caudal lesions (i.e., C4 to C5 level) have an improved chance to wean from ventilator support compared with those with more cranial lesions. (Forty percent of patients with C3 lesions remain ventilator dependent.) Patients with lower cervical (C6 to C8 ) and upper thoracic (T1 to T6) cord lesions have intact diaphragm and neck accessory muscle action, but have denervated intercostal and abdominal muscles. These patients usually require ventilatory support only during the period immediately after the injury and rarely require long-term ventilation. In a study of C5 or lower spinal cordâ&#x20AC;&#x201C;injured patients, inspiratory muscle strength was reduced to approximately 60 percent of predicted but was dependent on the level of cord injury. In this study, PImax values in low cervical, midthoracic, and lower thoracic-upper lumbar lesions were 61, 69, and 75 percent of predicted, respectively, whereas PEmax values were 30, 32, and 54 percent of predicted, respectively. The

lower PEmax values were explained by a paralysis of abdominal and intercostal muscles, resulting in reduced cough and decreased clearance of bronchial secretions. Abdominal muscle paralysis probably accounts for an abnormally compliant abdomen in patients with lower spinal cord injury, which is in stark contrast to the 30 percent reduction in chest wall compliance believed to be due to abnormal rib cage stiffness. Patients with spinal cord injuries also have alterations in thoracoabdominal motion during tidal breathing that is further accentuated by changing from the erect to supine position. In patients with quadriplegia with relatively intact diaphragm function, the distribution of respiratory muscle weakness results in paradoxical inward motion of the upper rib cage during inspiration owing to weakness of the parasternal and scalene muscles. This pattern of abnormal thoracoabdominal movement is more marked in the supine than the upright position. Patients with high quadriplegia (above C3 to C5 ) may be able to sustain short periods of spontaneous respiration because of inspiratory activity of the sternocleidomastoid and trapezius muscles. Phasic inspiratory electromyography (EMG) activity has been observed in the platysma, mylohyoid, and sternohyoid muscles. Analysis of rib cage motion in these patients shows increased upper rib cage diameter, due to the inspiratory action of the neck accessory muscles pulling the sternum cranially and expanding the upper rib cage. The distribution of muscle paralysis in low cervical cord spinal patients also has a profound effect on the performance of forced expiratory maneuvers. In contrast to healthy normal subjects, in whom VC is moderately decreased on assuming the supine position, in patients with quadriplegia there is a paradoxical increase in VC in the supine compared with seated position without a significant increase in TLC. In 14 patients with quadriplegia (C4 to C7 ), there was a 16 percent increase in VC on changing from the upright to supine position and a reduction in RV (29 percent) and TLC (on average, 6 percent). The mechanism believed to be responsible for the increase in VC in supine patients with quadriplegia is the hydrostatic effect of abdominal contents, causing cephalad displacement and diaphragm lengthening and thereby placing the diaphragm on a more favorable portion of its length tension curve. The use of elastic binders when quadriplegics assume upright posture has been advocated to prevent the increase in abdominal compliance. Abdominal binding may have physiological benefit by maintaining diaphragm precontraction length in a more optimum position on its lengthtension curve. It was previously believed that all expiratory muscles were paralyzed in lower cervical cord injuries. However, studies of C5 to C8 quadriplegics indicate that phasic EMG activity of the clavicular portion of the pectoralis major is associated with a marked decrease in the anteroposterior diameter of the upper rib cage. This portion of the pectoralis muscle receives innervation from the C5 to C6 cord level. With the arms placed at the subjectâ&#x20AC;&#x2122;s side, contraction of the caudate head of the pectoralis major causes caudal displacement of the manubrium sterni and upper rib cage. This expiratory action

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has been shown to decrease expiratory reserve volume (ERV) by 60 percent when the shoulders are held in abduction. After 6 weeks of pectoralis muscle isometric training, patients with low quadriplegia can have a marked increase in maximum pectoralis muscle isometric strength and a significant reduction in ERV. Conceivably, therefore, training of this muscle could improve the effectiveness of cough in patients with low spinal cord injury. Pulmonary function typically improves in the months following spinal cord injury. In patients with spinal injuries below the C5 level, VC is approximately 30 percent of predicted in the first week after injury, but by the fifth week increases to 45 percent of predicted, and by the fifth month to approximately 60 percent of predicted. Improvements in VC have been attributed to spasticity developing in previously flaccid intercostal and abdominal muscles, thereby increasing the rigidity of the thorax and abdomen and improving diaphragm force generation. There is a role for corticosteroid use in the acute management of spinal cord injury. Methylprednisolone given as a 30 mg/kg bolus followed by a 24-h infusion at 5.4 mg/kg/h has been shown to improve motor function at 6 weeks, 6 months, and one year, but only in those who received the drug within 8 hours of injury. A subsequent study compared methylprednisolone infusion (5.4 mg/kg/h) for 48 to 24 hours after the administration of a bolus (30 mg/kg). There was no difference in functional outcome between the two infusion periods except in those in which the bolus dose was given 3 to 8 hours after the injury. If the methylprednisolone was started 3 to 8 hours after the injury, then those who received the infusion for 48 hours did have improved motor function at 6 weeks and 6 months. There were higher rates of pneumonia and sepsis in the 48-hour infusion group, but mortality was not different. No trial has shown a mortality benefit, and it should be recognized that the outcome measured was an improvement in the functional independence measure (FIM) score and not a return to normal motor function. Parkinson’s Disease Parkinson’s disease is due to degeneration of neurons in the substantia nigra and has a prevalence in the United States of approximately 200 cases per 100,000 people. Parkinson’s disease can be primary (e.g., idiopathic); or secondary, as in postencephalitic parkinsonism associated with the influenza pandemic, or part of a more generalized disorder, such as multiple system atrophy or drug abuse with MPTP (1-methyl4-phenyl-1,2,3,6-tetrahydropyridine). Respiratory abnormalities are common in Parkinson’s disease, with pneumonia being the most common cause of death. A substantial problem with Parkinson’s disease is glottic muscle dysfunction. An abnormal flow-volume loop contour showing regular or irregular flow oscillations commonly occurs. On direct fiberoptic visualization of the upper airway, these oscillations correspond to rhythmic involuntary movements of glottic and subglottic structures. Physiological evidence of upper-airway obstruction may be present. In

Effects of Neuromuscular Diseases on Ventilation

addition to the presence of oscillations in flow, a rounding off of the peak of the midexpiratory flow-volume curve, a lowered peak expiratory flow rate, and a delayed appearance of peak expiratory flow have been observed in Parkinson’s patients. These results have been interpreted as evidence for less coordinated or less “explosive” respiratory muscle contractions. Patients with mild to moderate Parkinson’s disease are able to perform simple single respiratory efforts (e.g., measurements of lung volume and maximum static inspiratory pressures), but have difficulty performing more complex, repetitive ventilatory efforts (i.e., sustaining inspiratory resistive loads to exhaustion and performing maximum unloaded breathing efforts). Performance of repetitive respiratory tasks is associated with an increased work of breathing when compared with that of an age-matched control group. These findings are similar to derangements in task performance exhibited by peripheral skeletal muscle groups in Parkinson’s patients. Treatment (e.g., with apomorphine) significantly improves neurological scores, maximum expiratory pressures, and peak inspiratory flow. Deep brain stimulation by stereotactically placing electrodes into the suprathalamic nucleus or globus pallidus nucleus recently has been shown to be effective when treating medically resistant patients. The electrodes produce a low-voltage high-frequency stimulation that results in inhibition of the neurons in the nucleus. Although the effect on respiratory function has not been directly studied, this procedure has been shown to improve motor function by about 60 percent. In summary, Parkinson’s disease results in problems in coordination and activation of upper airway and chest wall muscles that may result in functional glottic obstruction and/or failed coordination of repetitive respiratory tasks. These abnormalities are favorably treated with antiparkinsonian medications. Multiple Sclerosis Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system, characterized clinically by remissions and relapses of clinical symptoms due to disseminating central nervous system lesions. MS is the most common neurological disease afflicting young adults, with an estimated prevalence of 250,000 to 300,000 cases in the United States in 1990. The cause of the disease is unknown, although epidemiological evidence points to genetic and environmental factors. Classic clinical symptoms include paresthesia, motor weakness, diplopia, blurred vision, dysarthria, bladder incontinence, and ataxia. Symptoms are typically aggravated by an increase in temperature, which precipitates conduction block in partly demyelinated fibers. Although the disease course initially is remitting and relapsing and may persist for years, many patients will develop a progressive form of MS known as secondary progressive MS. The duration of the secondary progressive stage is variable with some progressing to severe debilitation rapidly whereas others have slow progression over a number

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of years. Some patients will develop primary progressive MS and have a steady deterioration in function related to recurrent acute attacks. Pathologically, the lesions of MS have a predilection to invade the periventricular white matter of the cerebral hemispheres, optic nerves, brain stem, and cervical spinal cord. Because MS can cause focal lesions anywhere in the central nervous system, different patterns of respiratory impairment can occur. Impairment of the respiratory centers and the medulla can cause failure of automatic breathing (Ondine’s curse), apneustic or neurogenic pulmonary edema. The three most common respiratory manifestations of MS are respiratory muscle weakness, bulbar dysfunction, and abnormalities in respiratory control. Acute respiratory failure rarely occurs in this disease, but it can occur because of severe demyelination of the cervical cord. Diaphragmatic paralysis resulting in respiratory insufficiency has also been reported. Even with severe disability and impaired respiratory muscle strength, patients with MS seldom complain of dyspnea. This paucity of respiratory complaints may be due to restricted motor activities and greater expiratory than inspiratory muscle dysfunction. Clinical signs that may be helpful in predicting respiratory muscle impairment are weak cough and inability to clear secretions, limited ability to count on a single exhalation, and upper extremity involvement. Advanced MS is frequently complicated by aspiration, atelectasis, and pneumonia. In a group of 38 patients that were not bed ridden or wheelchair bound without bulbar involvement and a diagnosis of MS for 9.2 years, there was a significant decrease in the maximal inspiratory pressure (MIP) and the maximal expiratory pressure (MEP) to 77 and 60 percent predicted, respectively. However, in 60 patients who were bed ridden secondary to advanced MS, pulmonary function studies revealed severely decreased MIP (47 percent predicted), MEP (30 percent predicted), and vital capacity that was 80 percent of predicted. In those with a vital capacity below 80 percent predicted, the MIP and MEP were significantly lower than those with a normal vital capacity. In both of these studies the MEP was more affected than the MIP, and the respiratory muscle weakness directly correlated with the severity of the subject’s overall neurological function. Smeltzer et al. developed a pulmonary dysfunction index for patients with MS and found that it correlated with MEP measurements. The score assesses the patient’s assessment of cough and ability to handle secretions, the examiner’s assessment of cough, and how high the patient can count on a single exhalation (Table 93-6). A subject with normal cough efficacy would have a score of 4, while an individual with the most impairment would have a score of 11. Gosselink et al. examined the effect of respiratory muscle training (e.g., three sets of 15 expiratory contractions at 60 percent of MEP twice daily) on respiratory muscle strength and the subject’s pulmonary index score in a group of MS patients. At 3 months there was a statistically significant improvement in the MIP, but although the MEP improved, the p value was 0.07 compared with con-

Table 93-6 Pulmonary Dysfunction Index for Multiple Sclerosis Patients Clinical Signs Patient rating History of difficulty handling secretions Cough Examiner rating Strength of cough when asked to cough voluntarily as hard as possible Value reached when patient counts aloud on a single exhalation after a maximal inspiratory effort

Score No Yes Normal Weak

1 2 1 2

Normal Weak Very weak/ inaudible >30 20–29 10–19 <9

1 2 3 1 2 3 4

Based on data from Smeltzer SC, Skurnick JH, Troiano R: “Respiratory function in multiple sclerosis. Utility of clinical assessment of respiratory muscle function.” Chest 101:479–484, 1992.

trol patients. The pulmonary index was statistically better at 3 and 6 months. Patients who are quadriplegic with prominent bulbar involvement are at high risk for the development of acute respiratory failure. Treatment of MS has traditionally included the use of immunosuppressive agents such as high-dose corticosteroids, cyclophosphamide, and azathioprine. Other treatments included intravenous immunoglobulin (IVIG), plasmapheresis, and recently medications such as glatiramer, mitoxantrone, and interferon-β (INFβ-1b). The choice of therapy depends on the clinical situation and whether relapsing remitting or secondary progressive disease is being treated. Most of the available data have focused on treating acute attacks of the relapsing remitting form of the disease. The use of ACTH or methylprednisolone during an acute attack has been shown to be protective against disease worsening, but the exact duration of therapy has not been determined. In one randomized placebo-controlled study, treatment with 10 days of high-dose oral methylprednisolone resulted in improved neurological function, but there was no difference in the reoccurrence of future acute exacerbations. There are no data available on the effect of long-term use of corticosteroids on MS progression. Cyclophosphamide, methotrexate, and cyclosporine are not recommended secondary to limited clinical benefit and the risk of severe adverse reactions. Interferonβ1a has been shown in a multicenter, double-blind placebo controlled study to decrease the relapse rate after 1 and 2 years of therapy. Additionally, therapy delayed progression of disability and lowered the number of active lesions on brain

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MRI when compared with placebo. A follow-up multicentered study found that interferon-β1a at 44 µg given three times weekly was more effective at preventing relapses of the disease and decreased the number of brain lesions seen on MRI compared with 30 µg given once weekly. Both the American Academy of Neurology and the MS Council for Clinical Practice Guidelines recommend the use of interferon-β for the treatment of acute attacks in relapsing-remitting MS. Currently there is no evidence to support the use of interferon-β for the treatment of secondary progressive MS. The use of IVIG has been controversial due to a lack of randomized controlled trials, but it does appear that IVIG can both delay and prevent the occurrences of acute attacks in the relapsing and remitting form of the disease in some patients. Achiron et al. has shown that in patients given IVIG within the first 6 weeks of neurological symptoms there was a significant reduction in disease activity as measured by MRI imaging and neurological symptoms. However, there was no significant additional benefit to adding IVIG to methylprednisolone therapy, and a recent study looking at the effect of IVIG use for 27 months in secondary progressive multiple sclerosis failed to show any difference in progression of disability. Glatiramer acetate, a random polypeptide made up of four amino acids, is thought to act by modulating the activity of T cells. The early studies with this agent showed a significant but minimal benefit. However, a recently published study has shown a significant decrease in the relapse rate when compared with placebo. Additionally, subjects in the placebo arm were permitted to crossover at the end of the trial to the glatiramer arm, and all patients were followed for 8 years. After 8 years the relapse rate decreased to a rate of one every 5 years, and those that were in the glatiramer arm from the beginning had better disability scores throughout the study, suggesting an advantage to starting the medication earlier. Mitoxantrone, an anthracenedione antineoplastic agent, is approved for use in secondary progressive MS. It has been shown to have a beneficial effect on disease progression in those with progressive disease, but its use is limited because the drug can cause heart failure. Plasmapheresis has no role in the treatment of secondary progressive MS, but may have a role in the treatment of severe acute attacks in previously nondisabled patients.

Lower Motor Neuron Lesions Poliomyelitis In the early part of the twentieth century, poliomyelitis was the most common cause of lower motor neuron disease in the United States. Paralytic poliomyelitis is the most devastating respiratory presentation of poliomyelitis infection and is preceded by a period of fever and mild illness. After several days of mild fever and myalgia, symptoms disappear; then, 5 to 10 days later, fever reoccurs with signs of meningeal irritation and asymmetric flaccid paralysis. Respiratory motor nuclei may be directly involved, resulting in diaphragmatic or other respiratory muscle dysfunction. In 6 to 25

Effects of Neuromuscular Diseases on Ventilation

percent of paralytic cases, bulbar symptoms may arise, increasing the risk of upper-airway obstruction, pooling of pharyngeal secretions, and pulmonary aspiration. Moreover, the central respiratory centers can be directly affected, resulting in irregular respirations. In contrast to GuillainBarr´e syndrome, sensation is intact. Tendon reflexes are significantly diminished or absent. Cerebrospinal fluid analysis shows a pleocytosis associated with mild protein elevation, and electroneuromyography shows widespread patchy denervation. Fifteen to 30 percent of adults with paralyzing infection die and treatment overall is supportive. Many patients require aggressive ventilatory and hemodynamic support during the acute phases of their illness. As temporarily damaged nerve cells regain function, recovery begins and may continue for as long 6 months. Paralysis persisting beyond that point is permanent, however, and may be associated with complaints of severe pain, which sometimes recurs years after the illness. Some patients develop progressive muscle weakness 20 to 30 years after the initial infection. This has been termed “postpolio syndrome.” Symptoms vary from mild to moderate deterioration of function, with fatigue, joint pain, or weakness that may progress to muscle atrophy. The most common symptom is muscle pain (typically after exertion), which occurs in 36 to 86 percent of the patients. The weakness tends to progress slowly, with an average decline in muscle strength of approximately 1 percent per year. The pathogenesis appears to be due to dysfunction of surviving motor neurons, with slow disintegration of axonal terminals eventually leading to muscle denervation. Although respiratory complaints are common in this disorder, significant hypoventilation with elevated PaCO2 rarely occurs. Respiratory failure is more common in those that required mechanical ventilation during the acute poliomyelitis phase. Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a chronic, degenerative neurological disorder characterized by death of motoneurons in the cerebral cortex and spinal cord. The result is a combination of upper and lower motoneuron dysfunction, manifested by spasticity and hyperreflexia muscle wasting, weakness, and fasciculations. It has an incidence of approximately one to two cases per 100,000 people. Males are more commonly affected than females, by a 2:1 ratio. Most cases are sporadic, but approximately 5 to 10 percent of cases demonstrate an autosomal dominant inheritance pattern. Recent reports incriminate abnormal glutamate metabolism as a potential cause in the development of sporadic ALS. Glutamate has been shown to exert specific neurotoxic effects and induces neuronal degeneration, both in vivo and in vitro. Additional mechanisms are likely important as well with recent work focusing on oxidative stress, loss of neurotrophic factors such as vascular endothelial growth factor (VEGF), and chronic inflammation. A familial form of ALS has been localized to

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chromosome 20, and a defect in gene coding for superoxide dismutase has been identified in some families. The usual clinical presentation is progressive weakness of the distal extremities, although severe respiratory muscle weakness, particularly intercostal muscle and diaphragm weakness, has resulted in some ALS patients presenting with respiratory insufficiency as the initial symptom. Respiratory muscle impairment is more evident in the advanced stages of the disease. Abnormalities in pulmonary function are apparent, even in patients with mild extremity weakness. Progression of respiratory impairment is much faster in ALS than in other chronic neuromuscular disorders, and serial lung function studies in ALS patients show progressive reduction in FVC and MVV. In contrast to patients with other neurological disorders, however, patients with ALS usually have a normal or slightly elevated transpulmonary pressure at FRC, and RV is usually increased and continues to rise as the disease progresses with maintenance of a normal TLC. These changes are thought to be due to earlier involvement of the abdominal musculature, with preservation of intercostal and diaphragm function. Support for these physiological findings comes from pathologic studies that show a more pronounced loss of motoneurons in the lumbosacral and lower thoracic spinal segments than in the upper and midthoracic regions. The use of respiratory muscle testing has been used to help determine the prognosis and help clinicians decide when to initiate ventilatory assistance. Recently, the sniff nasal inspiratory force (SNIF) was used to predict survival in ALS. The SNIF test is theoretically easier for the patient with ALS, particularly those with bulbar muscle involvement, because a tight seal around a mouthpiece is not required. A sniff is a short voluntary inspiratory maneuver, which has been shown to correlate with invasive nonvolitional tests of diaphragm strength. A SNIF less than 40 cm H2 O was found to predict nocturnal hypoxemia better than FVC. More importantly, a SNIF less than 40 cm H2 O was associated with a hazard risk for death of 9.1 with a median 6-month survival of 50 percent. Surprisingly, in those with SNIF less than 40 cm H2 O 66 percent had an FVC above 50 percent and the hazard risk for death was 13.6 in this group. When comparing the two techniques for the ability to predict 6-month mortality, the SNIF test had a sensitivity of 97 percent and specificity of 79 percent, while the FVC was 58 percent sensitive and 96 percent specific. A second study also has shown that in ALS patients without bulbar involvement the SNIF was superior to both vital capacity and maximal inspiratory pressure in predicting the development of respiratory failure as defined by hypercapnia (PaCO2 greater than 45 mm Hg). In patients with significant bulbar involvement, there was no single test of respiratory muscle function that reliably predicted the development of respiratory failure. The shape of the flow-volume curve may also pinpoint the subgroup of ALS patients with greater weakness of the expiratory muscles. In patients with severe expiratory muscle weakness, the flow-volume curve near RV shows a sharp drop in flow such that the maximum expiratory curve

has a concave appearance. This group of ALS patients usually has lower maximum expiratory pressures, smaller VC, reduced expiratory reserve volume, and a higher RV than do ALS patients with more-normalâ&#x20AC;&#x201C;appearing flow-volume curves. ALS is a progressive and uniformly fatal neuromuscular disease and all patients eventually develop respiratory failure, which necessitates the discussion of mechanical ventilation. Currently, guidelines from the American Academy of Neurology recommend treatment with noninvasive mechanical ventilation once the FVC is below 50 percent of predicted. Ventilation with bilevel positive airway pressure has been shown to increase both survival and quality of life in patients with ALS, while those with orthopnea seemed to derive the most benefit. One study examined the role of bulbar symptoms in the use of noninvasive ventilation. In a group of 57 patients receiving noninvasive ventilation the survival in those without bulbar involvement was significantly longer (27 months vs. 15 months) compared with those with bulbar involvement. Although not prospectively done, this paper also suggested that starting noninvasive ventilation earlier in those without bulbar involvement based on a protocol (presence of orthopnea, FVC less than 50 percent predicted or decrease in FVC of 500 ml, nocturnal desaturations, or PaCO2 greater than 45 mm Hg) improved survival. Treatment of the other respiratory complications of ALS includes a high index of suspicion for impaired swallowing due to bulbar involvement. Difficulty in swallowing food or even saliva predisposes ALS patients to a markedly high risk for pulmonary aspiration. Special swallowing precautions, earlier placement of enteral feeding tubes, or antisialogues may be required. Currently, the antiglutamate drug riluzole is the only pharmacologic agent approved for use in ALS. This drug has been shown to induce a significant improvement in survival and decrease the rate of deterioration in muscle strength in comparison with a placebo. So far, no other agent has been shown to be beneficial, but because of the discovery of a genetic mutation in the superoxide dismutase gene, a transgenic mouse model has been developed permitting the investigation of novel agents. Ceftriaxone, minocycline, insulin-like growth factor I (IGF-I), COX-2 inhibitors, and N-acetyl-lcarnitine have all been shown to prolong survival in transgenic animal models of ALS. Randomized, placebo controlled clinical trials are being designed to look at the effectiveness of these agents in patients afflicted with ALS. However, despite any pharmacologic interventions, ALS is a progressive and fatal neuromuscular disease and all patients eventually develop respiratory failure; therefore, ventilatory assistance needs to be considered. In those without bulbar involvement, noninvasive forms of ventilatory support are clearly indicated and will provide both a survival and quality of life benefit. Airway intubation may be required because of bulbar dysfunction further impairing cough and the inability to clear secretions. Long-term invasive ventilatory support is infrequently applied in ALS patients, but decisions must be made on an individual basis.

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Disorders of Peripheral Nerves Phrenic nerve dysfunction can be a significant cause of respiratory weakness in patients with neuromuscular diseases due to a variety of causes. Diaphragm Paralysis Unilateral or bilateral diaphragm paralysis following phrenic nerve injury can result from cardiac surgery, trauma, mediastinal tumors, infections of the pleural space, or forceful manipulation of the neck. Phrenic nerve injury during open heart surgery is one of the most common causes of unilateral and bilateral diaphragm paralysis and is due either to cold exposure during cardioplegia or to mechanical stretching of the phrenic nerve during surgery. Diaphragm paralysis may also be seen with a variety of motoneuron diseases, myelopathies, neuropathies, and myopathies. Bilateral diaphragm paralysis is characterized by a severe restrictive ventilatory impairment, with VC being frequently less than 50 percent of predicted in the upright position and a further reduction of 25 percent or more in VC in the supine position. TLC is also markedly decreased, as well as FRC and static pulmonary compliance. In most patients with nontraumatic bilateral diaphragm paralysis, the most important clinical feature is orthopnea out of proportion to the severity of the underlying cardiopulmonary disease. In patients with nontraumatic bilateral diaphragm paralysis, the diaphragm usually goes unrecognized until they present with cor pulmonale or cardiorespiratory failure. A chest radiograph showing elevation of both hemidiaphragms with volume loss and/or atelectasis at the lung bases is common. The diagnosis of bilateral diaphragm paralysis should be considered when any of the following four abnormalities is present: (a) a 40 percent or greater reduction in VC in the supine compared with upright position; (b) fluoroscopically observed paradoxical movements of both hemidiaphragms during a “sniff ” test; (c) absence of phrenic latency or phrenic nerve conduction velocity tests or lack of EMG evidence of spontaneous diaphragm activity; and (d) transdiaphragmatic pressure two standard deviations below the expected mean for normal subjects with paradoxical inward abdominal motion during maximum inspiratory efforts. Because in most patients, bilateral diaphragm paralysis occurs in the context of global respiratory muscle impairment, measurements of PImax and PEmax may be sufficient to arouse suspicion of diaphragm paralysis as a cause of the patient’s complaints. With diaphragm paralysis, a marked reduction in PImax with preservation of PEmax should be found, and in general, there is a correlation between maximum inspiratory pressures and Pdisniff . Reductions in Pdisniff to less than 30 cmH2 O are accompanied by orthopnea, a supine decrease in VC, and the presence of abdominal paradox. In most cases, the presence of severe bilateral diaphragm weakness can be diagnosed from physical exam, measurements of VC in the upright and supine positions, and PImax and PEmax . In cases in which the diagnosis is uncertain, or when definite documentation is desired, measurement of transdiaphragmatic

Effects of Neuromuscular Diseases on Ventilation

pressures, phrenic nerve conduction times, EMG activity, transdiaphragmatic pressures during phrenic nerve stimulation, or ultrasound imaging of the diaphragm may be desired. An elevation in PaCO2 , particularly in the supine position in patients with diaphragm paralysis has been reported, but is not consistent. Hemidiaphragm paralysis is more common than bilateral paralysis and is usually diagnosed from unilateral elevation of the hemidiaphragm on chest radiograph. Ultrasound of the diaphragm can be performed to confirm the diagnosis as well. Most disorders reported as causing bilateral diaphragm paralysis have also been reported as causes of unilateral paralysis (e.g., cervical spondylosis, spine cord injury, poliomyelitis, and muscular dystrophy). Other, more specific causes of unilateral diaphragm paralysis are pneumonia, trauma from central vein cannulation, and viral infections of the cervical nerve roots. Patient complaints and physical examination abnormalities in unilateral diaphragm paralysis are usually the same as with bilateral diaphragm paralysis but are less striking. Orthopnea is a frequent complaint, but it is less dramatic than in patients with bilateral paralysis. Moreover, physical examination findings are nonspecific, but occasionally may show paradoxical inward motion of the paralyzed hemidiaphragm with a reduction in breath sounds at the affected lung base and an increase in percussible dullness. The alveolar arterial oxygen gradient may be increased with mild hypoxemia due to the reduction in ventilation and perfusion of the lower lobe on the affected side. Tests of diaphragm function are intermediate between those in patients with bilateral diaphragm paralysis and normal predicted values. VC in the upright posture may be reduced to 74 to 81 percent of predicted, with a fall in VC also present in the supine compared with erect position, but of lesser magnitude than in patients with bilateral diaphragm paralysis. In patients with right hemidiaphragm paralysis, the fall in VC may be almost twice as great (19 versus 10 percent) in comparison with left-sided paralysis, owing to the weight of the liver further encroaching on lung volume. Maximum inspiratory mouth pressures are frequently reduced to approximately 50 to 62 percent of normal. Similar reductions are also found in maximum Pdi measured during maximum static voluntary efforts and during maximum sniff. Treatment of patients with bilateral diaphragm paralysis is similar to that of other patients with chronic neuromuscular diseases. Eliminating nocturnal hypoventilation, especially during REM sleep is warranted, and the implementation of noninvasive ventilation, especially positive-pressure ventilation, may be indicated. In some cases of symptomatic unilateral hemidiaphragm elevation, surgical plication of the affected hemidiaphragm may relieve symptoms and improve FVC and transdiaphragmatic pressure. Guillain-Barr´e Syndrome Guillain-Barr´e syndrome (GBS) precipitates respiratory failure more often than any other peripheral neuropathy. It is

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an acute idiopathic polyneuritis with an annual incidence of 0.6 to 1.9 cases per 100,000 people. It usually presents as paresthesia and ascending paralysis of the lower extremities with absent deep tendon reflexes in a symmetrical distribution. Objective findings of sensory loss are variable, and the degree of motor weakness can range from mild paresis to complete paralysis. Maximum weakness of the lower extremities occurs within 2 weeks in 50 percent of cases, and 90 percent of cases reach their nadir in weakness by 4 weeks. After the nadir is reached, patients remain at that level for an additional 1 to 4 weeks before recovery begins. Facial, ocular, and oropharyngeal muscles may be impaired as well as the respiratory muscles. Respiratory muscle weakness and, specifically, severe diaphragm weakness may be found in patients with GBS. The distribution of muscle weakness between respiratory and nonrespiratory muscles is not uniform in GBS, and peripheral muscle strength does not correlate with the presence or absence of respiratory muscle weakness. However, ventilatory failure correlates with diaphragmatic weakness. The impairment on respiratory tests in GBS is similar to that for other generalized neuromuscular diseases. A decline in FVC and maximum inspiratory and expiratory mouth pressures, impairment in nocturnal gas exchange during REM sleep, and the onset of hypercapnia detected by arterial blood gas analysis have all been reported in symptomatic GSB patients. An FVC of 15 cc/kg is a sign of imminent respiratory failure in GBS. Hypercapnia is a late sign of respiratory failure, with the average PaCO2 at the time of intubation 43 mmHg when FVC is less than 12 cc/kg. Respiratory treatment of GBS patients is mainly supportive. Since bulbar involvement, leading to swallowing dysfunction, increases the propensity for pulmonary aspiration, special precautions for feeding and control of upper-airway secretions may be required. Primarily because of bulbar dysfunction in those with respiratory failure, noninvasive ventilation has not been used outside of a few case reports. Individual cases without bulbar dysfunction merit special consideration and the use of noninvasive ventilation may be appropriate. Earlier intubation and assisted ventilation may be indicated to avoid complications that arise from progressive respiratory failure, overwhelming pulmonary infections, or both. When indicated, intubation and mechanical ventilation should be initiated early because emergent intubations have been associated with worse outcomes. It is well established that mechanical ventilation is indicated when the vital capacity falls below 15 cc/kg. However, it would be ideal to predict the need for mechanical ventilation at an earlier time. A recent study involving patients that were enrolled in plasma exchange trials showed by multivariate analysis that time from onset to admission (fewer than 7 days), inability to lift the elbows above the bed, inability to stand, inability to lift the head, ineffective cough, and increased liver enzymes all predicted the need for endotracheal intubation and mechanical ventilation. Patients that had at least four of these risk factors had an intubation rate of 85 percent. Aggressive pulmonary toilet, including repeated bronchoscopy, may be

needed to decrease atelectasis and the incidence of nosocomial pneumonia. In a multicenter trial, plasmapheresis (total of four treatments), using either albumin or fresh frozen plasma as replacement fluids, produced short-term benefits in earlier motor recovery, ambulation, reduction in number of patients who required assisted ventilation, and shortened the duration of mechanical ventilation. Plasmapheresis should be started within 2 weeks of the onset of symptoms or earlier, if possible. In patients with rapidly deteriorating neurological symptoms, however, plasmapheresis may still offer some benefit even if the duration of the disease is greater than 3 weeks. A subsequent study from the same group showed that two plasmapheresis treatments were better than none in mild disease, but four were better than two in moderate and severe disease. More than four treatments was not beneficial even in severe disease. Intravenous immunogammoglobulin (IVIG), given within 2 weeks after the onset of GBS, may also be effective therapy. Because plasmapheresis is an effective therapy, IVIG has never been compared with placebo. However, IVIG has been compared with plasmapheresis and recovery was as effective as plasmapheresis and may have been slightly better. In a study of 150 patients with GBS, 53 percent of the group treated with IVIG had an improvement of one grade (on a 7-point scale) in muscle strength compared with 34 percent of those treated with plasmapheresis after 4 weeks of therapy. A subsequent study comparing IVIG, plasmapheresis and IVIG with plasmapheresis showed that there was no difference between the groups. Currently, there is no evidence from randomized controlled trials to support the use of corticosteroids in the treatment of GBS. Critical Illness Polyneuropathy Critical illness polyneuropathy (CIP) was initially described in five patients that had survived sepsis and multisystem organ failure, and the entity is now recognized as a serious complication of critical illness that contributes significantly to morbidity and mortality. The disease is common with as many as 68 percent of patients with sepsis and multisystem organ failure requiring mechanical ventilation having evidence of CIP on electromyography/nerve conduction studies. Patients affected by this disorder typically exhibit varying degrees of musculoskeletal weakness, which ranges from mild weakness to near total paralysis with hyporeflexive deep tendon reflexes. Unfortunately, physical examination is unreliable as the sole means of diagnosis, and electromyography with nerve conduction studies (EMG/NCS) are required to confirm the diagnosis. EMG studies in these patients show a reduction in the amplitude of the compound muscle action potential without significant prolongation of stimulus latency, suggesting primarily axonal nerve damage rather than a demyelinating process. Recognition of CIP is important because the disease affects patient management and prognosis of the recovery from critical illness. Patients who develop CIP tend to require

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a longer period of mechanical ventilation and longer hospital stays compared with those without CIP. Garnacho-Montero et al. found that in a group of patients with sepsis and prolonged mechanical ventilation that those with CIP required 34 days of mechanical ventilation versus only 14 days for those without CIP. Additionally, the weakness associated with CIP results in an extended rehabilitation period, and there is evidence of persistent neuropathy on EMG/NCS as long as 5 years after discharge from the intensive care unit. Patients that develop CIP appear to have a higher mortality with one study showing a 3.5-fold increase in ICU mortality, and another with significantly higher in hospital mortality. Although the exact mechanism for axonal damage in this syndrome is unknown, several risk factors for the development of CIP have been described. Two of the most important risk factors are the presence of the systemic inflammatory response syndrome (SIRS) and the APACHE III score. One study looked at 98 patients prospectively and found that 72 percent of patients with SIRS and an APACHE III score above 85 develop CIP. Multivariate analysis of associated risk factors from another study found that hyperosmolality, parenteral nutrition, the use of neuromuscular blocking agents, and neurological failure (GCS less than 10) were associated with an increased risk of developing CIP. Exactly how these risk factors lead to the development of CIP is not known, but possibilities include nerve toxins released during episodes of multiple system organ failure, antibiotics impairing neuromuscular transmission, protracted use of neuromuscular blocking agents, and hyperglycemia causing nerve ischemia by endovascular shunting. Because no specific therapy for CIP exists, treatment is purely supportive and includes aggressive rehabilitation, nutrition support and treatment of any medical complications. It should be emphasized to both patient and family that recovery may be prolonged (as long as 5 years).

Disorders of the Neuromuscular Junction Myasthenia Gravis Myasthenia gravis is an autoimmune disorder characterized by impaired transmission of neural impulses across the neuromuscular junction due to the production of antibodies directed against the acetylcholine receptor. The prevalence of myasthenia gravis is estimated to be approximately 1 in 10,000 people with 2-to-1 female-to-male predominance. It occurs more often in younger than older adults. The typical myasthenic patient presents with fluctuating muscular weakness, with improvement after rest and the administration of anticholinesterase agents (e.g., edrophonium chloride). Ocular, facial, and neck muscles are commonly affected, but patients who have the most severe respiratory involvement have either acute fulminating or late severe classifications of myasthenia gravis. In patients with moderate, generalized myasthenia gravis, pulmonary function studies before the administration of edrophonium chloride reveal a mild reduction in FVC

Effects of Neuromuscular Diseases on Ventilation

and moderate reductions in both maximum inspiratory (approximately 46 percent of predicted) and expiratory (reduced to approximately 18 percent of predicted) mouth pressures. Because of increased lung recoil pressure, normal or supranormal values of maximal expiratory flow are seen in relation to lung recoil pressure or absolute lung volume. Although upper airway obstruction due to bulbar muscle involvement is theoretically possible, it has rarely been reported. However, Putman and Wise examined flow volume loops in myasthenia gravis patients that were adequate for interpretation. They found that in 12/61 patients with myasthenia gravis with reproducible flow volume loops 7 had either a variable extrathoracic or fixed upper airway obstruction suggesting that upper airway obstruction may be more common than previously thought. Acute respiratory failure usually occurs in the setting of a myasthenic crisis or cholinergic crisis or as the initial presentation of the disease. A myasthenic crisis refers to worsening of the basic underlying disease, usually precipitated by decreased anticholinesterase medication, surgery, administration of neuromuscular blocking medication, and emotional upset. The most common complications of myasthenic crisis are respiratory failure and recurrent pneumonias due to aspiration from bulbar involvement and impaired cough. The mean duration of mechanical ventilation in myasthenia gravis in a series of 22 patients (12 postoperative myasthenic or cholinergic crises, four myasthenic crises, two cholinergic crises, and four other medical disorders) was 8 days, with six patients (32 percent) requiring tracheostomy for prolonged mechanical ventilation. Of the 22 patients 21 survived and were totally weaned from ventilatory support over 1 to 32 days. Noninvasive bilevel (BiPAP) positive pressure ventilation is a viable option to treat respiratory failure during a myasthenic crisis until effective therapy is delivered. BiPAP was used in a series of 11 myasthenic crisis events in nine patients. The mean pressures used were 13/5 cm H2 O, and endotracheal intubation was avoided in all but four instances. Bulbar weakness was clearly documented in seven of the episodes and all patients were treated with either IV immunoglobulin or plasmapheresis. The only predictor for failure of BiPAP was a PaCO2 above 50 mmHg. Clinical parameters useful in predicting the development of postoperative respiratory failure include the severity of the disease (e.g., acute fulminating or late severe categories of myasthenia gravis), a low preoperative VC, and bulbar symptoms. The treatment of myasthenia gravis includes anticholinesterase agents, high-dose corticosteroids, thymectomy, and plasmapheresis in patients refractory to steroid or immunosuppressive therapy. Anticholinesterase agents are the first line of treatment. Most patients improve significantly with anticholinesterase agents, but only a few regain normal function. Remissions can be induced in up to 80 percent of patients with the use of corticosteroids. However, corticosteroids may cause temporary worsening of muscle weakness, usually on the sixth to tenth day of therapy, and close observation for signs of respiratory insufficiency is advisable. Other

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immunosuppressive agents (e.g., cyclosporine and azathioprine) may be useful with or without concomitant corticosteroids. In retrospective studies, thymectomy improves survival and relieves clinical symptoms, even in the absence of thymoma. In patients with thymoma, thymectomy is also indicated because the risk for malignant transformation is high in patients less than 55 years of age. In up to 80 percent of myasthenia gravis patients without thymoma, clinical improvement after thymectomy occurs during prolonged follow-up. Plasmapheresis and the use of intravenous immunoglobulin (IVIG) produce a temporary reduction in acetylcholine receptor antibody level and may be helpful in patients with respiratory failure not responding to anticholinesterase and immunosuppressive agents. Plasmapheresis and IVIG have been compared and both are equally efficacious. However, IVIG was associated with less severe adverse reactions and therefore is the preferred initial agent in the treatment of myasthenic crisis. Eaton-Lambert Syndrome Eaton-Lambert syndrome is a rare myasthenia disorder resulting from a reduction in neurotransmitter release from presynaptic terminals that develops in association with tumors (especially small-cell lung carcinoma). Although patients may respond weakly to administration of edrophonium chloride, the disease is differentiated from myasthenia gravis by the predominant involvement of limb and girdle muscles compared with the ocular and bulbar muscle involvement in myasthenia gravis. Respiratory muscle weakness is often detected on pulmonary function tests, but respiratory failure is infrequent.

Table 93-7 Myopathies Likely to Produce Respiratory Abnormalities Inherited Myopathies

Acquired Myopathies

Muscular dystrophies Duchenne Myotonic Fascioscapulohumeral Limb-girdle Oculopharyngeal Congenital myopathies Nemaline myopathy Centronuclear myopathy Metabolic myopathies Acid maltase deficiency Mitochondrial myopathies

Inflammatory (dermatomyositis, polymyositis) Systemic lupus erythematosus Endocrine myopathies Thyroid dysfunction Hyperadrenocorticism Acute steroid myopathy Electrolyte disorders Rhabdomyolysis

Muscular Dystrophies and Acquired Myopathies Respiratory function may be significantly affected by a variety of inherited muscle disorders and acquired myopathies (Table 93-7). The inherited muscular dystrophies refer to a heterogeneous group of progressive, degenerative, hereditary skeletal muscle diseases that cause severe muscle weakness, eventually resulting in repeated pneumonias, respiratory failure, and, in some cases, death. Respiratory failure, often accompanied by pneumonia, contributes to death in more than 75 percent of patients with Duchenne’s muscular dystrophy.

Inherited Myopathies Botulism Botulism is a rare disorder caused by the Clostridium botulinum toxin. It occurs as a result of eating improperly cooked food, wound contamination by the organism, or, especially in infants, the absorption of toxin from the gastrointestinal (GI) tract. There are eight types of toxins, although human diseases are usually caused by type A, B, or E. Botulinum toxin binds to the calcium channel in presynaptic terminals, impairing neuromuscular transmission of acetylcholine. GI symptoms predominate early in the disease, followed by neurological impairment, including descending paralysis of the neck, trunk, and limb muscles. Weakness of the respiratory muscles requiring mechanical ventilation is frequent, especially with botulinum type A toxins. Spirometry usually reveals a restrictive ventilatory defect, and recovery from respiratory muscle weakness may take months, often requiring prolonged mechanical ventilation. The average duration of ventilatory support for type A poisoning is 58 days, in contrast to 26 days for type B botulism. Exertional dyspnea and poor exercise tolerance may persist, even with normal lung function.

Duchenne’s Muscular Dystrophy Duchenne’s muscular dystrophy (DMD) is the best characterized of these heredofamilial muscle diseases. This disease is transmitted by an X-linked recessive gene, although approximately one-third of cases arise from spontaneous mutation. The disease is due to the mutation of the gene for skeletal protein dystrophin, a subsarcolemma protein believed to play a major role in providing structural integrity in the muscle cell surface membrane. Lack of dystrophin leads to a weaker cell membrane that is damaged and further worsened with muscle contraction. Muscle inflammation, necrosis and fibrosis subsequently lead to severe atrophy and loss of function. Approximately 30 to 40 percent of the normal amount of dystrophin must be expressed in order to prevent major myopathic symptoms. The diagnosis is confirmed by demonstrating mutation of the dystrophin gene in DNA from peripheral leukocytes, or an absence or abnormality in dystrophin in muscle biopsy samples. Symptoms usually present in early childhood. Gait disturbances and delayed motor development are common manifestations, with proximal weakness resulting in an

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Figure 93-10 Mean vital capacity (VC) and maximum static inspiratory pressures (MIP) in 37 DMD patients in three age groups (shaded bars) in comparison to normal predicted values (unshaded bars). MIP decreases gradually as DMD progresses, despite body growth, whereas VC increases until patients reach their early teens. (Based on data of Smith PEM, Edwards RHT, Evans GA, et al: Practical problems in the respiratory care of patients with muscular dystrophy. New Engl J Med 316:1197â&#x20AC;&#x201C;1205, 1987, used with permission.)

exaggerated lumbar lordosis. Most patients are wheelchair bound by the age of 12 to 15 years, with death occurring around the age of 20 years as a result of progressive respiratory failure and pneumonia. Kyphoscoliosis commonly develops as a result of severe muscle weakness and further contributes to a restrictive ventilatory deficit. Pulmonary symptoms are often minimal early on, despite significant weakness of the respiratory muscles. Maximum inspiratory pressure is reduced at all lung volumes in patients with DMD and declines with time. FVC increases with growth during the first decade and may mask early respiratory muscle dysfunction before it plateaus and progressively decreases about 5 to 6 percent per year after 12 years of age (Fig. 93-10). Reductions in maximum inspiratory pressure, therefore, occur early in the clinical course of DMD and may precede the reduction observed in VC. Inspiratory muscle weakness does not necessarily parallel the development of expiratory muscle weakness. Maximum expiratory mouth pressures are substantially lower than maximum inspiratory mouth pressures, possibly leading to a marked decrease in the effectiveness of cough. Despite severe and progressive muscle weakness, hypercapnia is uncommon in patients with DMD in the absence of pulmonary infections. The absence of hypercapnia despite severe muscle weakness is believed to be due to relative preservation of diaphragm function until very late in the illness.

Effects of Neuromuscular Diseases on Ventilation

Once hypercapnia occurs, however, the course is rapidly progressive and mean survival is approximately 10 months. Since ventilation is heavily dependent on diaphragmatic function in DMD patients, severe nocturnal hypoventilation may occur during REM sleep, when activity of chest wall and neck muscles is markedly attenuated. Indeed, REM hypoventilation may occur during REM sleep, when activity of chest wall and neck muscles is markedly attenuated. REM hypoventilation has been documented in DMD patients, even in those who have normal daytime gas exchange. Sleep-related hypoxemia may contribute to respiratory insufficiency and the development of cor pulmonale. Management of patients with DMD is mainly supportive. Ambulation should be maintained and encouraged as long as possible to retard the development of scoliosis. Surgical correction may attenuate the scoliotic contribution to the fall in VC and improve patient morale and quality of life overall. However, the downward trend in VC continues despite spine surgical stabilization. General physiotherapy may be helpful in preventing contractures. Maintenance of proper nutrition, with an emphasis on weight control, is important. Patients with DMD have a propensity to become overweight through a combination of inactivity, reduced energy requirements, and a misguided desire to improve muscle bulk by overeating. Some authors have emphasized a high-protein (more than 80 g protein daily), low-calorie diet, aiming to achieve a body weight somewhat lower than the ideal weight in patients of a similar height and normal muscle mass. Inspiratory muscle training (IMT) has been examined as a tool to prevent further decrease in respiratory muscle function in those with DMD, but its routine use remains controversial. Because there is loss of the protective mechanism of nitric oxide release in children with DMD, IMT could potentially be detrimental. Koessler et al. studied the effect of 2 years of IMT on a group of 27 patients with neuromuscular disease (18 with DMD and nine with spinal atrophy), and showed a clear increase in PImax and MVV. There was a plateau reached after 10 months of training, but despite this there was no change in the vital capacity at 2 years compared with baseline. Because there is potential for harm and no long-term studies to support its use, American Thoracic Society (ATS) guidelines do not suggest the use of routine IMT in this group of patients. Maintenance of cough and adequate airway clearance is extremely important in attempting to prevent atelectasis and pneumonia in this patient population. A PEmax of at least 60 cm H2 O has been shown to be adequate to generate an effective cough in patients with DMD, while a drop below 45 cm H2 O has been associated with ineffective cough. Once an ineffective cough is recognized there are multiple treatment modalities. The most studied technique is the use of a manual insufflator-exsufflator, which stimulates cough by providing a positive pressure breath immediately followed by a negative pressure exsufflation. The technique can be used on patients with or without a tracheotomy, and is generally well tolerated. It has been shown to be effective in generating cough and clearing airways in children with DMD, especially

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once scoliosis has developed. Respiratory tract infections are a serious complication in DMD patients, and must be treated aggressively with physiotherapy, postural drainage, assisted cough techniques, and appropriate antibiotics. All patients, regardless of cough status, should receive vaccination against pneumococcal pneumonia and influenza. In some patients, assisted ventilation is required once respiratory insufficiency or symptoms of sleep-related breathing disorders are present. Intermittent noninvasive positivepressure ventilation (NPPV) prolongs survival, improves quality of life, and may attenuate the decline in FVC and MVV. Longer-term follow-up of DMD patients treated with noninvasive ventilation demonstrates that pulmonary function continues to deteriorate 3 to 4 years after the initiation of noninvasive ventilation, with patients requiring longer periods of ventilation and/or transition to tracheostomy with positive-pressure ventilation. Once patients require the use of NPPV, the pressure should be titrated in the sleep laboratory to eliminate nocturnal apneas and hypopneas. Generally, bilevel positive airway pressure (BiPAP) should be used in those with significant daytime or nocturnal hypoventilation, and continuous positive airway pressure (CPAP) should be used primarily in those with obstructive sleep apnea without evidence of hypoventilation. DMD is a relentlessly progressive disease that eventually will lead to respiratory failure requiring invasive mechanical ventilation (see Chapter 94). End-of-life care and plans for the use of invasive mechanical ventilation should be discussed with the family and the patient well in advance if at all possible. While the institution of mechanical ventilation has been shown to prolong life in the appropriate setting, little is known of the effect on quality of life, and decisions must be made on an individual basis. There is evidence to suggest that prednisone treatment is beneficial. In a randomized, double-blind, controlled 6-month trial of prednisone in 103 boys, age 5 to 15 years, with DMD, patients were assigned to one of three regimens: prednisone 0.5 mg/kg per day, prednisone 1.5 mg/kg per day, or placebo. Both prednisone groups showed significant improvements in muscle strength and functional scores. After 6 months of therapy, patients randomized to high-dose prednisone had an improvement in time needed to stand, climb stairs, or lift weights, and a significantly larger FVC (1.7 versus 1.5 L), compared with the placebo group. A recent study examined the effect of alternate day dosing of prednisolone (0.75 mg/kg) for an average of 2.75 years in 66 boys with DMD compared with a historical control group not treated with steroids. The investigators found greater muscle strength and less scoliosis in the steroid group. Although there were more ankle contractures, the loss of ambulation was delayed in the steroid group compared with historical controls. Although these results are preliminary and not placebo controlled, they are encouraging and suggest that corticosteroid therapy may have a potential future role in DMD. To date there has not been a randomized controlled trial examining the effect of corticosteroids in the long-term management of the disease.

Gene therapy will be applicable to DMD in the future. Preliminary animal studies examining adenovirus-mediated in vivo gene transfer to dystrophic mouse diaphragm suggest that the adenovirus vector delivery of functional dystrophin gene to impaired muscle may be feasible. The large size of the dysmorphin gene limits the ability of viral vectors to deliver the gene to skeletal muscle. There has been more interest lately in using naked DNA plasmids and DNA plasmid-liposome complexes to deliver the gene to skeletal muscles. In fact, phase I trials have begun examining the effectiveness of this approach and early results show that the gene can be delivered to the target tissue. Myotonic Dystrophy Myotonic dystrophy is the most common form of hereditary muscular dystrophy in adults, with an estimated incidence of 1 in 8000 people. The gene responsible for the disease is located on the long arm of chromosome 19 and demonstrates an autosomal dominant inheritance pattern. Symptoms usually present during adolescence and in early adulthood, although the syndrome may be recognized as early as infancy. Respiratory muscle weakness is common and can be severe, despite mild limb muscle weakness. Myotonia of the respiratory muscles contributes to an increased work of breathing by increasing inspiratory impedance. Studies have suggested that the presence of a chaotic breathing pattern may explain the higher prevalence of chronic hypercapnia in patients with myotonic dystrophy than in patients with other forms of muscular dystrophy. Support for these findings came from studies that showed abnormal ventilatory responses to hypercapnic challenges in patients with myotonic dystrophy. However, studies that have used mouth occlusion pressures (P0.1 ) have revealed normal or supranormal responses in P0.1 in patients with myotonic dystrophy compared with controls. These data seem to suggest that prior studies showing hypercapnia in patients with myotonic dystrophy underestimated the severity of respiratory muscle weakness by itself as a limitation in the ability to mount a normal ventilatory response. The chaotic breathing pattern observed in some patients with myotonic dystrophy has been suggested to be related to disordered afferent information from diseased muscle spindles. Patients with myotonic dystrophy are particularly susceptible to development of respiratory failure with general anesthesia and sedatives. Postoperative respiratory monitoring is essential if surgery or the use of these agents is required. Pharyngeal and laryngeal dysfunction increases the risk of aspiration. Sleep-related breathing disturbances are common and may include both central and obstructive forms of sleep apnea. Nocturnal positive-pressure ventilation should be tried when hypercapnia and hypoxemia are present. Facioscapulohumeral Dystrophy Other inherited adult muscular dystrophies are facioscapulohumeral dystrophy (FSH) and limb-girdle dystrophy. FSH is an autosomal dominant dystrophy that primarily affects muscles of the face and the proximal portion of the upper

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extremities. FVC is significantly reduced in patients with FSH, although facial weakness complicates spirometric assessment. In 20 percent of patients with FSH, the disease affects pelvic girdle and trunk muscles, sometimes impairing respiratory function. Limb-Girdle Dystrophy Limb-girdle dystrophy is a heterogeneous group of autosomal dominant recessive disorders. The disease usually becomes evident in the second or third decade of life. Several case reports have documented the development of chronic hypercapnia in patients with limb-girdle dystrophy who have severe diaphragm weakness or bilateral diaphragm paralysis as the basis for hypercapnia. However, not all patients with limb-girdle dystrophy develop hypercapnia. Most patients have moderate respiratory muscle weakness with normal gas exchange. Acid Maltase Deficiency Two metabolic myopathies, acid maltase deficiency and mitochondrial myopathy, have received attention as potential causes of respiratory failure. Acid maltase deficiency is a type I glycogen storage disease due to the deficiency of the lysosomal enzyme responsible for hydrolysis of both the α 1 to 4 and α 1 to 6 linkages of glycogen. The disease presents in three clinical forms: infantile, childhood, and adult. In adult-onset disease, onset usually occurs after 20 years of age and presents with progressive proximal muscle weakness. The diagnosis may be difficult to establish in some patients, as respiratory failure or sleep-related complaints, secondary to respiratory deterioration during REM sleep, may be the initial presentation. Diagnostic studies include elevated serum muscle enzymes; myopathic changes on electromyography, and vacuoles filled with lysosomal breakdown products on muscle biopsy. A report that a weight-reducing, high-protein diet improved respiratory function in a patient with an acid maltase deficiency has not been confirmed, and treatment remains supportive. Mitochondrial Myopathy Mitochondrial myopathy represents a heterogeneous group of disorders that affect mitochondrial function and may present as complex multisystem disorders with brain and striated skeletal muscle being the predominant organs affected: (a) Kearns-Sayre syndrome; (b) myoclonic epilepsy, “ragged red fibers,” and mitochondrial myopathy; and (c) encephalopathy, lactic acidosis, and stroke-like episodes. The clinical manifestations may be broad and include myalgia and exercise intolerance, proximal muscle weakness, and external ophthalmoplegia with unexplained respiratory failure. All three disorders are characterized by hypoventilation and depressed responses to hypoxia and hypercapnia and, in some cases, unexplained respiratory failure. Skeletal muscle biopsy establishes the diagnosis of mitochondrial myopathy by showing “ragged red fibers,” which are accumulations of mitochondria identified with modified trichrome staining. Treatment

Effects of Neuromuscular Diseases on Ventilation

is supportive. Once identified, patients should be cautioned regarding the use of sedatives, and special attention is required when sedation or surgery is planned.

Acquired Myopathies Acquired myopathies include inflammatory polymyopathies (polymyositis and dermatomyositis), systemic lupus erythematosus, endocrine myopathies (hyper- or hypothyroidism), hyperadrenocorticism, electrolyte disturbances, rhabdomyolysis, and the use of high-dose exogenous corticosteroids, with or without concomitant use of neuromuscular blocking agents. Inflammatory Myopathies Pulmonary complications are the major cause of morbidity and mortality in dermatomyositis and polymyositis. These include interstitial pneumonitis, pulmonary vasculitis, recurrent aspiration from oropharyngeal dysfunction, and, rarely, hypoventilatory failure from respiratory muscle weakness. Respiratory failure is uncommon in the inflammatory myopathies and is usually due to clinically significant interstitial lung disease. Ten to 30 percent of patients with inflammatory myopathies have interstitial lung disease, manifested by dyspnea, nonproductive cough, and hypoxemia, with radiographic evidence of diffuse interstitial lung disease and impaired gas exchange. Corticosteroids may be successful in the treatment of interstitial pneumonitis and myositis. Successful treatment appears to be enhanced by early initiation of therapy, as patients in later stages of the disease become more refractory to corticosteroids and cytotoxic agents. Systemic Lupus Erythematosus Diaphragm dysfunction and respiratory muscle weakness with small lung volumes occur without apparent involvement of the peripheral skeletal muscles in patients with systemic lupus erythematosus (SLE). This syndrome has been called “the shrinking lung syndrome.” Decreased lung volumes appear not to be due to parenchymal lung disease or phrenic neuropathy but, rather, to a myopathic process affecting diaphragm strength. It is estimated that approximately 25 percent of SLE patients have diaphragm weakness, even in the absence of a generalized myopathy. Steroid Myopathy Although a syndrome of acute myopathy secondary to highdose steroid use was first described almost 30 years ago, the development of severe respiratory muscle weakness and prolonged respiratory failure following the use of high-dose steroids has received renewed interest. Most patients have received neuromuscular blocking agents, along with high-dose steroids before weakness becomes evident. Some patients require months of mechanical ventilation before eventual recovery. The serum CPKs are often normal, and EMG data show nonspecific changes. Overall, it is difficult to incriminate

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specific neuromuscular blocking agents or steroids as the only factors responsible for myopathic changes because an underlying severe illness, under nutrition, multiple medications, and disuse atrophy are usually concurrent.

TREATMENT Principles of Management Principles in management of respiratory dysfunction in patients with neuromuscular disease include: (a) preventive therapies designed to minimize the impact of impaired secretion clearance and alveolar hypoventilation on gas exchange and lower respirator tract infections; and (b) stabilization of patients who develop acute or chronic respiratory failure (see Chapters 94, 148). Because patients with neuromuscular disease usually have nonpulmonary symptoms and signs before the onset of respiratory problems, preventive actions can be taken to preserve their respiratory status. In neuromuscular disorders causing bulbar dysfunction, swallowing precautions and airway control measures are required. With advanced bulbar symptoms, upper-airway control with a cuffed tracheostomy tube may be needed to protect the airway and facilitate suction of lower respiratory track secretions, averting atelectasis and pneumonia. In patients with impaired cough, assisted coughing (e.g., ancillary hand thrust in the substernal location to increase intrathoracic pressure and expel secretions mouthward) may be helpful, along with posture drainage and the use of incentive spirometry.

muscle training may improve respiratory muscle endurance and strength. Some authors have questioned the wisdom of training respiratory muscles of patients with significant neuromuscular dysfunction. Breathing through resistive loads may be harmful and perhaps further damage or tire already weakened respiratory muscles. Also, the training techniques do not apply to upper-airway and pharyngeal musculature. The effects of inspiratory muscle training have also been examined in patients with quadriplegia, who may be a more appropriate group for respiratory muscle training because, although weakened, their respiratory muscles are normal. In small numbers of patients with quadriplegia, 6 to 16 weeks of inspiratory resistive training improved inspiratory muscle strength and endurance, and 6 weeks of pectoralis muscle isometric training significantly increased expiratory reserve volume in C6 to C8 patients with quadriplegia. Such increases in expiratory reserve volume suggest that these patients may have a more effective cough. Although these changes may be physiologically beneficial, no study has correlated such improvements with better clinical outcome; accordingly, the therapeutic value of inspiratory muscle training remains speculative. Mechanical Ventilation In patients with severe respiratory impairment, mechanical ventilation may be indicated to provide complete ventilatory support. Indications for mechanical ventilation are shown in Table 93-8. Comparisons of the situations in which invasive or noninvasive mechanical ventilation is applicable are

Table 93-8 Preventive Therapies Intermittent Positive Pressure Breathing There is no evidence for a beneficial effect of intermittent positive-pressure breathing on respiratory system compliance in patients with chronic neuromuscular disorders. Respiratory Muscle Training Inspiratory and expiratory muscle training may be helpful in some neuromuscular diseases. One could hypothesize that respiratory muscle weakness is key to the development of respiratory tract infections and ventilatory failure in patients with chronic neuromuscular disease. Besides weakened muscles, a reduction in lung and chest wall compliance and, in some cases, the presence of hypoxemia and hypercapnia all act to increase ventilatory workload in patients who already have markedly diminished ventilatory pump capacity. Strengthening weakened respiratory muscles relieves cough, improves secretion clearance, and increases ventilatory capacity. Respiratory muscle training improves strength and ventilatory endurance in normal subjects and in patients with pulmonary diseases. Several uncontrolled studies, performed in patients with muscular dystrophy, showed that inspiratory

Indications for Mechanical Ventilation in Patients with Neuromuscular Diseases Acute respiratory failure Severe dyspnea Marked accessory muscle use Copious secretions Unstable hemodynamic state Hypoxemia refractory to supplemental O2 Acute severe gas exchange disturbances (increased PaCO2 with pH â&#x2030;¤7.25) Chronic respiratory failure Symptoms of nocturnal hypoventilation (e.g., morning headaches, decreased energy, nightmares, enuresis) Dyspnea at rest or increased work of breathing impairing sleep Cor pulmonale due to hypoventilation, PaCO2 >45, pH <7.32 after treating reversible conditions Nocturnal desaturation (SaO2 <88%) despite supplemental O2 therapy

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Table 93-9 Invasive Versus Noninvasive Mechanical Ventilation in Patients with Neuromuscular Disease Invasive Ventilation (Endotracheal or Tracheostomy Tube and Positive-Pressure Ventilation)

Noninvasive Ventilation (No Airway Cannulation)

Copious secretions

Awake, cooperative patient

Inability to control upper airway

Good airway control

Inability to tolerate or failure of noninvasive ventilation

Minimal secretions

Impaired cognition

Hemodynamic stability

Unstable hemodynamics

Reversible cause of respiratory failure

Effects of Neuromuscular Diseases on Ventilation

summarized in Table 93-9. The types of ventilation available and their advantages and disadvantages are provided in Table 93-10. Patients who present with the onset of severe dyspnea, CO2 retention and moderate to severe hypoxemia require intubation and mechanical ventilation. In patients with acute respiratory failure who are awake, alert, and able to control their airway and do not have copious secretions, noninvasive ventilation (e.g., positive-pressure ventilation with a face mask rather than an endotracheal or tracheostomy tube) may obviate intubation (see Chapter 148). In some patients, the onset of respiratory failure is insidious, manifested by the gradual onset of dyspnea, daytime hypersomnolence, morning headaches, nightmares, enuresis, and easy fatigability. In patients with these symptoms, arterial blood gas analysis is warranted, especially if vital capacity falls below 1.5 to 1 L. Daytime measurements may be misleading, however, because impaired gas exchange may occur only during REM sleep. Nocturnal oximetry or a full polysomnogram should be considered to exclude the presence of nocturnal hypoventilation. In patients who have chronic hypoventilation, uncompensated respiratory acidosis, hypoxemia refractory to supplemental oxygen, or worsening symptoms such as easy fatigability and morning headaches, the implementation of nocturnal mechanical ventilation should be anticipated (Table 93-8). In most cases, noninvasive forms of ventilatory support should be considered first. Since the polio epidemic in the 1940s and 1950s, correction of nocturnal and daytime hypoventilation with a range of noninvasive

Table 93-10 Types of Noninvasive and Alternative Forms of Ventilation Used in Patients with Neuromuscular Disease Tank

Advantages

Disadvantages

Negative-pressure ventilators Tank Pulmowrap Cuirass

Familiar and dependable No airway cannulation Can significantly augment ventilation Rare hemodynamic concerns Simple devices

Cumbersome Induces obstructive apnea Constrains body posture Bulky (tank) Limits nursing care Controlled ventilation

Positive-pressure by mask or mouthpiece

Averts upper-airway obstruction, pressure preset, leak compensates Patient initiated machine breaths

Attachment bothersome Leaks Aerophagia Skin breakdown

Glossopharyngeal breathing

Decreases ventilator dependency

Learning curve Limited ventilation

Diaphragmatic pacing

Decreases ventilator dependency

Expensive Upper-airway obstruction Requires surgery Diaphragm fatigue

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ventilators—including Drinker respirators, cuirasses, and poncho-wrap ventilators—has supported patients’ nocturnal and daytime gas exchange for months to years. Although these types of ventilators are relatively inexpensive, durable, and successful, there are limitations to their use (Table 93-10). Negative-pressure ventilators function by intermittently applying subatmospheric pressure to the thorax and abdomen that increases transpulmonary pressure and inflates the lung. The efficacy of negative-pressure ventilation is determined by thoracic and abdominal compliance, as well as the surface area over which negative pressure is applied. Tank ventilators are the most efficient form of negative-pressure ventilators and cuirass ventilators, less so, since tank ventilators surround a greater thoracic and abdominal surface area. Although tank ventilators are very reliable, they are large, cumbersome, and claustrophobia inducing for patients, and markedly interfere with nursing care. Chest cuirasses and poncho-wrap ventilators are more portable than tank ventilators, but both require that the patient remain recumbent, induce a rocking motion in the lower posterior thoracic spine, and may induce discomfort and pressure sores at areas of skin contact. Moreover, all forms of negative-pressure ventilation tend to induce obstructive sleep apnea due to upper-airway collapse during a mechanically delivered breath. This problem is overcome by noninvasive positive-pressure ventilation, whereby positive pressure applied to the upper airway acts as a pneumatic stent that maintains a patent upper airway during a machine-delivered breath. Rocking beds and pneumobelts (abdominal displacement ventilatory) have been used as ventilatory assist devices in patients with mild to moderate ventilatory failure. Both devices augment diaphragmatic motion by displacing the abdominal viscera against gravity. The rocking bed consists of a mattress on a motorized platform that rocks in an arc of 40 degrees with the patient lying recumbent. As the bed rocks with the head dependent, gravity induces the abdominal contents and diaphragm to move cranially, thereby assisting exhalation. In the next cycle, as the bed tilts upward, gravity acts to move the diaphragm and abdominal contents in a caudad direction, thereby assisting inspiration. The bed rocks between 12 and 24 times per minute and may be adjusted to optimize patient comfort and achieve minute ventilation targets. The pneumobelt is an inflatable bladder that is worn over the anterior abdomen and connected to a positivepressure ventilator that intermittently inflates it. With a patient seated upright, bladder inflation increases intraabdominal pressure, forcing the diaphragm cephalad and thereby inducing active exhalation. When the bladder deflates, gravity moves the abdominal contents and diaphragm caudally, thereby facilitating passive inspiration. Tidal volume can be augmented by increasing bladder inflation pressures to target goals. Both devices should be considered methods to assist ventilation in impaired patients rather than to replace mechanical ventilation in more acutely ill subjects. Both devices are limited by their constraints on patient posture. The rocking bed is bulky, stationary, and limited by the degree of

ventilatory assistance that it provides. Similarly, the pneumobelt requires that the patient use it in the upright position, the amount of ventilatory assistance provided is limited, and some patients complain of pain and discomfort when high bladder inflation pressures are required to sufficiently augment ventilation. Several studies have examined the application of noninvasive positive-pressure ventilation given only at night or intermittently throughout the 24-hour period using nasal, oronasal, or mouthpiece attachment. Several authors have shown significant improvements in daytime gas exchange after 3 months of nocturnal ventilation, with the mean increase in PaO2 approximately 15 mmHg and the decrease in PaCO2 approximately 14 mmHg. Beneficial effects of chronic intermittent noninvasive ventilation, besides better gas exchange, include abatement in patients’ symptoms and improvement in functional status. There is an inconsistent effect on increasing maximum inspiratory and expiratory mouth pressures and lung volumes. The mechanisms for the improvement with chronic intermittent noninvasive ventilation in daytime gas exchange in patients with neuromuscular diseases are unknown, but several hypotheses have been proposed: (a) respiratory muscle resting treats patients who suffer from chronic intermittent fatigue; (b) preventing nocturnal hypoventilation resets the central respiratory center PaCO2 threshold; (c) there is improved ventilation-perfusion matching; and (d) improved lung and chest wall compliance decreases the work of breathing. Although none of the above mechanisms has been established as a conclusive mechanism for the improvement in gas exchange observed in these patients following noninvasive ventilation, resetting of the central controller PaCO2 level appears to be the most tenable. The presence of chronic inspiratory muscle fatigue has never been proved in any patient group, and other studies have shown that intermittent positive-pressure breathing does not decrease the incidence of atelectasis or improve lung volume. Whatever the mechanism(s), however, all studies reported to date show that noninvasive positive-pressure ventilation improves gas exchange and alleviates symptoms of nocturnal hypoventilation in patients with chronic neuromuscular diseases.

Other Forms of Ventilatory Assistance In certain patients with neuromuscular diseases, glossopharyngeal breathing and diaphragmatic pacing may be important aids to augment ventilation. Glossopharyngeal Breathing Intermittent glossopharyngeal breathing using oral, pharyngeal, and laryngeal muscles, may augment ventilation (see Chapter 94). Short periods of spontaneous ventilation are possible once patients have mastered this technique. With glossopharyngeal breathing, the patient gulps in air by lowering and raising the tongue against the palate in a piston-like fashion, thereby injecting air into the trachea. After practice,

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Effects of Neuromuscular Diseases on Ventilation

Subject #1 Left Alone

Bilateral

Right Alone

600

1200

600

Week #15

400

Initial

200

Volume (ml)

Week #15 Week #4 400

Week #15 Week #4 Initial

200

Volume (ml)

1000 800

Week #4

600

Initial

400 200

2s Figure 93-11 Reconditioning of the diaphragm as evidenced by increased inspired volumes initially, at 4 and 15 weeks postoperatively after left and right hemidiaphragm and bilateral diaphragm contraction via diaphragmatic electrode pacing. (From data of DiMarco AF, Onder BP, Ignagni A, et al. Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects. Chest 127:671â&#x20AC;&#x201C;678, 2005, used with permission.)

patients may be able to gulp approximately 50 to 150 cc of air every half second. Patients may then repeat gulps in series without preventing air from escaping into the trachea so that, with repeated gulping, a tidal volume of approximately 500 to 600 cc may be achieved. With a repeating series of gulps, normal minute ventilation can be achieved for short periods. Although this technique is difficult for some patients, patients with high spinal cord injuries, postpolio syndrome, and other neuromuscular disease successfully utilize this technique. Diaphragmatic Pacing To increase independence from mechanical ventilation, diaphragmatic pacing may be a treatment option in selected patients. Although phrenic nerve pacing by external stimulation has been well documented since the late 1940s, longterm phrenic nerve stimulation did not become a reality until a small implantable electrode and receiver were developed in the late 1960s. Diaphragmatic pacing consists of a radiofrequency transmitter and an antenna that discharges stimulatory signals to a receiver that when activated by radiofrequency waves, transmits electrical impulses in an electrode placed over the phrenic nerve. Surgery is required to implant the electrodes and receiver. Electrode implantation around the phrenic nerves can be achieved by a cervical or thoracic approach; however, the thoracic approach is preferred, to ensure stimulation of all phrenic nerve roots while avoiding the brachial plexus. The subcutaneous receiver is usually placed in the lower anterolateral rib cage to allow it to be superficial, but in an area in which soft-tissue movement is limited. The subject must have intact phrenic nerves in order for the procedure to be successful, and the phrenic nerve is typically assessed by measuring conduction times along the nerve. Electric stimulation is applied transcutaneously in the neck region and surface diaphragm EMG is monitored.

The nerve conduction time can then be calculated with normal being around 7.5 to 9 ms. Diaphragmatic pacing has a number of potential limitations, including its high cost, the potential to fail abruptly, the development of upper-airway obstruction, and the induction of diaphragm fatigue. On the other hand, successful implantation allows patients to be independent from ventilatory support for prolonged periods, and to speak more freely. While implantation of phrenic nerve electrodes has become an accepted procedure, there is ongoing research into placing diaphragmatic electrodes laparoscopically. This approach would be less invasive, more cost efficient and have less morbidity than the current approach. Two electrodes are placed on each hemidiaphragm near the motor points of the phrenic nerve. Initially, removable suction electrodes are placed until a location is found that induces maximal contraction of the diaphragm and a large intra-abdominal pressure change both by twitch and high-frequency stimulation. The wires are then brought through the skin and connected to the stimulator. Because patients on chronic mechanical ventilation develop diaphragm atrophy, a reconditioning period is required before the restoration of maximal diaphragm function. Figure 93-11 shows the tidal volume generated gradually increased with time as the muscle is reconditioned and the tidal volume is greatest with bilateral stimulation. In a recent case series using this technique, three of five subjects achieved independence from mechanical ventilation. One other was free of mechanical ventilation for 20 hours per day, and the other did not have activation of the diaphragm. This individual most likely did not have intact phrenic nerves. Intact phrenic nerves are required for successful intramuscular diaphragm pacing as evidenced by animal studies showing no diaphragm activation with intramuscular pacing after

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transection of the phrenic nerves. This probably occurs because the mechanism of intramuscular pacing is by stimulation of phrenic nerve roots in the diaphragm. Because the intercostal muscles are capable of contributing up to 35 to 40 percent of the vital capacity they should be able to liberate a subject from mechanical ventilation if stimulated through pacing. In animal models, stimulation of the ventral surface of T1-T3 resulted in maximal inspired volumes, and when combined with bilateral phrenic nerve pacing results in tidal volumes that approach the inspiratory capacity. However, when applied to a group of spinal cord injury patients with phrenic nerve damage; very little volumes were generated with stimulation of ventral aspect of T1-T3, and subject were unable to breath without mechanical ventilation for short time periods (20 min to 2.45 h). This discrepancy between animal and human studies may be secondary to the different shape of the human thoracic cage or the reduction in rib cage and lung compliance in those with tetraplegia. Additionally, stimulation of T1-T3 resulted in the movement of several nonrespiratory muscles, which led to hypertrophy of the upper trunk musculature. A follow-up trial that combined intercostal pacing with unilateral diaphragm pacing in a small group of patients that had unilateral phrenic nerve injuries in addition to spinal cord injury demonstrated that all patients were able to have significant periods of free time from mechanical ventilation. The main limitations to this approach remain contraction of nonrespiratory muscles, which makes the process metabolically inefficient and can lead to uncontrollable muscle activity. The main group of patients who appear to benefit from diaphragmatic pacing are ventilator-dependent patients following high cervical cord injury. Approximately one-third of patients with high cervical spinal cord injuries may be suitable for this type of treatment. Although short-term improvements are noted in terms of ventilator independence and improvement in functional status, no long-term studies demonstrating efficacy have been published to date.

SUGGESTED READING Achiron A, Kishner I, Sarova-Pinhas I, et al: Intravenous immunoglobulin treatment following the first demyelinating event suggestive of multiple sclerosis. A randomized, double-blind placebo-controlled trial. Arch Neurol 61:1515–1520, 2004. American Thoracic Society consensus statement: Respiratory care of the patient with Duchenne Muscular Dystrophy. AJRCCM 170:456–465, 2004. American Thoracic Society: Consensus statement on respiratory muscle testing. AJRCCM 166:518–624, 2002. Baydur A: Respiratory muscle strength and control of ventilation in patients with neuromuscular disease. Chest 99:330– 338, 1991. Bourke SC, Bullock RE, Williams TL, et al: Noninvasive ventilation in ALS: Indications and effect on quality of life. Neurology 61:171–177, 2003.

Bracken MD, Shepard MJ, Holford TR, et al: Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the third national acute spinal cord injury randomized controlled trial. National acute spinal cord injury study. JAMA 277:1597–1604, 1997. De Troyer A, Estenne M: The respiratory system in neuromuscular disorders, in Roussos E (ed), The Thorax. New York, Marcel Dekker, 1995, pp 2177–2212. DiMarco AF: Restoration of respiratory muscle function following spinal cord injury. Review of electrical and magnetic stimulation techniques. Resp Physiol Neurobiol 147:273–287, 2005. DiMarco AF, Onders RP, Ignangni A, et al: Phrenic nerve pacing via intramuscular diaphragm electrodes in tetraplegic subjects. Chest 127:671–678, 2005. Estenne M, De Troyer A: The effects of tetraplegia on chest wall statics. Am Rev Respir Dis 134:121–124, 1986. Farrero E, Prats E, Povedano M, et al: Survival in amyotrophic lateral sclerosis with home mechanical ventilation. The impact of systemic respiratory assessment and bulbar involvement. Chest 127:2132–2138, 2005. French Cooperative Group on Plasma Exchange in GuillainBarr´e Syndrome. Efficiency of plasma exchange in Guillain-Barr´e syndrome: Role of replacement fluids. Ann Neur 22:753–761, 1987. Garay SM, Turino GM, Goldring RA: Sustained reversal of chronic hypercapnia in patients with alveolar hypoventilation syndrome. Am J Med 70:269–274, 1981. Garnacho-Montero J, Rossario AV, Garcia-Garmendia J, et al: Effect of critical illness polyneuropathy on the withdrawal from mechanical ventilation and the length of stay in septic patients. Critical Care Med 33:349–354, 2005. Goodin DS, Frohman EM, Garmany GP, et al: Disease modifying therapies in multiple sclerosis. Report of the therapeutics and technology assessment subcommittee for the American Academy of Neurology and the MS council for clinical practical guidelines. Neurology 58:169–177, 2002. Gosselink R, Kovacs L, Ketelaer P, et al: Respiratory muscle weakness and respiratory muscle training in severely disabled multiple sclerosis patients. Arch Phys Med Rehabil 81:747–751, 2005. Koessler W, Wanke T, Winkler G, et al: 2 Years experience with inspiratory muscle training in patients with neuromuscular disorders. Chest 120:765–769, 2001. Mendell JR, Moxley RT, Griggs RC, et al: Randomized, double blind six-month trial of prednisone in Duchenne’s muscular dystrophy. N Engl J Med 320:1592–1597, 1989. Morgan RK, McNally S, Alexander M, et al: Use of sniff nasalinspiratory force to predict survival in amyotrophic lateral sclerosis. AJRCCM 171:266–274, 2005. Polkey MI, Duguet A, Luo Y, et al: Anterior magnetic phrenic nerve stimulation: Laboratory and clinical evaluation. Int Care Med 26:1065–1075, 2000. PRISMS (prevention of relapses and disability by interferon β-1a subcutaneously in multiple sclerosis) Study Group: Randomised double-blind placebo-controlled study of

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interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 352:1498–1504, 1998. Sellebjerg F, Frederiksen JL, Nielsen PM, et al: Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 51:529– 534, 1998. Sharshar T, Chevret S, Bourdain, et al: Early predictors of mechanical ventilation in Guillain-Barr´e syndrome. Crit Care Med 31:278–283, 2003.

Effects of Neuromuscular Diseases on Ventilation

Van der Meche FGA, Schmitz PIM: The Dutch GuillainBarr´e Study Group: A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barr´e syndrome. N Engl J Med 326:1123–1129, 1992. Vincken WG, Elleker MG, Cosio MG: Flow-volume loop changes reflecting respiratory muscle weakness in chronic neuromuscular disorders. Am J Med 83:673–680, 1987.

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94 Management of Neuromuscular Respiratory Muscle Dysfunction John R. Bach

I. PATHOPHYSIOLOGY The Respiratory Muscle Groups

IV. NONINVASIVE VS. TRACHEOSTOMY IPPV OUTCOMES

II. INSPIRATORY AND EXPIRATORY MUSCLE AIDS

V. GLOSSOPHARYNGEAL BREATHING

III. CLINICAL GOALS Goal 1: Maintain Pulmonary Compliance and Chest Wall Mobility Goal 2: Maintain Normal Alveolar Ventilation Goal 3: Facilitate Clearance of Airway Secretions The Oximetry Feedback Respiratory Aid Protocol

VI. EXTUBATION AND DECANNULATION

Patients with ventilatory impairment due to ventilatory muscle dysfunction are often evaluated and managed according to practices developed for patients with chronic lung diseases. However, pulmonary function laboratories, designed primarily for assessment of lung diseases, do not evaluate breathstacking (insufflation) capacities or cough flows, which are important in the assessment of patients with ventilatory muscle dysfunction. In the setting of ventilatory muscle dysfunction, polysomnograms may be misinterpreted as central or obstructive apneas and hypopneas instead of hypoventilation due to inspiratory muscle dysfunction, and continuous positive airway pressure (CPAP) or nocturnal bilevel positive airway pressure (BiPAP) is prescribed. In the context of ventilatory muscle dysfunction CPAP does not increase tidal volumes, and may actually reduce them by causing them to approach maximum lung capacity in these patients with severe pulmonary restriction, while BiPAP is often used at pressures inadequate to support alveolar ventilation, provide inspiratory muscle rest, or assist in coughing. In addition, the patients are often treated with supplemental oxygen to correct hypoxemia when efforts to improve oxygenation should be directed at clearance of airway secretions. With advancing inspiratory and expiratory muscle weakness, the common scenario

VII. INSPIRATORY AND EXPIRATORY AIDS AND SURGICAL ANESTHESIA

is that respiratory failure ensues that is treated by mechanical ventilation via endotracheal intubation. When ventilator weaning fails, a tracheostomy is performed and mechanical ventilation is continued indefinitely, often in an institution. Therapeutic modalities commonly used for respiratory diseases can have adverse effects in patients with neuromuscular disorders. Bronchodilator therapy can augment anxiety and tachycardia that are common in myopathic patients, many of whom have cardiomyopathies. Oxygen therapy increases the risk of pulmonary morbidity, rate of hospitalizations, and mortality by comparison with the use of ventilatory assistance or no treatment at all. As noted, oxygen therapy may obscure recognition of mucus plugging because it alleviates oxyhemoglobin desaturation without attention to the expulsion of airway mucus. Oxygen therapy may also prolong hypopneas and apneas during rapid eye movement (REM) sleep, and it appears to suppress the reflex muscular activity needed for effective noninvasive intermittent positive pressure ventilation (IPPV) during sleep. Translaryngeal intubation, tracheostomy, and tracheal suctioning continue to be used for patients with neuromuscular diseases, even though noninvasive IPPV, noninvasive suctioning, and mechanical in-exsufflation can be more effective and comfortable.

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Despite the proven effectiveness of measures to support ventilation noninvasively for long periods, even in situations of dire ventilatory muscle dysfunction, these therapeutic modalities have yet to be adopted by many physicians. In the United Kingdom, 82 percent of patients with ALS die receiving morphine and 64 percent receive benzodiazepines, while few are provided with respiratory muscle aids to prevent respiratory failure. This approach both smoothes and hastens passage to the grave by leading to CO2 narcosis. Often, without consulting the patient, the physician judges the patient’s quality of life to be unacceptable and the disease terminal, ignores options that prevent respiratory complications, renders the patient and family hopeless, and biases the family against ventilator use, which the physician associates with tracheostomy. Proclaimed as “palliation,” the results of this professional point of view are anguish and hopelessness and frequently result in patients seeking assisted suicide. Over a recent 5-year period, 12 publications in the New England Journal of Medicine concerned clinical management and assisted suicide for patients with ALS. In none of these reports was prevention of respiratory complications or ventilatory assistance by invasive or noninvasive means considered. Surveys of Jerry Lewis Muscular Dystrophy Association clinic directors in 1992 and 2000 demonstrated that the great majority of morbidity and mortality in neuromuscular disease continues to be due to respiratory muscle weakness and is preventable.

PATHOPHYSIOLOGY Patients with neuromuscular disorders can develop respiratory failure because of some combination of respiratory muscle dysfunction (Table 94-1); that is, dysfunction of inspiratory, expiratory, and bulbar-innervated muscles. These muscle groups are considered here and the reader is referred to Chapters 92 and 93 for detailed discussions of the physiological disturbances associated with chest wall and neuromuscular disorders that affect ventilation. Ventilatory muscle weakness, mechanical dysfunction of the chest wall and lungs associated with thoracic deformities, hypopharyngeal collapse or other upper airway narrowing, extreme obesity, abdominal distention, and the use of improperly fitting thoracolumbar orthoses can cause or exacerbate alveolar hypoventilation and lead to respiratory failure. In individuals with neuromuscular disorders, pulmonary infiltrations and respiratory failure are often precipitated by bronchial mucus plugging due to an ineffective cough and fatigue during acute respiratory infections. Autonomously breathing patients with advanced ventilatory muscle dysfunction develop a rapid, shallow breathing pattern with inability to take deep breaths. If untreated, this can lead to chronic microatelectasis and decreased lung and chest wall compliance. Acute respiratory tract infections with

Table 94-1 Physical Medicine Respiratory Interventions Benefit Patients with the Following Conditions Myopathies Muscular dystrophies Dystrophinopathies—Duchenne and Becker dystrophies Other muscular dystrophies—limb-girdle, Emery-Dreifuss, facioscapulohumeral, congenital, childhood autosomal recessive, and myotonic dystrophy Non-Duchenne myopathies Congenital and metabolic myopathies, such as acid maltase deficiency Inflammatory myopathies, such as polymyositis Diseases of the myoneural junction, such as myasthenia gravis, mixed connective tissue disease Myopathies of systemic disease, such as carcinomatous myopathy, cachexia/anorexia nervosa, medication associated Neurological disorders Spinal muscular atrophies Motor neuron diseases Spinal cord injuries Poliomyelitis Neuropathies Hereditary sensory motor neuropathies Phrenic neuropathies—associated with cardiac hypothermia, surgical or other trauma, radiation, phrenic electrostimulation, familial, paraneoplastic or infectious etiology, and lupus erythematosus Guillain-Barr´e syndrome Multiple sclerosis Disorders of supraspinal tone such as Friedreich’s ataxia Myelopathies of rheumatoid, infectious, spondylitic, vascular, traumatic, or idiopathic etiology Tetraplegia associated with pancuronium bromide, botulism Sleep-disordered breathing, including obesity hypoventilation, central and congenital hypoventilation syndromes, and hypoventilation associated with diabetic microangiopathy, or familial dysautonomia Skeletal pathology, such as kyphoscoliosis, osteogenesis imperfecta, and rigid spine syndrome

1669 Chapter 94

pulmonary scarring and the kyphosis and scoliosis that are common in these patients can cause further loss of lung compliance. In the context of neuromuscular disorders, hypercapnia develops insidiously as a consequence of shallow breathing. It can decrease respiratory muscle strength. If not corrected by using inspiratory muscle aids, respiratory control centers reset to accommodate hypercapnia, and increasing central nervous system bicarbonate levels depress ventilatory drive. This permits worsening of hypoventilation and decreases the effectiveness of its treatment by the nocturnal use of noninvasive IPPV. The risk of pulmonary morbidity and mortality from acute respiratory failure correlates with increasing hypercapnia. Patients with generalized muscle dysfunction usually also have concomitant expiratory and oropharyngeal muscle weakness that decrease cough peak flows (CPF). When CPFs do not exceed 2.7 L/s, cough may be completely ineffective. CPFs are reduced by airway obstruction caused by tracheal stenosis, laryngeal incompetence, postintubation vocal cord adhesions or paralysis, hypopharyngeal collapse due to bulbar-innervated muscle weakness or spasticity, or obstructive pulmonary disease. CPFs are reduced further when patients cannot take or receive a breath greater than 1.5 L. Thus, the airway secretions that develop during upper respiratory tract infections and after surgical anesthesia often result in pneumonia and acute respiratory failure. Smoking, the presence of an endotracheal cannula that causes bronchorrhea, or bronchorrhea for any other reason increases the tendency to develop mucus plugging that is all too frequently managed by intubation, repeated bronchoscopy, and tracheotomy. The latter results in a burden of pathogenic bacteria that exceeds the commonly accepted threshold for diagnosing ventilator-associated pneumonia. For patients with ventilatory muscle dysfunction, arterial hypoxemia and hypercapnia occur initially during REM sleep and later extend throughout sleep and eventually throughout the awake hours (see Chapter 93). Cough reflex is also suppressed during sleep, which is when mucus plugs are most likely to cause sudden and severe hypoxemia. Normocapnic arterial hypoxemia is also common during sleep, most likely reflecting ventilation-perfusion mismatches associated with microatelectasis, scoliosis, and pulmonary scarring. Narcotics and other sedatives, and supplemental oxygen can reduce ventilatory drive and exacerbate alveolar hypoventilation. Beta blockers may increase airway resistance. Malnutrition, acidosis, electrolyte disturbances, cachexia, infection, fatigue, and muscle disuse or overuse can all exacerbate ventilatory insufficiency. Oxygen therapy often results in CO2 narcosis; otherwise hypoventilation is usually first recognized during an intercurrent respiratory infection when bronchial mucus plugging triggers acute respiratory failure. Ventilatory failure can develop suddenly or over a period of hours or days in patients with acute cervical myelopathies, Guillain-BarrÂ´e syndrome,

Management of Neuromuscular Respiratory Muscle Dysfunction

myasthenia gravis, acute poliomyelitis, or exacerbations of multiple sclerosis.

The Respiratory Muscle Groups The diaphragm is the principal muscle of inspiration. The abdominal muscles are the principal muscles of expiration or coughing. The bulbar-innervated muscles are the muscles of the upper airway. They include the muscles of the mouth, uvula and palate, tongue, larynx and hypopharynx. While these muscles do not have a direct action on the chest wall, they are essential for keeping the upper airway patent; they affect airway resistance and airflow; and they permit glossopharyngeal breathing. Decreased inspiratory muscle function results in decreased vital capacity (VC), atelectasis, increased relative work of breathing, and eventually hypoventilation. Expiratory, inspiratory, and bulbar-innervated muscle dysfunction results in an ineffective cough. The latter can also result in loss of speech, swallowing, and aspiration of food and saliva. Fortunately, the inspiratory and expiratory muscles can be substituted for by physical medicine interventions. Indeed, numerous patients with no muscle function below the neck and no measurable VC for over 50 years do not need tracheostomy tubes or develop hypercapnic respiratory failure. However, a tracheotomy needs to be performed if bulbarinnervated muscles deteriorate to the point that aspiration of saliva results in an irreversible decrease in SpO2 below 95 percent (Table 94-1).

INSPIRATORY AND EXPIRATORY MUSCLE AIDS Inspiratory and expiratory muscle aids are devices and techniques that involve the manual or mechanical application of forces to the body or pressure changes to the airway to assist or substitute for inspiratory or expiratory muscle function. Negative pressure applied to the airway during expiration assists the expiratory muscles for coughing, just as positive pressure applied to the airway during inhalation (noninvasive IPPV) assists inspiratory function. A manual thrust applied to the abdomen during expiration, especially when in combination with mild chest compression, assists expiratory muscle function and increases cough flows. The devices that act on the body to enhance inspiratory and expiratory muscle function include body ventilators. The intermittent abdominal pressure ventilator (IAPV) involves the intermittent inflation of an elastic air sac that is contained in a corset or belt worn beneath the patientâ&#x20AC;&#x2122;s outer clothing (Fig. 94-1). The sac is inflated by a positive pressure ventilator. Bladder action against the abdominal wall moves the diaphragm upward, causing a forced exsufflation. During bladder deflation, the abdominal contents and diaphragm return to the resting position, and inspiration occurs passively. A trunk angle of 70 to 80 degrees from the

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Figure 94-1 The girdle of the intermittent abdominal pressure ventilator with its air sac connected to the tubing of a volumecycled ventilator. This Duchenne muscular dystrophy patient with no measurable vital capacity used the abdominal pressure ventilator for daytime ventilatory support for 15 years.

horizontal is ideal for use. The patient who has any inspiratory capacity or is capable of GPB can add autonomous volumes to the mechanical insufflations. The IAPV generally augments tidal volumes by about 300 ml, but volumes as high as 1200 ml have been reported when there is no scoliosis or obesity. Patients with less than 1 h of ventilator-free breathing ability tend to prefer to use the IAPV rather than use noninvasive IPPV during daytime hours. Note, CPAP does not assist inspiratory or expiratory muscles and should rarely if ever be used for these patients whose symptoms of sleep-disordered breathing are associated with muscle weakness rather than central or obstructive sleep apneas.

these volumes with a closed glottis. The air is delivered via a mouth piece, a lip seal (Fig. 94-2) if the lips are too weak to retain the air, or nasal interface. This is performed multiple times in three daily sessions. The patient stacks the volumes until the lungs are maximally expanded. Patients who learn glossopharyngeal breathing can often air stack consecutive gulps to or beyond the MIC. The difference between the MIC and the VC is a function of bulbar-innervated muscle integrity (force of glottic closure). If the bulbar muscles are too weak for deep air stacking, single deep insufflations are provided via a mechanical insufflator-exsufflator at 40 to 70 cm H2 O

CLINICAL GOALS The goals of management are to optimally inflate the lungs and chest wall to maintain pulmonary compliance, maintain normal alveolar ventilation around-the-clock, and maximize CPF. Many patients who require continuous ventilatory support can be sustained for decades without being hospitalized.

Goal 1: Maintain Pulmonary Compliance and Chest Wall Mobility Incentive spirometry or deep breathing can expand the lungs; however, no greater than the vital capacity. As the vital capacity decreases, the effectiveness of incentive spirometry as a tool for lung expansion vanishes. Like limb articulations, the lungs and chest wall require regular mobilization. This can be achieved by air stacking, providing deep insufflations, or nocturnal noninvasive ventilation for infants. A patient’s maximum insufflation capacity (MIC) is the largest volume of air that can be held with a closed glottis. The patient “air stacks” consecutively delivered volumes from a volume-cycled ventilator or a manual resuscitator, holding

Figure 94-2 A 37-year-old with Duchenne muscular dystrophy, continuously dependent on mouth piece/lip seal intermittent positive pressure ventilation (IPPV) since age 12, is seen here using lip seal IPPV for nocturnal ventilatory support.

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Management of Neuromuscular Respiratory Muscle Dysfunction

three times daily. Deep insufflations can also be delivered via manual resuscitator with the expiratory valve blocked. The primary objectives of lung expansion therapy are to increase voice volume and MIC, maximize CPF, improve pulmonary compliance, prevent atelectasis, and master noninvasive IPPV. Occasionally the VC also increases with increases in MIC. Should the situation arise, anyone who can air stack can be extubated to noninvasive IPPV. This is extremely important for avoiding tracheostomy because such patients can be easily extubated without being ventilator weaned. There is some evidence that inflation measures are helpful in promoting lung growth and chest wall development in children. While infants can not air stack, nocturnal use of high span (IPAP â&#x20AC;&#x201C; EPAP > 10 cm H2 O) BiPAP has been demonstrated to prevent pectus excavatum and promote lung and chest wall growth for infants with spinal muscular atrophy (SMA), all of whom have paradoxical breathing when not using it.

Goal 2: Maintain Normal Alveolar Ventilation Noninvasive Ventilation BiPAP is not optimal for patients with neuromuscular disorders, because one can not air stack using pressure-cycled ventilators or fully expand the lungs with the machines currently on the market. IPPV from volume-cycled machines can be delivered via lip seals, nasal, or oral-nasal interfaces for ventilatory support during sleep. The patients can usually be trained and equipped in the outpatient and home settings. Patients requiring around-the-clock support use simple 15- or 22-mm angled mouth pieces that they grab with their teeth for IPPVs (Fig. 94-3) during the day. To use mouth piece IPPV, adequate neck rotation and oral motor function are necessary to grab the mouth piece and receive IPPV without insufflation leakage out of the mouth or nose. In addition, the patient must open the glottis and vocal cords, dilate the hypopharynx, and maintain airway patency to receive the air. When the lips are too weak to grab a mouth piece, the patient can use an IAPV or continue nocturnal nasal IPPV into daytime hours (Fig. 94-4). In the latter case, nasal interfaces are alternated to vary skin pressure. Inconspicuous nasal interfaces that permit the use of eyeglasses can also be used. Although oronasal interfaces are popular in some centers, we have rarely found them to be necessary. Closed systems are unnecessary provided that ventilatory drive is not blunted by oxygen therapy, sedative medications, or excessive daytime hypercapnia, all of which can result in excessive air leakage out of the nose or mouth when using the open systems of mouth piece or nasal ventilation. If necessary, one can provide an essentially closed system of ventilatory support by using a lip seal device and placing cotton pledgets in the nostrils and sealing the nostrils with a Band-aid. Even patients with little or no measurable VC can be safely ventilated day and night by open systems of nasal or oral ventilation. While noninvasive ventilation can be used for continuous long-term ventilatory support, the benefits derived from

Figure 94-3 Sixty-six-year-old post-polio survivor who has been using noninvasive ventilation for 60 years, including 57 years of intermittent positive pressure ventilation via an angled mouth piece fixed adjacent to the sip and puff controls of her motorized wheelchair.

its part-time, usually nocturnal, use appear to be due to some combination of respiratory muscle rest, increasing tidal volumes and alveolar ventilation, improving blood gases, lung compliance, and chemotaxic sensitivity, and possibly by improving ventilation-perfusion matching by reducing atelectasis and small airway closure. To accomplish optimal rest, high volumes or pressure spans are used for all patients; that is, assist-control mode at volumes of 800 to 1500 ml for adults and inspiratory to expiratory-positive airway pressure spans of 13 to 17 cm H2 O for BiPAP users. Patients vary the volume of air taken in from ventilator cycle to ventilator cycle to vary

Figure 94-4 Fifty-one-year-old man with amyotrophic lateral sclerosis and no ventilator-free breathing ability using daytime nasal intermittent positive pressure ventilation.

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tidal volume, speech volume, and cough flows, as well as air stack and provide lung expansion. Complications of Noninvasive IPPV

Besides orthodontic deformities and skin pressure from the interface, other potential difficulties include allergy to the plastic lip seal or silicone interfaces (∗ 5 percent for nonsilicone interfaces), dry mouth (65 percent), eye irritation from air leakage (about 24 percent), nasal congestion (25 percent) and dripping (35 percent), sinusitis (8 percent), nose bleeding (4 to 19 percent), gum discomfort (20 percent), and gum receding from nasal interface or lip pressure, maxillary flattening in children, aerophagia, and, as for invasive ventilation, barotrauma. Occasional patients express claustrophobia. Switching to lip-delivered IPPV can relieve most if not all difficulties associated with nasal IPPV; however, it is more difficult to speak when using lip-delivery devices. Abdominal distention tends to occur sporadically. It can be decreased by pressure limiting volume-cycled ventilators or at times by switching from one ventilator style to another. It is relieved as the air passes as flatus once the patient sits up in the morning or by “burping” of a gastrostomy tube if present. Barotrauma can occur with invasive or noninvasive ventilation, but is rare with the latter for patients with neuromuscular disorders.

Goal 3: Facilitate Clearance of Airway Secretions Chest percussion and vibration can help mobilize deep airway secretions, but they are not substitutes for coughing. Cough can be assisted manually or by mechanical means. Manually Assisted Coughing Manually assisted coughing requires substantial lung inflation attained by air stacking or a deep lung insufflation. This is followed by an abdominal thrust applied as the glottis opens. If the VC is under 1.5 L, air stacking or insufflation is especially important before the abdominal thrust. Whereas the bulbar-innervated muscles, as well as inspiratory and expiratory muscles are needed for spontaneous coughing, only bulbar-innervated muscle function is required for assisted coughing. This is because airway pressure changes and abdominal thrusts substitute for inspiratory and expiratory muscles, but there is nothing noninvasive that can substitute for the function of the glottis. Manually assisted coughing requires a cooperative patient, good coordination between the patient and care giver, and adequate physical effort and often frequent application by the care giver. When inadequate, and especially when inadequacy is due to difficulty air stacking or diminished glottic strength, the most effective alternative is mechanically assisted coughing (MAC). Mechanically Assisted Coughing

The combination of mechanical in-exsufflation with an abdominal thrust is a MAC. Mechanical insufflator-exsufflators

deliver deep insufflations followed immediately by deep exsufflations. The MAC cough volumes normally exceed 2 L at flows of 10 L/s. Insufflation to exsufflation pressures of +40 to –40 cm H2 O delivered via oronasal interface or adult tracheostomy or translaryngeal tubes with the cuff inflated are usually most effective. However, machine pressures are secondary. What is important is to fully expand and then fully and rapidly empty the lungs. Whether via the upper airway or via indwelling airway tubes, routine airway suctioning misses the left main stem bronchus about 90 percent of the time. This explains high rates of left lower lobe pneumonia. MAC, on the other hand, provides the same exsufflation flows in both left and right airways without discomfort, fatigue, or airway trauma and it can be effective when suctioning is not. Indications for MAC

MAC predominantly takes the place of the inspiratory and expiratory muscles. Thus, the patients who need MAC are those whose inspiratory and expiratory muscles are too weak for effective coughing but whose bulbar-innervated muscle function can maintain adequate airway patency but not permit sufficient air stacking for assisted CPF over 5 L/s. This is typical of most patients with neuromuscular disease. On the other hand, MAC is not usually necessary for patients with intact bulbar-innervated muscle function such as those with spinal cord injury, as they can usually air stack sufficiently such that with a properly applied abdominal thrust (assisted) CPF can exceed 6 L/s. These flows are more than adequate to clear the airways without MAC. MAC can not be used to avert tracheostomy very long if bulbar-innervated muscle function is inadequate to prevent airway collapse or continuous aspiration of saliva as is often the case in advanced bulbar ALS.

The Oximetry Feedback Respiratory Aid Protocol This protocol consists of using inspiratory and/or expiratory aids in combination with pulse oximetry feedback to maintain patients’ room air oxyhemoglobin saturation (SpO2 ) greater than 94 percent. The protocol is most important during respiratory tract infections and when extubating patients with little or no ventilatory capacity. Noninvasive IPPV and MAC with oximetry feedback have averted hundreds of hospitalizations for patients with DMD, SMA, ALS, and other neuromuscular conditions. On the other hand, tracheostomy is indicated when saliva is continuously aspirated and the SpO2 remains below 95 percent despite optimal use of noninvasive IPPV and MAC. This is the only indication for tracheotomy in patients with neuromuscular disorders and it occurs in advanced bulbar ALS patients and in very few other situations. Without tracheostomy most patients with ALS whose SpO2 baseline has decreased below 95 percent despite respiratory aids will be deceased within 2 months.

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NONINVASIVE VS. TRACHEOSTOMY IPPV OUTCOMES No one has done a controlled study comparing outcomes of long-term noninvasive vs. invasive ventilation. However, a great deal can be inferred from what is already known. In a recent study, 25 patients with ALS became dependent on noninvasive IPPV, including 13 who became continuously dependent for 19.7 ± 16.9 months without developing acute respiratory distress or oxyhemoglobin desaturation. For another 76 patients the daytime Sp O2 baseline persistently decreased below 95 percent 78 times because of some combination of alveolar hypoventilation and airway secretions. For 41 patients the baseline was corrected by some combination of noninvasive IPPV and MAC for 11.1 ± 8.7 months before desaturation reoccurred for 27. Of the latter, 11 underwent tracheotomy, 14 died in less than 2 months, and two were

Management of Neuromuscular Respiratory Muscle Dysfunction

again corrected by the addition of MAC to noninvasive IPPV. Thirty-three of the 35 patients for whom the SpO2 could not be normalized required tracheotomy or died within 2 months. The difference between the patients who could be spared respiratory failure from those who could not was that the latter had significantly poorer glottic function with no ability to air stack or generate measurable assisted CPF. We have decannulated ALS patients with no ventilator-free breathing capacity who have survived as much as 10 years using continuous noninvasive IPPV before requiring tracheotomy. Once bulbar ALS patients undergo tracheostomy for ventilatory support, survival has been reported to be about 5 years before most patients die from complications related to their tracheostomies. Infants with SMA type 1 have 70 percent mortality by 6 months of age and 90 percent by 24 months of age from respiratory failure. In a recent study of 80 such patients, all of whom developed respiratory failure before 24 months of age, the protocol extubation (Table 94-2) success rate was

Table 94-2 Protocol for Extubation in Neuromuscular Diseases Oxygen administration limited to achieve SpO2 of ∼95%, no higher Mechanically assisted coughing used via the endotracheal tube up to every few minutes as needed to fully expand and quickly empty the lungs to reverse oxyhemoglobin desaturations due to airway mucus accumulation, when there is auscultatory evidence of secretion accumulation, and on patient demand. Tube and upper airway are suctioned following use of expiratory aids. Ventilator weaning attempted without permitting hypercapnia Extubation whether or not the patient is ventilator weaned when meeting the following criteria: Afebrile and normal white blood cell count No supplemental oxygen required to maintain SpO2 >94% for >24 h Chest radiograph abnormalities cleared or clearing Respiratory depressants discontinued with no residual effects Airway secretions normal and suctioning required <1–2x/8 h Coryza diminished sufficiently to permit use of nasal ventilation Extubation to continuous high span BiPAP or noninvasive IPPV via mouth/nasal interface, no supplemental oxygen Oximetry feedback used to guide the use of MAC, postural drainage, and chest physical therapy to reverse desaturations below 95% due to airway mucus With CO2 retention or ventilator synchronization difficulties, nasal interface leaks are eliminated. For small children with rapid breathing rates who are using high span BiPAP, the inspiratory ramp may need to be shortened or the IPAP decreased. Back-up BiPAP rates may need to be set at one-half the child’s breathing rate to capture every other breath. Synchrony may also improve by switching to using a more trigger-sensitive volume cycle ventilator. Persistent oxyhemoglobin desaturation despite eucapnia and aggressive MAC can indicate impending severe respiratory distress and need to reintubate. Following reintubation the protocol is used for a second trial of extubation to nasal IPPV or high span nasal BiPAP. Once extubation is successful and SpO2 remains greater than 94% in ambient air, the patient weans him- or herself to the preintubation regime of ventilator use by taking fewer and fewer mouthpiece IPPVs as tolerated and as presented in Fig. 94-3.

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87 percent by comparison to 6 percent by conventional extubation approaches. Hospitalization rates for the noninvasively managed patients fell from 1.6 per year up to age 3 to 0.04 per year after age 5. Four such patients are currently over 10 years of age using nasal ventilation up to 24 hours a day. Only five of 80 underwent tracheotomy because of severe bradycardias in two, bronchomalacia in two, and persistent desaturations due to saliva aspiration in one. SMA type 1 patients who undergo tracheotomy can also have long-term survival. In another study of 91 ventilator users with DMD, 51 went on to require continuous noninvasive IPPV for 6.3 Âą 4.6 (range to 25) years. None of the 34 full-time noninvasive IPPV users who had access to MAC died from respiratory complications, whereas three died from severe cardiomyopathy. Five patients with no breathing capacity were extubated or decannulated to continuous noninvasive IPPV, and five became continuously dependent on noninvasive IPPV for 1 year or more without ever being hospitalized. It has previously been reported that DMD patients undergoing tracheotomy tend to have a prolongation of survival of about 7 years but also have a tendency to die from complications related to invasive mechanical ventilation. Although both noninvasive and invasive interventions can prolong survival, noninvasive IPPV is overwhelmingly preferred by patients over tracheostomy for speech, sleep, swallowing, comfort, appearance, security, use of GPB, and overall. One study also demonstrated a 200 percent cost savings by using noninvasive ventilatory support methods for patients with no ventilator-free breathing ability by facilitating community placement with personal care attendants rather than nursing care or long-term institutionalization. Despite the benefits of noninvasive interventions, few clinicians are aware that they can be used instead of tracheostomy IPPV and even fewer are familiar with all of the techniques available. As stated, however, when bulbar-innervated musculature is completely dysfunctional, tracheostomy can offer further prolongation of survival. A review of the criteria for successful use of noninvasive ventilatory support can be found in Table 94-3.

GLOSSOPHARYNGEAL BREATHING Both inspiratory and, indirectly, expiratory muscle activity can be assisted by glossopharyngeal breathing. This technique involves the glottis capturing air and propelling it into the lungs. One breath usually consists of 6 to 9 gulps of 60 to 100 ml each. Glossopharyngeal breathing (GPB) can provide an individual with no inspiratory muscle function with normal ventilation throughout daytime hours without using a ventilator, and safety in the event of ventilator failure during sleep. The safety and versatility afforded by GPB are vital to avoiding tracheostomy or removing one in favor of using noninvasive aids for neuromuscular ventilatory failure. About 65 percent of patients with functional bulbar-innervated musculature

Table 94-3 Criteria for Successful Use of Noninvasive Ventilatory Support for Neuromusculoskeletal Disorders Patient cooperative and no use of heavy sedation or narcotics No substance abuse or convulsions Cough flows (with or without manual or mechanical assistance) sufficient to eliminate airway debris and maintain baseline SpO2 >94% No mechanical obstacles to using IPPV interfaces (e.g., facial fractures or interfering devices)

have been reported to be able to use GPB to increase tidal volumes.

EXTUBATION AND DECANNULATION Intubation is a clinical decision based on the clinicianâ&#x20AC;&#x2122;s perception of need for invasive respiratory management. Intubation is often avoidable by using noninvasive ventilatory support and manually and mechanically assisted coughing. If needed, however, it is often delayed for fear of unsuccessfully extubating the patient. This misconception occurs because effective approaches to both avoid intubation and extubate unweanable patients are not widely used. It is because of the ability to successfully extubate ventilator dependent patients to noninvasive respiratory muscle aids that chronic tracheotomy can be averted for the great majority of patients with neuromuscular disease. As for any patient presenting with respiratory distress, patients with neuromuscular disorders conventionally receive supplemental oxygen along with bronchodilators, mucolytics, chest physical therapy, and possibly, sedation, but not noninvasive IPPV or MAC. Oxygen therapy and sedation often result in respiratory arrest. Once intubated, the same ventilator weaning parameters used for patients with lung disease are often used to guide subsequent extubation (i.e., resting minute ventilation, maximum voluntary ventilation, tidal volume, VC, maximum inspiratory pressure, arterialalveolar oxygen gradient on 100 percent oxygen, and ratio of dead space to tidal volume). The large number of parameters signals their lack of efficacy. This is because most of them relate to inspiratory rather than expiratory function. Most physicians feel that intubated patients need to be weaned from ventilator use before they can be extubated, whereas patients with neuromuscular disorders can be routinely extubated to noninvasive IPPV despite little or no measurable VC. Postextubation CPF are a sensitive

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parameter to predict successful extubation because they best reflect bulbar-innervated muscle integrity and, therefore, the ability to eliminate airway secretions. Preextubation generation of peak expiratory flows, as well as a measure of expiratory muscle function has been shown to be useful in predicting success in extubating patients with primarily respiratory impairment. In patients with lung disease, ventilator weaning attempts are conventionally done at the cost of hypercapnia. However, for patients with neuromuscular disorders the extent of hypercapnia is directly associated with subsequent pulmonary complications and death. For patients with neuromuscular disorders, “weaning schedules” can cause anxiety because the patient is not ready to breathe autonomously, or the schedule may be too conservative, delaying respiratory muscle reconditioning. Because an SpO2 of 90 to 95 percent is acceptable for most lung disease patients, patients with neuromuscular disorders are often extubated without concern for their ability to maintain normal SpO2 in ambient air. An SpO2 in ambient air less than 95 percent indicates that there is still hypoventilation, airway mucus, or residual lung disease. Further, they are often extubated to CPAP or inappropriately low span BiPAP and cough aids are not used. Once extubation fails, the clinician feels justified in recommending tracheotomy. Instead of conventional extubation approaches that may be appropriate for patients with lung diseases for whom “permissive hypercapnia” might be acceptable, a more appropriate approach for patients with primarily ventilatory impairment is presented in Table 94-2. It is because of the success of this protocol that tracheotomy can be averted for the great majority of patients with neuromuscular disorders.

INSPIRATORY AND EXPIRATORY AIDS AND SURGICAL ANESTHESIA Prevention or correction of spinal deformities is crucial to maintain quality of life for patients with neuromuscular disorders. Surveys of neuromuscular disease clinics indicated that most children with neuromuscular scoliosis were not undergoing spinal instrumentation and fusion. As a result, the ability to sit is often lost. Scoliosis can also decrease the effectiveness of the IAPV. Clinicians avoid surgery because of fear of respiratory complications. However, respiratory complications are preventable when patients are trained in noninvasive IPPV and MAC before undergoing general anesthesia and are extubated to these interventions postoperatively, as described in Table 94-2.

SUGGESTED READING Bach JR: Pulmonary rehabilitation considerations for Duchenne muscular dystrophy: The prolongation of life by respiratory muscle aids. Crit Rev Phys Rehabil Med 3:239– 269, 1992.

Management of Neuromuscular Respiratory Muscle Dysfunction

Bach JR: A comparison of long-term ventilatory support alternatives from the perspective of the patient and care giver. Chest 104:1702, 1993. Bach JR: Amyotrophic lateral sclerosis: Communication status and survival with ventilatory support. Am J Phys Med Rehabil 72:343, 1993. Bach JR: Noninvasive Mechanical Ventilation. Philadelphia, Hanley & Belfus, 2002. Bach JR: Prevention of pectus excavatum for children with spinal muscular atrophy type 1. Am J Phys Med Rehabil 82:815, 2003. Bach JR: The Management of Patients with Neuromuscular Disease. Philadelphia, Hanley & Belfus, 2004. Bach JR, Alba AS: Noninvasive options for ventilatory support of the traumatic high level quadriplegic. Chest 98:613– 619, 1990. Bach JR, Alba AS: Intermittent abdominal pressure ventilator in a regimen of noninvasive ventilatory support. Chest 99:630, 1991. Bach JR, Baird JS, Plosky D, et al: Spinal muscular atrophy type 1: Management and outcomes. Pediatr Pulmonol 34:16, 2002. Bach JR, Bianchi C, Aufiero E: Oximetry and prognosis in amyotrophic lateral sclerosis. Chest 126:1502, 2004. Bach JR, Chaudhry SS: Management approaches in muscular dystrophy association clinics. Am J Phys Med Rehabil 79:193, 2000. Bach JR, Intintola P, Alba AS, et al: The ventilator individual: Cost analysis of institutionalization versus rehabilitation and in-home management. Chest 101:26, 1992. Bach JR, Kang SW: Disorders of ventilation: Weakness, stiffness, and mobilization. Chest 117:301, 2000. Bach JR, Rajaraman R, Ballanger F, et al: Neuromuscular ventilatory insufficiency: The effect of home mechanical ventilator use vs. oxygen therapy on pneumonia and hospitalization rates. Am J Phys Med Rehabil 77:8, 1998. Bach JR, Saporito LR: Criteria for extubation and tracheostomy tube removal for patients with ventilatory failure: A different approach to weaning. Chest 110:1566, 1996. Baram D, Hulse G, Palmer LB: Stable patients receiving prolonged mechanical ventilation (PMV) have a high alveolar burden of bacteria. Chest 127:1353 2005. Gomez-Merino E, Bach JR: Duchenne muscular dystrophy: Prolongation of life by noninvasive respiratory muscle aids. Am J Phys Med Rehabil 81:411, 2002. Kang SW, Bach JR: Maximum insufflation capacity. Chest 118:61, 2000. Kang SW, Bach JR: Maximum insufflation capacity: The relationships with vital capacity and cough flows for patients with neuromuscular disease. Am J Phys Med Rehabil 79:222, 2000. Leger SS, Leger P: The art of interface: Tools for administering noninvasive ventilation. Med Klin 94:35, 1999. Mier-Jedrzejowicz A, Brophy C, Green M: Respiratory muscle weakness during upper respiratory tract infections. Am Rev Respir Dis 138:5, 1988.

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Neudert C, Oliver D, Wasner M, et al: The course of the terminal phase in patients with amyotrophic lateral sclerosis. J Neurol 248:612, 2001. Pepin JL, Leger P, Veale D, et al: Side effects of nasal continuous positive airway pressure in sleep apnea syndrome: Study of 193 patients in two French sleep centers. Chest 107:375, 1995. Polkey MI, Lyall RA, Davidson AC, et al: Ethical and clinical issues in the use of home noninvasive mechanical ventilation for the palliation of breathlessness in motor neurone disease. Thorax 54:367, 1999.

Sinha R, Bergofsky EG: Prolonged alteration of lung mechanics in kyphoscoliosis by positive hyperinflation. Am Rev Respir Dis 106:47, 1972. Smina M, Salam A, Khamiees M, et al: Cough peak flows and extubation outcomes. Chest 124:262â&#x20AC;&#x201C;268, 2003. Smith PEM, Edwards RHT, Calverley PMA: Oxygen treatment of sleep hypoxaemia in Duchenne muscular dystrophy. Thorax 44:997, 1989.

PART

XIII Sleep and Sleep Disorders

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95 The Stages of Sleep Adrian R. Morrison

I. WHAT IS SLEEP? II. WHY SLEEP? III. AUTONOMIC REGULATION DURING SLEEP

Approximately 45 years ago, two reports published within a few years of each other revolutionized our thinking about sleep and wakefulness. In 1949, Moruzzi and Magoun reasoned, on the basis of results with electrical stimulation of the brain stem, that its central core, the reticular formation, contained the elements essential for arousal and, consequently, wakefulness. Previously the view had been that various stimuli operated on the cerebrum via the “classic” long sensory pathways to arouse the individual. Moruzzi and Magoun recognized that the multisynaptic complexity of the reticular formation lay at the heart of consciousness. Nonetheless, the idea persisted, until 4 years later, that only wakefulness required active participation of the nervous system. At that time, Aserinsky and Kleitman reported periods during sleep in which the EEG resembled that of wakefulness. They also observed the rapid eye movements that give this stage of sleep its name, rapid eye movement (REM) sleep, and reported that vivid dreams occurred then. Clearly, more than a simple withdrawal of sensory influences had to be involved in the changes from wakefulness to sleep. As a result of this insight, the dominant view of sleep shifted from regarding it as a passive process to the belief in active processes that still prevails. Kleitman had previously been a proponent of the earlier view, arguing that it was the mechanism of wakefulness requiring explanation, not sleep. Sleep disorders medicine began to emerge as a clinical specialty just 30 years ago. Thanks to the earlier recognition of the “curious” state of REM and then a considerable amount of basic research aimed at unraveling its mechanisms and those of sleep in general, various medical specialties began to recognize that serious disease can accompany this seemingly peaceful portion of daily life. Previously, sleep was almost

IV. SUBSTRATE AND PHYSIOLOGICAL MECHANISMS OF SLEEP V. THE NATURE OF REM

exclusively an interest of psychiatrists. Of course, pulmonary physicians now play a major role in sleep disorders medicine. This chapter focuses on the mechanisms underlying the daily alternation of sleep and wakefulness. Emphasis is placed on emerging ideas about the organization of a largely hidden portion of our lives, particularly ideas that push us beyond conventional thought. Physician readers of this chapter should keep in mind the tremendous debt that sleep disorders medicine owes to animal-based research and that such research has been a particular target of animal rights activism.

WHAT IS SLEEP? Sleep is a period of bodily rest characterized by reduced awareness of the environment, a species-specific posture, and for most species, a particular sleep place. During each period of sleep, mammals cycle between two phases, non–rapid eye movement sleep (NREM) and REM: NREM always precedes a bout of REM. In humans, the cycle length averages 90 min, although NREM and REM are not evenly distributed through the night (Fig. 95-1). Cycle length varies directly with brain weight; hence, the family dog or cat cycles between NREM and REM more frequently, about every 25 minutes, as well as having multiple sleep periods. The physiological characteristics of the two phases of sleep are dramatically different. Figure 95-2 illustrates the appearance of the human electroencephalogram (EEG) during the four stages of NREM in which there are lower-frequency EEG waves than in wakefulness. In other mammals, NREM is not as well individuated into different stages, but the

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Figure 95-1 The progression of sleep stages across a single nightâ&#x20AC;&#x2122;s sleep of a normal young adult. The histogram was drawn on the basis of continuous recordings scored in 30-second epochs. (From Carskadon MA, Dement WC.: Normal human sleep: An overview, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 13, with permission.)

Figure 95-2 Electroencephalographic tracings recorded from a normal young adult demonstrating the four stages of NREM sleep. In the stage 2 recording, the arrow points to a characteristic K complex and the underlining to sleep spindles. (From Carskadon MA, Dement WC.: Normal human sleep: An overview, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 13, with permission.)

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Figure 95-3 Characteristics of the states of sleep in the cat: A. Quiet wakefulness. B. NREM. C. Transition to REM. D. REM. EOG = eye movements; EEG = electroencephalogram; LGN = recordings of spontaneous PGO waves in the lateral geniculate body in (C) and (D); EMG = electromyographic recordings in the dorsal cervical muscles. Note the decreasing muscle tone at the end of the transition period and throughout REM. Time = 1 s. (From Morrison AR: Brainstem regulation of behavior during sleep and wakefulness, in Sprague JM, Epstein AW (eds): Progress in Psychobiology and Physiological Psychology, vol 8. New York, Academic Press, 1979, p 91, with permission.)

largest-amplitude, lowest-frequency waves occur as the animal approaches REM. A most striking feature is the similarity in appearance of the waking and the REM EEG patterns in humans and animals: low-amplitude, high-frequency waves (Fig. 95-3A). Another event that characterizes REM can be detected in animals with deeply implanted electrodes. Just before and during REM, large-amplitude waves appear in recordings from the lateral geniculate body (Figs. 95-3C ,D). They are termed ponto-geniculo-occipital (PGO) waves, after the sites in which they were first recorded. Rather than being part of a REM-generating mechanism, as first thought, they appear to be another sign of the “peculiar” brain alertness that is an essential feature of REM. These waves are discussed further in The Nature of REM. Behaviorally, REM is recognized by body twitches, rapid eye movements, and irregularity in rate and depth of respiration. Electromyographic (EMG) recordings of postural muscles reveal a striking generalized atonia, the result of the postsynaptic inhibition of spinal motor neurons by glycine. Brain stem excitatory barrages using a glutamatergic substance briefly overcome this inhibition, leading to the muscle twitches. The source of the inhibitory glycine is either local or produced by neurons in the medullary inhibitory region. The latter, in turn, are excited by several pontine pathways employing such neurotransmitters as acetylcholine, glutamate, and corticotrophin releasing factor. Bilateral, pontine lesions in cats and rats eliminate the atonia of REM, which permits expression of alert-like behavior in REM. “REM without atonia” led directly to the recognition of REM sleep behavior disorder. NREM is characterized by behavioral quiescence with residual muscle tone and very regular, deep breathing. A

further distinction is a marked suppression of hypothalamic regulation of homeostasis in REM (see Autonomic Regulation during Sleep). Many aspects of sleep have been experimentally manipulated in animals (cats and rats in particular), with the result that we have a much greater understanding of the mechanisms that might be altered in human sleep pathology now than we did even 20 years ago. A feature linking birds and mammals is their homeothermy. Because hypothalamic control of thermoregulation is suspended in REM, converting mammals briefly into poikilotherms, it may be that poikilotherms (i.e., fish, amphibians, and reptiles), do not have the means or the “need” to express this or other features of REM. The echidna, a monotreme (a nonplacental, nonmarsupial mammal), has always complicated the picture because there was no evidence for REM. Siegel et al. found that the echidna’s brain stem neural activity presented a composite picture of the two phases during sleep; that is, the decreased discharge rate of NREM and the increased variability of firing rate of REM were accompanied by EEG synchronization. Thus, NREM and REM may have differentiated later from this primordial state in mammals. Just as sleep is not uniform among different groups of animals, its characteristics also vary with age. Human infants, for example, sleep in a polyphasic pattern for much of the time. During the first year of life, their sleep consolidates into one major period with shorter naps. In parallel fashion, REM, which occupies a large portion of sleep at birth—as much as 90 percent in some species—decreases to about 25 percent of total sleep time as wakefulness increases with maturity. This percentage remains relatively constant into old age, although the total amount of sleep decreases. However,

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because neural activity in infant animal sleep resembles that of the undifferentiated sleep state of the primitive echidna, we may question whether it is appropriate to speak of a very high REM percentage in newborns.

WHY SLEEP? Unlike other behaviors, the actual function of sleep remains a subject for debate. Thinking in broad terms, some have suggested that energy is saved when an animal has nothing better to do or that there is a survival value for certain prey species to nestle out of harm’s way. Other aspects of life to which sleep contributes, according to some, are consolidation of memory and improved learning. Of course, one feels better or restored after a night’s sleep; but what has been restored, and how? A possible way out of the dilemma is to focus on sleep not as a behavior (like feeding, which happens only during wakefulness), but as a state that can subserve multiple functions (just as the waking state does). Indeed, the dramatic physiological differences between NREM and REM suggest this, and the many theories of the function of sleep tacitly acknowledge the idea: They generally present a hypothesis accounting for only one phase. In a tightly reasoned article, Rechtschaffen illustrates the weaknesses of all claims for a particular function, leaving us somewhat stymied. Certainly, the survival value of a stage of sleep, REM, in which an animal is depressed sensorially, paralyzed, and poorly regulated homeostatically is a real mystery. The reduced homeostatic regulation of normal REM may rest vital, undetermined processes in small animals.

AUTONOMIC REGULATION DURING SLEEP Pulmonologists will be particularly interested that two major changes in autonomic regulation occur during sleep. One of them is predictable or at least not surprising: an increase in parasympathetic activity over that in the sympathetic system. The second is truly remarkable, though—suppression if not abolition of homeostatic regulation by the hypothalamus in REM. When an animal passes from wakefulness to NREM, the metabolic and behavioral demands on the body are obviously reduced. The heartbeat becomes slower and more regular. This is one sign that parasympathetic tone has increased; cutting the sympathetic nerves to the heart has little effect, indicating that central parasympathetic neurons increase their activity in sleep. Respiration slows and becomes more regular in NREM, but the normal compensatory mechanisms remain unchanged other than a moderate reduction in sensitivity to CO2 and O2 . Normal thermoregulatory mechanisms—such as panting, shivering and appropriate vascular changes— occur as well.

In REM, the organization of autonomic regulation is quite different. Although local and brain stem reflexes may still be operational, hypothalamic control is not. This has been most completely demonstrated in the case of thermoregulation. Hypothalamic cooling and heating during REM is ineffective in eliciting responses normally associated with heat gain (increased metabolic rate) and heat loss (panting). The suppression of thermoregulation in REM has been demonstrated further in a very graphic way. The atonia of REM can be eliminated with small pontine lesions; allowing organized movements to occur in REM (see The Nature of REM). Cats with such lesions shiver during wakefulness and NREM but cease shivering as soon as they enter REM without atonia. They also leave their protective curled posture and lose piloerection. Furthermore, they are actually more sensitive to cold and heat than normal animals during wakefulness, which further emphasizes the disruption of thermoregulation that occurs during REM. These indirect measures have been supplemented by direct recordings of single thermosensitive hypothalamic neurons during different behavioral states. Cold- and warmsensitive neurons either increase or decrease their rate of firing as a response to hypothalamic cooling or warming during wakefulness and NREM, but the majority loses its sensitivity in REM. Thus, the preoptic hypothalamic drive of thermoregulatory effectors is lost in REM. Alterations in respiratory control occur during REM, and there is evidence that the hypothalamus no longer modulates lower reflexes. Electrical stimulation in the hypothalamus that elicits inflation- and deflation-like effects during wakefulness and NREM will no longer do so in REM; in contrast, vagal stimulation remains effective, indicating that the brain stem circuits are not altered in REM. Tone in upper airway muscles is diminished during NREM and virtually absent during REM; the atonia during REM of the upper airway and intercostal muscles imposes a considerable burden on respiration. The respiratory rhythm is disrupted by irregularities in rate and depth of respiration due to the excitatory barrages responsible for muscle twitches in postural muscles. Ventilatory responses to hypercapnia are depressed, and, compared to NREM, the arousal threshold is increased. Activity in the sympathetic nerves of cats drops drastically during REM, although there are phasic increases that accompany rapid eye movements and muscle twitches. As a consequence, paradoxical responses in skin temperature occur, due to passive reductions in vasoconstrictor or vasodilator tone upon entrance into REM (e.g., the skin will warm in a cool environment after the animal enters REM due to relaxation of the constricted skin vessels). Not all vascular beds are passive in REM: A spinal reflex triggered from muscle afferents induces vasoconstrictor activity in hind-limb muscle beds, thereby reducing hypotension due to atonia in these muscles. Blood pressure increases during REM in rats and humans. It seems that the blood pressure decrease earlier reported in cats is reversed if sufficient time for recovery from surgery is permitted. In all species the same central mechanisms are probably operative during REM, but the eventual

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patterns may depend on species-specific differences in feedback loops and autoregulation.

SUBSTRATE AND PHYSIOLOGICAL MECHANISMS OF SLEEP Research in the earlier part of this century pointed to the diencephalon as the region critical for the organization of the sleep-wake cycle. This view was supported by: (1) the association of insomnia or somnolence with pathological changes in the anterior or posterior hypothalamus after encephalitis in humans described by von Economo; (2) elicitation of sleep in cats by electrical stimulation of various limbic structures; and (3) the results of experimental hypothalamic lesions in rats that corroborated the human disease observations. Yet until the discovery of REM, the prevailing opinion pictured sensory inflow as the governing factor. In 1962, emphasis shifted to the hindbrain because of an important experiment designed to determine the area of the brain that plays the predominant role in REM regulation. Jouvet found that even after removal of the brain rostral to the pons (i.e., decerebration), major elements of REM continued to appear periodically; indeed, rapid eye movements and atonia even overcame decerebrate rigidity. Transection caudal to the pons eliminated all signs of REM. In addition to the active inhibition of the motor neurons there is as well a withdrawal of facilitation by pontine locus ceruleus noradrenergic neurons and the serotonergic brain stem raphÂ´e neurons. The early decerebration experiments led researchers to neglect the forebrain for a number of years in favor of the pons in their search to understand the mechanisms of REM and, indeed, sleep in its entirety. However, two observations led us to propose that the initiation of REM in intact animals might well require interactions among forebrain and hindbrain mechanisms. (1) Decerebrate cats can be induced to enter a REM-like state by a number of stimuli not normally sleep-promoting, such as passing a stomach tube, inserting a rectal probe, opening the mouth, and hypothermia. Consequently, the brain stem, lacking modulation by rostral structures, appears to be in an unstable, supersensitive state. (2) In the normal cat, homeostatic mechanisms usually regulated by the hypothalamus are suppressed during REM, and the same could be argued for the decerebrate cat. Clearly, a central reorganization in the hypothalamus and/or other rostral structures must take place at or before the transition from NREM to REM. Given the decerebrate catâ&#x20AC;&#x2122;s abnormal propensity to enter REM, midbrain transection might well serve as a substitute for the suppression of forebrain control that we argued precedes natural REM. These ideas did not deny the important role played in REM by the caudal brain stem, but implied that full understanding of the mechanisms initiating and maintaining REM would require a more global outlook. A variety of investigations have since revealed interesting effects of forebrain

The Stages of Sleep

manipulations of REM. Shifting attention to the forebrain in seeking a fuller understanding of REM mechanisms and sleep in general has recently paid huge dividends. The forebrain, of course, is involved in sleep regulation, as the early studies of brains from those with encephalitis indicated. Many lesion, stimulation, and unit recording studies in the basal forebrain have demonstrated its importance for the onset of sleep (i.e., NREM). The suprachiasmatic nucleus has a role in the timing of sleep occurrence. And a group of neurons in the hypothalamic ventrolateral preoptic nucleus (VLPO) has gained prominence in recent years as the so-called sleep switch. These neurons are located in the region where lesions described by von Economo resulted in insomnia. VLPO consists of a dense cluster of cells and a more extended part, the former concerned with NREM and the latter with REM. Its neurons project to all relevant nuclei participating in arousal in the hypothalamus and brain stem. VLPO neurons are sleep active; and lesions of the cluster reduce NREM primarily; while lesions of the extended portion decrease REM. They use the inhibitory transmitters, GABA and galanin, and in turn, they are inhibited directly by noradrenaline and serotonin and indirectly by histamine. Saper proposes that this arrangement of mutually inhibitory systems constitutes a flip-flop switch that promotes rapid transitions between behavioral states (Fig. 95-4 A). We do not spend much time in transitions as a result. Often, switching states rapidly is a good thing, of course: Think of awakening rapidly to a danger signal. Figure 95-5 diagrammatically illustrates the switch from NREM to REM when hypothalamic control is lost and brain stem control of REM takes over. Cats with REM without atonia demonstrate this dramatically if placed in the cold: Although they shiver violently and maintain a tightly curled position in NREM, they cease shivering immediately and lose piloerection and the curled posture the moment they enter REM. The same occurs when orientingâ&#x20AC;&#x201D;an immediate cessation of shivering and increase in brain temperature as in REM. However, there is the problem of instability with such a switch. Figure 95-4B illustrates the introduction of a modulatory influence by a newly discovered group of hypothalamic neurons with widespread projections that contain two closely related neuropeptides called orexins or hypocretins, the terminology depending on the research group. Their absence or degeneration has been shown to accompany narcolepsy in knockout mice and dogs and humans with naturally occurring disease. (One characteristic of narcolepsy is the rapid transition from alert wakefulness to REM and particularly one component, cataplexy, with sudden emotional stimuli or situations as well as dozing off during the day and waking up more often at night.) They project to the various brain stem neurons involved with the sleep as well as the cerebral cortex and serve to balance the activities of competing groups of neurons. (See Fig. 95-4 legend for a complete explanation.) Orexin/hypocretin neurons are particularly active during exploration of the environment, and orexin/hypocretin levels collected via microdialysis are significantly higher in

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Figure 95-4 A schematic diagram of the flip-flop switch model. During wakefulness (A), the monoaminergic nuclei inhibit the ventrolateral preoptic nucleus (VLPO), thereby relieving the inhibition of the monoaminergic cells and that of the orexin (ORX) neurons, cholinergic pedunculopontine (PPT), and laterodorsal tegmental nuclei (LDT). Because the VLPO neurons do not have orexin receptors, the orexin neurons serve primarily to reinforce the monoaminergic tone, rather than directly inhibiting the VLPO on their own. During sleep (B), the firing of the VLPO neurons inhibits the monoaminergic cell groups, thereby relieving their own inhibition. This also allows it to inhibit the orexin neurons, further preventing monoaminergic activation that might interrupt sleep. The direct mutual inhibition between the VLPO and the monoaminergic cell groups forms a classic flip-flop switch, which produces sharp transitions in state, but is relatively unstable. The addition of the orexin neurons stabilizes the switch. eVLPO, extended ventrolateral preoptic nucleus. (From Saper CB, Scammel TE, Lu J: Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257, 2005, with permission.)

active waking than in quiet waking. These observations led to the proposal that a more general role is to facilitate the arousal and motor activity that underlies any motivated behavior. The identification of the monoamines, noradrenaline and serotonin, as transmitters with widespread connections extending to the cerebral cortex, following Jouvetâ&#x20AC;&#x2122;s decerebration experiments actually reinforced the attention on the pons as the key region for regulating all of sleep. A series of experiments involving destruction of these neurons and/or pharmacological manipulations led to the hypothesis that serotonin regulates NREM and noradrenaline, REM. Although the monoamine hypothesis of sleep regulation stimulated a number of important experiments, it eventually had to

Figure 95-5 Diagrammatic representation of the changing control from the forebrain as an individual passes from NREM to REM when hypothalamic control is suppressed. The same shift in control may occur briefly during orienting in wakefulness. (From Morrison AR: Brainstem regulation of behavior during sleep and wakefulness, in Sprague JM, Epstein AW (eds): Progress in Psychobiology and Physiological Psychology, vol 8. New York, Academic Press, 1979, p 91, with permission.)

be abandoned because recordings of serotonergic and noradrenergic neurons revealed that these neurons begin to reduce their firing rates when cats pass from wakefulness to NREM, becoming almost totally inactive during REM. Thus, their roles can only be permissive (i.e., allowing REM to occur as a result of their inactivity). Another transmitter, acetylcholine, clearly plays an active role in REM processes. Many studies have demonstrated that acetylcholine and agonists (e.g., carbachol), will induce REM when injected into the dorsal pons. A cluster of cholinergic neurons in the dorsal pons and midbrain are the

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natural source of the cholinergic stimulation. Two effects are clear: They excite directly and indirectly the neurons in the medullary inhibitory area that are responsible for the postsynaptic inhibition of spinal motor neurons in REM, and they induce the changes in thalamic neurons that contribute to the waking pattern of the EEG. At the same time, noradrenergic and serotonergic neurons are inhibited by GABA-containing neurons. Cholinergic neurons in the medulla with ascending projections also appear to play a facilitatory role in the generation of REM. Cholinergic stimulation of thalamocortical neurons by mesopontine cholinergic cells changes them from the burstfiring mode that underlies the EEG spindles and slow waves that characterize NREM to a tonic-firing mode with an increased transfer function. Cholinergic neurons in the basal forebrain play a parallel role in the cortex. In both sites adenosine induces sleep via a postsynaptic inhibitory effect, long counteracted by drinkers of caffeine-containing coffee. Evidence is also mounting that glutamatergic systems play a parallel role in EEG activation: Because noradrenergic neurons in the pontine locus coeruleus also change the firing mode of thalamocortical neurons in parallel with the nearby mesopontine cholinergic neurons and glutamatergic neurons, their silence in REM is possibly an important feature distinguishing mental activity of wakefulness from REM. In terms of maintaining wakefulness and counteracting sleeppromoting activity of the anterior hypothalamus, histaminergic projections from the posterior hypothalamus play a significant role. Although EEG patterns allow us to detect the various sleep stages, they do not as accurately reflect the type of mental activity occurring during sleep as some still present it. Initially, REM was equated with dream sleep, and many still accept this convenient distinction. The similarity of the REM EEG pattern to that of wakefulness and the vividness of REM dreams (bizarre, perhaps, but still waking-like) make this a tidy classification. Unfortunately (for the sake of simplicity), mental activity is frequently reported from NREM awakenings, and it can resemble REM dreams, although REM and NREM mental activity can be discriminated on the basis of perceptual vividness and thematic coherence. (The earliest experiments finding few or no dreams in reports from NREM awakenings were designed in ways that were biased against collection of NREM dreams.) Furthermore, stage 1 NREM and REM have similar EEG patterns, yet reports of mental activity are quite different. The elements within the various patterns of neural activity underlying the dramatically different EEG patterns of NREM and REM that determine dreaming in humans remain uncertain. A recent candidate is the fast, spontaneous EEG rhythm between 20 and 40 Hz observed during attentive waking behavior and REM and also during the depolarizing phases of slow brainwave oscillations occurring in NREM. Because the mesopontine cholinergic neurons that induce fast rhythms are spontaneously active in REM and are responsible for PGO waves (a sign of alerting, remember), they may provide the conditions that make the REM

The Stages of Sleep

dream invariably vivid. However, the dangers of relating specific electrophysiological events to complex mental activities should be obvious. How the caudal brain stem cholinergic neurons normally affect the full expression of REM is not known. At first blush, they do not seem to require the rostral brain: Decerebrate cats spontaneously exhibit REM atonia and the pontine component of PGO waves, and carbachol injection is also effective in decerebrate cats. Absence of noradrenaline must be a factor, because noradrenergic blockers also induce the REM state in the same way that cholinergic agonists do. A reduction of serotonergic influence is likely a factor as well. Recent experiments by Chase and colleagues suggest that GABA gates the appearance of natural REM versus wakefulness as well as REM induced by the cholinergic agonist, carbachol, in the nucleus pontis oralis (NPO). GABA agonists injected in NPO induce prolonged episodes of wakefulness; GABA antagonists lead to extended REM; and preinjection of the GABA A agonist, muscimol, will block the induction of REM by carbachol. In concluding this section, it should be noted that rarely have workers considered the possibility that sleep changes thought to be effects of manipulating specific sleep mechanisms might be secondary to changes in thermosensitivity, other sensory thresholds, blood gases, etc.

THE NATURE OF REM Earlier, we observed that a various answers have been proposed for the question “What does REM do for the individual?” but no one asks “Why does REM occur in the form that it does?” In other words, can one make physiological sense out of the characteristics observed or is there no coherent organization? As a seemingly disparate assemblage, one finds the REM EEG resembling the waking EEG: the almost total paralysis, the ineffectual muscle twitches, the rapid eye movements, and, of course, the depression of homeostasis. A mechanistic explanation brings order out of this assortment and also leads to a broader view of the pontine tegmentum, a region that has assumed so much importance in sleep research. The premise is that the brain in REM resembles to a surprising degree the brain of an individual during alert wakefulness when he or she orients to a novel or unexpected stimulus. From this point of view one can begin to make sense of the apparently unrelated features of REM— in particular, the reticular activation, atonia, and depressed homeostasis. To begin with, certain features are common to REM and alert wakefulness: the EEG pattern; synchronous waves recorded from the hippocampus, called theta rhythm; an increase in brain temperature during orienting and REM; and suppression of panting and shivering in both of the latter two states. Two additional observations made in the laboratory reinforce this line of reasoning.

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1. As briefly noted, the atonia of REM can be eliminated in cats by small lesions in the pontine tegmentum that destroy a complex of cells and fibers that normally excite the medullary inhibitory area of cats. In such animals, behavior during REM consists largely of orienting, searching, or startle unassociated with any obvious external stimuli. Depending on lesion site, some cats can even walk during REM without atonia, although their axial and hind limb support does not equal that of waking. REM without atonia completely replaces normal REM—permanently in some cases; while in others there is gradual recovery to a more normal-appearing REM. Other than the lack of skeletal muscle paralysis, REM without atonia is identical to normal REM. 2. The PGO waves that normally appear spontaneously just prior to and throughout REM in recordings from the lateral geniculate body of cats can be elicited by loud sounds in NREM and REM. These waves occur in wakefulness after stimulation with sound, and others have reported that intracellular recordings from geniculate neurons are the same during the spontaneous waves and those induced by auditory stimuli or electrical stimulation of the reticular formation. Their occurrence is associated with an increase in information transfer through the lateral geniculate body. Taken together, these observations support the concept of an “alert” brain in REM. This counterintuitive idea becomes less so if one is open to the suggestion that in REM, the brain is focused upon itself and the world of dreams. Interestingly, though, cats show the same degree of orientation to an external sound source in REM without atonia as they do when awake. In addition, we have proposed a linkage between the “alert” brain and atonia in REM on the basis of a behavioral observation and a concept: The observation is that when an awake animal orients to an unexpected stimulus its ongoing behavior ceases for an instant; the concept is that nature is a parsimonious organizer, very often using the same structures and mechanisms in slightly different ways for various tasks. The respiratory system is a good example of the latter, for the airway and lungs are used for respiration, phonation, and temperature regulation. Therefore, the extreme motor inhibition in REM can be explained in a mechanical way as an inevitable link between an exaggerated, continuing state of “orienting” and the suppression of motor activity. Moreover, the brain seems to employ the same structures and mechanisms in both wakefulness and REM, but not identically, of course (Fig. 95-5). Rather than global activation during alert wakefulness, one should see in the brain stem reticular formation selective activation of neurons associated with specific movements, not driving them but modulating the set of muscle contractions and relaxations for movement from any posture in response to a sudden stimulus. There are, in fact, such neurons. Thus,

I suggest that the dorsal pons, the focus of so much attention from sleep researchers, is probably more generally involved in any behaviors dependent upon abrupt input into the reticular formation.

ACKNOWLEDGMENTS Preparation of this chapter was partially supported by NIH grant MH-72897. Many workers have made significant contributions that could not be mentioned or cited in this brief, general chapter, and I apologize for not doing so. Also, I owe a great debt to my various colleagues and my assistant of many years, Graziella Mann.

SUGGESTED READING Aserinsky E, Kleitman N: Regularly occurring periods of eye motility, and concomitant phenomena during sleep. Science 118:273, 1953. Basheer R, Strecker RE, Thakkar MM, et al.: Adenosine and sleep-wake regulation. Prog Neurobiol 73:379, 2004. Carskadon MA, Dement WC: Normal human sleep: An overview, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 13. Chase MH: Control of motoneurons during sleep, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 154. de Lecea L, Sutcliffe JG: The hypocretins and sleep. FEBS J 212:5675, 2005. Hu B, Steriade M, Deschenes M: The cellular mechanism of thalamic ponto-geniculo-occipital waves. Neuroscience 31:25, 1989. Jacobs BL: Brain monoaminergic unit activity in behaving animals, in Epstein AN, Morrison AR (eds): Progress in Psychobiology and Physiological Psychology, vol 12. New York, Academic Press, 1987, p 171. Jones BE: Basic mechanisms of sleep-wake states, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 136. Jouvet M: Recherches sur les structures nerveuses et les mecanismes responsables des differentes phases du sommeil physiologique. [Study of the neural structures and mechanisms responsible for the different phases of sleep] Arch Ital Biol 100:125, 1962. Lydic R, Baghdoyan HA: Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 103:1268, 2005. Morrison AR: The power of behavioral analysis in understanding sleep mechanisms, in Parmeggiani PL, Velluti RA (eds): The Physiologic Nature of Sleep, London, Imperial College Press, 2005, p 187.

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Morrison AR: Brainstem regulation of behavior during sleep and wakefulness, in Sprague JM, Epstein AW (eds): Progress in Psychobiology and Physiological Psychology, vol 8. New York, Academic Press, 1979, p 91. Morrison AR: Personal reflections on the â&#x20AC;&#x153;animal-rightsâ&#x20AC;? phenomenon. Perspect Biol Med 44:62, 2001. Morrison AR, Reiner PB: A dissection of paradoxical sleep, in McGinty DJ, Drucker-Colin R, Morrison AR, Parmeggiani PL (eds): Brain Mechanisms of Sleep, New York, Raven Press, 1985, p 97. Moruzzi G, Magoun HW: Brainstem reticular formation and activation of the EEG. Electroenceph clin Neurophysiol 1:455, 1949. Parmeggiani PL: Physiologic regulation in sleep, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Saunders Elsevier, 2005, p 185. Parmeggiani PL: Sleep behavior elicited by electrical stimulation of cortical and subcortical structures in the cat. Helv Physiol & Pharmacol Acta 20:347, 1962. Rechtschaffen A: Current perspectives on the function of sleep. Perspect Biol Med 41:359, 1998.

The Stages of Sleep

Rechtschaffen A: The psychophysiology of mental activity during sleep, in McGuigan FJ, Schoonover RA (eds): The Psychophysiology of Thinking, New York, Academic Press, 1973, p 153. Saper CB, Scammell TE, Lu J: Hypothalamic regulation of sleep and circadian rhythms. Nature 437:1257, 2005. Siegel JM: Clues to the functions of mammalian sleep. Nature 437:1264, 2005. Siegel JM: Hypocretin (orexin): Role in normal behavior and neuropathology. Annu Rev Psychol 55:125, 2004. Siegel JM: REM sleep, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 120. Steriade M: Brain activity and sensory processing during waking and sleep states, in Kryger MH, Roth T, Dement WC (eds): Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, p 101. Xi MC, Morales FR, Chase MH: Interactions between GABAergic and cholinergic processes in the nucleus pontis oralis: Neuronal mechanisms controlling active (rapid eye movement) sleep and wakefulness. J Neurosci 24:10670, 2004.

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96 Changes in the Cardiorespiratory System During Sleep Allan I. Pack

I. CHANGES IN CARDIOVASCULAR CONTROL DURING SLEEP

IV. PERIODICITIES OF VENTILATION IN LIGHT NREM SLEEP

II. CHANGES IN VENTILATION AND ITS CONTROL WITH SLEEP

V. CIRCADIAN CLOCKS IN THE CARDIOVASCULAR SYSTEM AND LUNG

III. AROUSAL DURING SLEEP

VI. CONCLUSION

As outlined in Chapter 98, sleep occurs in distinct states classified broadly as nonâ&#x20AC;&#x201C;rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. These occur in a temporally organized fashion across the sleep period. There are alterations in autonomic regulation during sleep. This chapter presents additional information on alterations in cardiopulmonary function.

CHANGES IN CARDIOVASCULAR CONTROL DURING SLEEP In NREM sleep, heart rate slows and blood pressure drops. These changes are not particularly large, being most marked in the deepest stage of NREM sleep, i.e., stage 4 (slow wave sleep). The reduction in heart rate is of the order of 5 to 10 percent, with the fall in mean blood pressure being typically about 10 percent. In NREM sleep there is reduction in sympathetic outflow as is revealed by the seminal studies of Somers et al. using microneurography to record sympathetic bursts in the peroneal nerve in healthy humans during wake and in the different stages of sleep (Fig. 96-1). Thus, the balance of parasympathetic/sympathetic activity is altered during NREM sleep, with the parasympathetic being dominant. This results in alteration in heart rate variability during sleep. The high-frequency component of this heart rate variability is said to reflect parasympathetic activity,

while the low frequency component is related to sympathetic activity. Thus, during NREM sleep there is an increase in the high-frequency component compared with wakefulness and a quite marked reduction in the low-frequency component of heart rate variability. Changes in REM sleep are different. During this stage of sleep there is a return of sympathetic activity such that heart rate and blood pressure return to wakefulness levels. This has been shown directly by sympathetic nerve activity in humans (Figs. 96-1 and 96-2). Thus, during REM sleep the high- and low-frequency component of heart rate variability are the same as in wakefulness. During REM sleep there is also phasic activity that occurs in bursts. These phasic bursts of activity result in rapid eye movements and hence the name for the state. Phasic bursts of activity can lead to both brief periods of increases in heart rate and periods of decrease. These have pathophysiological significance. During surges of heart rate, there are also increases in coronary blood flow. But these can be mismatched such that the increased delivery of blood flow is insufficient to meet the extra myocardial demands consequent to the increase in heart rate. Moreover, in animal models of severe coronary stenosis, phasic decreases in coronary arterial blood flow are found when heart rate increases. Such changes may play a role in the known diurnal rhythm of timing of reported acute cardiac events in humans. Episodes of slowing of heart rate can also occur. At the extreme, brief episodes of asystole in phasic REM sleep have been described in otherwise healthy adults.

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CHANGES IN VENTILATION AND ITS CONTROL WITH SLEEP As with the cardiovascular system, there are important changes in ventilation during sleep. These, too, are different in NREM and REM sleep. During NREM sleep ventilation declines. The various studies in this area have been summa-

rized by Krieger et al. All studies have reported this decrease, although the magnitude of change varies from study to study (see summary in Fig. 96-3). In general, there is a decline in tidal volume while the change in respiratory rate is more variable (see Table 1 in Krieger J et al., 1990). Ventilation in REM sleep is also consistently less than in wakefulness; some studies report a small increase in ventilation in REM compared with NREM sleep (0.9 to 7.1 percent), while other studies

REM Sleep

Stage 2 Sleep

REM Sleep

Figure 96-1 Alterations in recorded bursts of sympathetic nerve activity (SNA) and blood pressure in wakefulness, different stages of nonâ&#x20AC;&#x201C;rapid eye movement sleep (stages 2, 3, and 4), and rapid eye movement (REM). With deepening of NREM sleep, there is progressive loss of sympathetic activity, which is virtually absent in slow wave sleep (stage 4). Sympathetic activity returns in REM but is highly variable. (From Somers VK, Dyken ME, Mark AL, et al.: Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328:303, 1993, with permission.)

Stage 1 + Microarousals

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10 sec

Figure 96-2 Changes in recorded sympathetic nerve bursts in a healthy human during transitions between different sleep stages. There are more bursts, i.e., more sympathetic activity, in REM sleep compared with stage 2 NREM sleep (top panel) and more activity in stage 2 sleep when it is transitional with many microarousals than when fully established (bottom panel). (From Somers VK, Dyken ME, Mark AL, et al.: Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328:303, 1993, with permission.)

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−25

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report a further decrease (−1.1 to −10.8 percent). This variability is likely related to the variability of ventilation in REM sleep itself. As in the cardiovascular system, there are changes in ventilation in association with the phasic events of REM sleep. Both acceleration and slowing of respiratory rate are found as are declines in ventilation. These effects seem to vary between subjects (Fig. 96-4). The changes in NREM sleep in normal humans are largely the result of increases in upper airway resistance. This resistance progressively increases going from stage 1 to stage 3/4 NREM sleep (Fig. 96-5). This increase in resistance is associated with decreases in upper airway muscle activity in muscles such as the genioglossus and in the soft palate. While an increase in upper airway resistance is the major mechanism, it is, however, not the only mechanism since even in laryngotomized subjects with tracheostomies, thereby bypassing the upper airway, PCO2 increases in NREM sleep compared to wakefulness.

Changes in the Cardiorespiratory System During Sleep

Figure 96-3 Percentage change in minute ventilation from wakefulness to NREM sleep in several different studies. There is some variation between studies in the magnitude of the drop in ventilation in NREM sleep, but all studies show a decline. (Krieger J, Maglasiu N, Sforza E, et al.: Breathing during sleep in normal middleaged subjects. Sleep 13:143, 1990.)

The relative importance of the increase in upper airway resistance reflects different neural control of upper airway muscles and the respiratory pump muscles such as the diaphragm. The former is much more coupled to state, i.e., wake and sleep, while the latter, the diaphragm, is more affected by chemical control rather than variations in state (Fig. 96-6). This is why clinically we are typically talking about obstructive sleep apnea while central sleep apnea is relatively rare. Recent evidence suggests that a major neurotransmitter responsible for the state-dependent change in upper airway motoneuron activity controlling upper airway dilator muscles is noradrenaline. Sleep also alters the ventilatory response to hypoxia and hypercapnia. The ventilatory response to hypoxia declines in NREM sleep compared to wakefulness. It declines further in REM sleep. Likewise, the slope of the ventilatory response to carbon dioxide is reduced in NREM sleep compared to wakefulness and further reduced in REM sleep. However, there is

HIGH RESPONDER EOG (R) EOG (L)

RC ABD

LOW RESPONDER EOG (R) EOG (L)

RC ABD 10 sec

Figure 96-4 Changes in respiration during REM sleep. The data shown are for two normal healthy adults. The top traces are right and left electro-oculogram [(EOG(R) and EOG(L)] that show phasic eye movements during REM sleep. The bottom traces are ribcage (RC) and abdominal (ABD) motion. The subject in the top panel (labeled High Responder) has a marked fall in ribcage and to a lesser extent abdominal motion in association with the eye movements. The subject in the bottom panel (labeled Low Responder) has little alteration in ventilatory movements during these phasic eye movements. (From Neilly JB, Gaipa EA, Maislin G, et al.: Ventilation during early and late rapid-eye-movement sleep in normal humans. J Appl Physiol 71:1201, 1991, with permission.)

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Stage 3/4

Figure 96-5 Upper airway resistance increases progressively on going from wakefulness to the deeper stages of NREM sleep. (Data from Tangel DJ, Mezzanotte WS, White DP: Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol 70:2574, 1991, with permission.)

no compelling evidence that there is alteration in central neural response to chemical stimuli since there is, as outlined, a change in upper airway resistance that will alter the increase in ventilation produced by increases in the neural output to the diaphragm. As a consequence of these changes in ventilation and its control, PaCO2 rises, typically from its normal value of 40 mmHg by a few mmHg in NREM sleep. The magnitude of this increase in PaCO2 is a function of the responsiveness of the system to CO2 during wakefulness; subjects with low ventilatory responses to CO2 have larger increases in PaCO2 during NREM sleep than do subjects with high responsivity (Fig. 96-7). Parallel to this increase in PaCO2 , the PaO2 falls. In normal persons, who are operating on the flat part of the oxygen saturation curve, the PaO2 does not fall to a level where significant desaturations occur. However, in persons with low PaO2 during wakefulness, who operate closer to the “knee” of the oxygen saturation curve, this fall in PaO2 during sleep may lead to a significant hypoxemia. For example, patients with chronic obstructive pulmonary disease may require supplemental oxygen during sleep but not during wakefulness.

Wake Stimulus

Diaphragm Phrenic mns

Chemical Stimulus, e.g., CO2

Upper airway Genioglossus mns

Figure 96-6 Schematic diagram illustrating the relative role of the ‘‘wakefulness drive” to breathe and that related to the chemical control system determined by PCO2 and PO2 . The diaphragm is only little affected by the wakefulness drive (dashed line) and is predominantly responding to chemical stimuli (thick line). In contrast, upper airway motoneurons, such as genioglossus, are more affected by the ‘‘wakefulness stimulus” coupled to sleep state.

Figure 96-7 Relationship between the increase in PCO2 that occurs in normal subjects in going from wakefulness to stages 1 and 2 NREM sleep and the CO2 ventilatory response in wakefulness. Persons with the lowest ventilatory responses show the largest change in PCO2 in going to sleep. (From Gothe B, Altose MD, Goldman MD, et al.: Effect of quiet sleep on resting and CO2 stimulated breathing in humans. J Appl Physiol 50:724, 1981, with permission.)

Another major change that occurs during NREM sleep is an increase in the CO2 apnea threshold. This apnea threshold is the PaCO2 at which there is insufficient chemical drive and ventilation ceases. During wakefulness, PaCO2 can be reduced by assisted ventilation to values as low as 20 mmHg and rhythmic ventilation will be maintained; thus, the CO2 apnea threshold during wakefulness is extremely low. In contrast, during NREM sleep, the PaCO2 needs be reduced only to values close to the normal awake PaCO2 (38 to 40 mmHg) and ventilation will cease. Thus, the normal increase in PaCO2 that occurs during NREM sleep is often necessary to maintain rhythmic ventilation. This NREM sleep–related increase in apnea threshold has profound implications. In situations in which ventilation is stimulated—for example, by hypoxia—PaCO2 may be reduced below the apnea threshold typical for normoxic conditions, creating a state of increased vulnerability to central apneas. It is likely that unexplained central apnea during sleep occurs in association with hypocapnia. If this is the mechanism for these apneas, increase in the PaCO2 should abolish them. This has been demonstrated in idiopathic central apnea. Relative hypocapnia is also a risk factor for development of Cheyne-Stokes respiration in patients with congestive heart failure. The specific cellular and neurochemical mechanisms for this NREM sleep–related change in the apnea threshold are currently unknown. Conceptually, however, it may be considered within the same category as the so-called wakefulness stimulus for breathing. Brain stem neuronal groups, such as

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the locus ceruleus and raphe nuclei, in which the major transmitters are norepinephrine and serotonin, respectively, decrease their activity with sleep. Since both these transmitters have important excitatory effects at various levels of the central respiratory control system, these neuronal groups likely represent major components of the wakefulness stimulus.

AROUSAL DURING SLEEP During sleep various sensory stimuli, including auditory and tactile, can lead to a sudden change in sleep state to a lighter stage of sleep or complete wakefulness. Arousal can be detected with abrupt changes in the electroencephalogram. Arousal also results in an increase in heart rate and blood pressure as well as an increase in ventilation. So-called subcortical or brain stem arousals can arise, including in patients with obstructive sleep apnea, i.e., when there is an abrupt change in cardiopulmonary variables but no change in the electroencephalogram. As would be anticipated from the discussion of the wakefulness stimulus, arousals produce much more marked increases in activity of upper airway muscles than in diaphragm. Respiratory stimuli can also lead to arousal during sleep. Such stimuli include airway occlusion, increased upper airway resistance, hypoxia, and hypercapnia. Isocapnic hypoxia is, however, a poor stimulus to arousal. Subjects can remain asleep without interruption even with an SaO2 at 70 percent. It appears that the major respiratory stimulus to arousal is the degree of respiratory effort. Arousal occurs at a relatively constant increased respiratory neural output, i.e., respira-

Changes in the Cardiorespiratory System During Sleep

tory effort that is independent of the causes of this increased effort.

PERIODICITIES OF VENTILATION IN LIGHT NREM SLEEP Periodic (oscillatory) ventilation is more likely to occur during light NREM sleep (stages 1 and 2) than in slow-wave sleep (stages 3 and 4). This is highly relevant to the problem of obstructive sleep apnea; most apneas occur in stages 1 and 2 sleep. If a subject with sleep apnea is able to enter stages 3 and 4 NREM sleep, regular ventilation resumes and apneas are less likely to occur. Oscillatory ventilation is also typically observed during hypoxia, as in lung disease or at high altitude, and in certain cardiovascular diseases. Ventilation may be periodic because of particular dynamic properties of the chemical feedback system that controls respiration. As in any feedback system, the critical determinants of this unstable (oscillatory) behavior are the overall response (gain) of the control system and the time delay (phase lag) between the plant and the controller. For the respiratory system, the plant is the gas exchange apparatus in the lung; the controllers are the chemoreceptors, peripheral and central; and the controlled variables are the arterial blood-gas tensions PaCO2 and PaO2 . Thus, in the case of the respiratory control system, this time delay is that between the lung and the sensors, the peripheral and central chemoreceptors. The importance of this delay is illustrated in Fig. 96-8 for a situation in which a disturbance to the ventilatory control system leads to a change in PaCO2 . If there is no delay,

Figure 96-8 Implications for a control system with a delay between the plant and the control system. The left panel (A) shows how a control system will respond to a sinusoidal perturbation when there is no delay. The perturbation is essentially neutralized. The right panel (B) shows how a control system acts if it has a delay that results in the corrective action being 180 degrees out of phase with the perturbation. In this case, the controllerâ&#x20AC;&#x2122;s action acts to sustain, and not to neutralize, the original sinusoidal perturbation.

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the control system responds immediately to this perturbation by adjusting ventilation to correct the change in PaCO2 (Fig. 96-8A). In contrast, if there is a delay in the feedback loop, the controller may act to sustain the cyclical disturbance (Fig. 96-8B); this is because during the time it takes the altered PaCO2 level to reach the sensor, the controller may make an inappropriate correction. For example, when the PaCO2 in the blood leaving the lung is low, the controller should respond by reducing ventilation, returning the PaCO2 to the regulated value. If, however, the delay is such that by the time the low PaCO2 signal reaches the sensor, the PaCO2 of the blood leaving the lung is already higher (e.g., due to the presence of an external perturbation or already existing oscillations, as in Fig. 96-8B), the controller will act incorrectly to reduce ventilation and further increase the PaCO2 . Such a situation promotes self-sustaining periodic ventilation. Thus, the time delay determines not only whether periodic ventilation will or will not occur, but also the period of this oscillation. Periodic ventilation would not occur if the control system failed to respond, or responded weakly, to these perturbations. Thus, the gain of the response of the system is as important as the magnitude of the delay in determining whether unstable operation of the ventilatory control system will occur. This gain is usually defined as the product of the response of the controller (the change in ventilation per unit change in PaCO2 —i.e., CO2 sensitivity) and the gain of the plant (the change in PaCO2 per unit change in ventilation—i.e., the plant gain). Overall loop gain is the product of these. Periodic breathing occurs in clinical situations, particularly in hypoxic subjects (e.g., patients with lung disease) and normal sojourners at high altitude: Hypoxia increases the gain of the response of the controller, making the system more unstable. The period of the oscillations in ventilation induced by hypoxia is on the order of 20 seconds—i.e., much shorter than those typically seen in patients with obstructive sleep apnea. Abnormally increased circulatory time, which prolongs the delay between the lung and chemoreceptors, can also produce an unstable system and ventilatory periodicities. This mechanism is likely to be responsible, at least in part, for the ventilatory oscillations that occur during sleep in patients with severe congestive heart failure (Cheyne-Stokes respiration). In addition to these mechanisms that are related to instability of the chemical control system for ventilation, state instability can produce sleep-related oscillations in ventilation; state instability is defined as periodic changes in the stages of sleep that cause discrete and periodic changes in the level of the wakefulness stimulus to ventilation. As discussed in the preceding section, at the onset of sleep, there are decreases in ventilation and increases in upper-airway resistance that cause an increase in PaCO2 ; the increase in PaCO2 may, in turn, directly or indirectly interfere with the normal progression of the sleep cycle. For example, an abrupt change in sleep state may occur as a result of airflow limitation and increased respiratory effort, leading to an awakening to a lighter stage of sleep—i.e., to an arousal. Upon arousal, ventilation increases, upper-airway resistance decreases, and PaCO2 drops.

The subject returns to sleep, and the whole cycle may repeat itself. This state instability is more likely to arise if the ventilatory response to CO2 is low, since the PaCO2 increases more at sleep onset and is more apt to drive the level of respiratory effort to a point at which an arousal from sleep occurs. The period of ventilatory oscillation caused by this mechanism is longer than that seen with chemical instability—i.e., around 60 to 90 seconds. This mechanism, we believe, predominates in producing the sleep apnea syndrome and periodic breathing in patients with low ventilatory responses to CO2 (e.g., patients with hypothyroidism, in whom central and obstructive apneas are common).

CIRCADIAN CLOCKS IN THE CARDIOVASCULAR SYSTEM AND LUNG While much is known about the physiology of cardiopulmonary changes during sleep, recently attention has turned to changes in molecular mechanisms. In the late 1990s the discovery of the molecular components that produce circadian clocks led to study of expression of circadian clock genes in many different organs. Surprisingly, functioning clocks were not only found where they were expected, i.e., in the suprachiasmatic nucleus of the hypothalamus—the site of the circadian clock—but in many organs. In particular, functioning clocks have been demonstrated in the lung and cardiovascular system. In cardiac myocytes and vascular smooth muscle cells, the clocks are intrinsic to these cells since they maintain a circadian rhythm even when the cells are isolated and in culture (for review, see Young ME, 2006). (Many other cell types have not been as extensively tested to date.) These clocks likely alter the temporal pattern of expression of genes in the relevant organs. Microarray studies indicate that about 10 percent of all genes have a diurnal variation in their expression levels. In heart, there is, for example, diurnal variation of genes promoting fatty acid oxidation. Expression of these genes in rats peaks during the dark phase, i.e., their active period. Expression of genes for K+ channels also exhibit diurnal variation in heart and likely contributes to the altered excitability of cardiac myocyte across the day. These observations indicate that at a fundamental molecular level the heart and lung at night are not the same as during the day. It seems likely that molecular processes in these organs will also be affected by sleep and sleep deprivation, but this is an area that has not been studied to date, and is likely to be a fruitful area of inquiry.

CONCLUSION In conclusion, there are major changes in cardiopulmonary function during sleep as compared with wakefulness. These changes are sleep-state specific, being different between NREM and REM sleep. The changes have important

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pathogenetic significance. This significance includes the following: the timing across the day of acute cardiovascular events; the periodic breathing that occurs during sleep at high altitude; the neuronal changes that lead to obstructive apnea during sleep; the pathogenesis of Cheyne-Stokes respiration. Currently a new window on changes in the cardiopulmonary system with sleep is opening, i.e., changes at the molecular level. This is likely to lead to new insights that will also have implications for the pathogenesis of disease and treatment.

SUGGESTED READING Carlson DM, Carley DW, Onal E, et al.: Acoustically induced cortical arousal increases phasic pharyngeal muscle and diaphragmatic EMG in NREM sleep. J Appl Physiol 76:1553, 1994. Chan E, Steenland HW, Liu H, et al.: Endogenous excitatory drive modulating respiratory muscle activity across sleepwake states. Am J Respir Crit Care Med 174:1264, 2006. Dempsey JA, Smith CA, Harms CA, et al.: Sleep-induced breathing instability. University of Wisconsin-Madison Sleep and Respiration Research Group. Sleep 19:236, 1996. Dickerson LW, Huang AH, Thurnher MM, et al.: Relationship between coronary hemodynamic changes and the phasic events of rapid eye movement sleep. Sleep 16:550, 1993. Fenik VB, Davies RO, Kubin L: REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 172:1322, 2005. Fink BR, Hanks EC, Ngai SH, et al.: Central regulation of respiration during anesthesia and wakefulness. Ann NY Acad Sci 109:892, 1963. Gleeson K, Zwillich CW, White DP: The influence of increasing ventilatory effort on arousal from sleep. Am Rev Respir Dis 142:295, 1990. Gothe B, Altose MD, Goldman MD, et al.: Effect of quiet sleep on resting and CO2 -stimulated breathing in humans. J Appl Physiol 50:724, 1981. Guilleminault C, Pool P, Motta J, et al.: Sinus arrest during REM sleep in young adults. N Engl J Med 311:1006, 1984. Javaheri S: Central sleep apnea-hypopnea syndrome in heart failure: prevalence, impact, and treatment. Sleep 19:S229, 1996.

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Khoo MC, Gottschalk A, Pack AI: Sleep-induced periodic breathing and apnea: A theoretical study. J Appl Physiol 70:2014, 1991. Kirby DA, Verrier RL: Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav 45:1017, 1989. Krieger J, Maglasiu N, Sforza E, et al.: Breathing during sleep in normal middle-aged subjects. Sleep 13:143, 1990. Morrell MJ, Harty HR, Adams L, et al.: Breathing during wakefulness and NREM sleep in humans without an upper airway. J Appl Physiol 81:274, 1996. Neilly JB, Gaipa EA, Maislin G, et al.: Ventilation during early and late rapid-eye-movement sleep in normal humans. J Appl Physiol 71:1201, 1991. Orem J, Kubin L: Respiratory physiology: Central neural control, in Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia: Elsevier, 2005, p 215. Shea SA: Behavioural and arousal-related influences on breathing in humans. Exp Physiol 81:1, 1996. Sin DD, Fitzgerald F, Parker JD, et al.: Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 160:1101, 1999. Skatrud JB, Dempsey JA: Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 55:813, 1983. Somers VK, Dyken ME, Mark AL, et al.: Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328:303, 1993. Tangel DJ, Mezzanotte WS, White DP: Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol 70:2574, 1991. Xie A, Rutherford R, Rankin F, et al.: Hypocapnia and increased ventilatory responsiveness in patients with idiopathic central sleep apnea. Am J Respir Crit Care Med 152:1950, 1995. Yamashita T, Sekiguchi A, Iwasaki YK, et al.: Circadian variation of cardiac K+ channel gene expression. Circulation 107:1917, 2003. Young ME: The circadian clock within the heart: potential influence on myocardial gene expression, metabolism, and function. Am J Physiol 290:H1, 2006. Zylka MJ, Shearman LP, Weaver DR, et al.: Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20:1103, 1998.

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97 Sleep Apnea Syndromes N. P. Patel R. J. Schwab

I. HISTORY OF SLEEP-DISORDERED BREATHING II. DEFINITIONS OF OBSTRUCTIVE SLEEP APNEA, PICKWICKIAN SYNDROME, CENTRAL SLEEP APNEA, AND THE UPPER AIRWAY RESISTANCE SYNDROME III. SPECTRUM OF DISEASE IV. PATHOGENESIS OF OBSTRUCTIVE SLEEP APNEA Anatomic Features That Predispose to Apnea Neural Modulation of Upper Airway Patency The Apneic Event V. EPIDEMIOLOGY AND RISK FACTORS Risk Factors for Sleep Apnea Clinical Presentation Screening for Sleep Apnea VI. DIAGNOSIS VII. CONSEQUENCES OF SLEEP APNEA Neurocognitive Consequences of OSA

HISTORY OF SLEEP-DISORDERED BREATHING Sleep-disordered breathing is an extremely common medical disorder associated with important morbidity. Recognition of its relevance in medicine is relatively recent, although clinical descriptions of sleep-disordered breathing were made in the nineteenth century by Hunter, Cheyne, and Stokes. Descriptions of an entity constituting obesity and extreme somnolence were highlighted in the character description of the “fat boy” in Charles Dickens’ series, Posthumous Papers of the Pickwick Club, first published in 1835. Dickens described Joe, the fat boy, as a loud snorer who was obese and excessively somnolent—the classical description of Pickwickian syndrome. Sir William Osler in 1918 was credited with first linking the relationship between obesity and Pickwick-

Cardiovascular Consequences of OSA Economic Consequences of OSA VIII. TREATMENT General Measures Weight Loss Pharmacologic Treatment Oxygen Therapy Nasal Dilators Specific Medical Therapies Surgical Treatment of OSA IX. MANAGEMENT OF OTHER DISORDERS Obesity-Hypoventilation Syndrome Central Sleep Apnea Upper Airway Resistance Syndrome Pulmonary Diseases during Sleep X. CONCLUSION

ian syndrome. In the mid-twentieth century, further work led to the association of Pickwickian syndrome with alveolar hypoventilation by Burwell and colleagues in 1956, and periodic cessation of respiration by Drachman and Gummit in 1962. Gastaut and associates in 1965 showed that cessation of respiration was due to obstruction of the upper airway, and obstructive sleep apnea was recognized. In 1972, a conference organized by Lugaresi and his Bologna group (Italy) entitled Hypersomnia and Periodic Breathing, served as a springboard for the growth of interest and research in sleepdisordered breathing. Guilleminault et al. coined the terms sleep apnea syndrome and obstructive sleep apnea syndrome in 1976 to underscore that airway obstruction during sleep was not restricted to obese subjects. Over the last 30 years, we have begun to understand the pathogenesis of sleep apnea and have developed effective diagnostic and treatment modalities for this common disorder.

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DEFINITIONS OF OBSTRUCTIVE SLEEP APNEA, PICKWICKIAN SYNDROME, CENTRAL SLEEP APNEA, AND THE UPPER AIRWAY RESISTANCE SYNDROME Sleep-disordered breathing (SDB) is present when there are repetitive episodes of cessation of respiration (apnea) or decrements in airflow (hypopnea) during sleep, associated with sleep fragmentation, arousals, and reductions in oxygen saturation. An apnea can be obstructive (absence of airflow but continued respiratory effort), central (absence of airflow and respiratory effort), or mixed. A mixed apnea starts as a central event and then becomes obstructive during the latter portion of the same episode. A majority of patients with obstructive sleep apnea (OSA) have both obstructive and mixed apneas. A hypopnea is defined as a decrement in airflow of 50 percent or more associated with a 4 percent fall in oxygen saturation and/or electroencephalographic (EEG) arousal. However, there is some debate over the exact definition of a hypopnea. Hypopneas have been shown to produce identical clinical consequences as apneas. A respiratory effort-related arousal event (RERA) is a sequence of breaths characterized by increasing effort leading to an arousal from sleep that does not fulfill criteria for apnea or hypopnea. It should last for at least 10 seconds and is terminated by an arousal. The apnea/hypopnea index (AHI—the number of apneas plus hypopneas per hour of sleep) is the standard metric used to quantitate the severity of obstructive sleep apnea. Although the AHI has been proven to be superior metric when assessing the overall effect of OSA, it excludes the degree of oxygen desaturation, degree of hypoventilation, and total number of arousals. An AHI greater than 5 to 10 events per hour is indicative of OSA. The obstructive sleep apnea syndrome (OSAS) is said to be present when the AHI is greater than 5 to 10 events per hour and the patient has symptoms of excessive daytime somnolence, unrefreshing sleep, or chronic fatigue. Individuals must fulfill criterion A or B, plus criterion C to be diagnosed with OSAS: A. Excessive daytime sleepiness that is not explained by other factors B. Two or more of the following that are not explained by other factors: Choking or gasping during sleep Recurrent awakenings from sleep Unrefreshing sleep Daytime fatigue Impaired concentration C. Overnight monitoring demonstrates 5 to 10 or more obstructed breathing events per hour during sleep or greater than 30 events per 6 hours of sleep. These events may include any combination of obstructive apnea, hypopnea, or respiratory effort–related arousals. The clinical implications of patients diagnosed with OSA in the absence of daytime symptoms remains to be clar-

ified. However, patients with an AHI greater than 30 events per hour should be treated regardless of their symptoms. In general, as the AHI increases, so does the severity of symptoms. Three other syndromes (central sleep apnea, obesityhypoventilation, upper airway resistance syndrome) can either coexist with OSA or present independently. Central sleep apnea (CSA) is less common than obstructive sleep apnea and is characterized by a transient cessation of rhythmic breathing: The respiratory pump muscles do not receive central input. It is defined as repeated episodes of apnea in the absence of respiratory muscle effort and is observed on the polysomnogram as an absence of nasal-oral airflow and thoracoabdominal excursion. The individual must fulfill A, B, and C to be diagnosed with the central sleepapnea-hypopnea syndrome. A. At least one of the following symptoms that is not explained by other factors: Excessive daytime sleepiness Frequent nocturnal arousals/awakenings B. Overnight monitoring that demonstrates 5 to 10 or more central apneic events plus hypopneic events per hour of sleep. C. Normocarbia while awake (PaCO2 less than 45 torr). A number of etiologies for central sleep apnea have been recognized, of which heart failure and stroke are the most common. Patients with CSA experience sleep fragmentation and can report similar daytime symptoms as OSA patients. (For further discussion of central sleep apnea, see Management of Other Disorders, below.) Upper airway resistance syndrome (UARS) was first described by Guilleminault et al. in 1993. The advent of nasal cannula–pressure transducer system and esophageal pressure monitoring allowed recognition of increasing negative intrathoracic pressure associated with upper airway flow limitation, resulting in arousals from sleep. UARS is not associated with apneas or significant oxyhemoglobin desaturations. The arousals result in sleep fragmentation and daytime sleepiness. UARS may represent a milder form of the OSA spectrum, although there is debate whether or not UARS patients demonstrate different clinical and upper airway characteristics compared with OSA patients. Further study employing standardized techniques that detect respiratory-related EEG changes are being developed to clarify the incidence and prevalence of UARS as a separate entity. Nonetheless, many patients with the upper airway resistance syndrome also have evidence for concomitant obstructive sleep apnea. Obesity hypoventilation syndrome (OHS), or the Pickwickian syndrome, also frequently coexists with OSA. It is defined by morbid obesity (body mass index greater than 40 kg/m2 ) and chronic hypoventilation with hypercapnia (PaCO2 greater than 45 mmHg) during wakefulness. OSA patients, in general, do not exhibit hypercapnia during wakefulness as a result of preserved minute ventilation. Characteristic findings observed with obesity-hypoventilation syndrome include awake resting hypoxemia, hypersomnolence, signs of cor pulmonale (right-sided heart failure and lower

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extremity edema), and nocturnal hypoventilation. The diagnosis of OHS requires a demonstration of at least a 10 mmHg increment in PaCO2 during sleep. Patients with obesity hypoventilation syndrome often can be confused with patients with COPD since both of these patients manifest daytime hypercapnia. However, patients with COPD have an obstructive pattern on their pulmonary function studies, whereas patients with OHS usually have a restrictive pattern on their pulmonary function studies. In addition, patients with COPD are usually not morbidly obese.

SPECTRUM OF DISEASE Therefore, obstructive sleep apnea should be considered as a continuum of disease, i.e., a spectrum of abnormalities from snoring to obesity-hypoventilation syndrome (Fig. 97-1). Although common, snoring should not be considered normal; it is often the first manifestation of SDB and may be associated with deleterious effects (see the following). This concept of a continuum of abnormality is important since it is likely, although not proved, that the natural history of disease follows this continuum. Significant weight gain or loss, and other comorbidities such as heart failure may be factors that move an individual along this continuum of SDB. Weight gain is an important risk factor for sleep apnea and the Pickwickian syndrome. Acutely, an individual may change position on the continuum for a number of reasons. Alcohol may worsen the degree of SDB by preferentially suppressing the activity of upper airway dilator muscles. Alcohol, sedatives, or hypnotics can cause normal individuals to snore during sleep and turn a patient who snores into a one with obstructive apnea during sleep. Weight loss moves patients along the continuum in the opposite direction.

PATHOGENESIS OF OBSTRUCTIVE SLEEP APNEA The pathogenesis of OSA involves both an anatomic and a neurologic component. The upper airway is an extremely complicated structure performing several different physiologic functions, including vocalization, respiration, and deg-

Figure 97-1 Spectrum of sleep-disordered breathing.

Figure 97-2 Mid-sagittal magnetic resonance image (MRI) in a normal subject demonstrating the anatomic regions of the upper airway and relevant craniofacial and soft tissue structures. The retropalatal (RP) region is defined from the level of the hard palate to the distal margin of the soft palate; the retroglossal (RG) region is defined from the distal margin of the soft palate to the base of the epiglottis. In patients with sleep apnea, obstruction usually occurs in the retropalatal or retroglossal levels or at both locations. (Reproduced with permission from Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152:1673â&#x20AC;&#x201C;1689.)

lutition. The upper airway extends from the posterior margin of the nasal septum to the larynx and has a paucity of rigid bony support. It is divided into four anatomic regions: 1. Nasopharynx: between nares and hard palate 2. Retropalatal: between hard palate and caudal margin of the soft palate 3. Retroglossal: between the caudal margin of the soft palate and base of the epiglottis 4. Hypopharynx: from the base of the tongue to the larynx Fig. 97-2 displays a mid-sagittal magnetic resonance image (MRI) in a normal subject in which the retropalatal and retroglossal regions are outlined. In addition, this mid-sagittal image highlights the airway, tongue, soft palate, mandible, and subcutaneous fat. The critical lateral upper airway soft tissue structures, i.e., the lateral pharyngeal walls and lateral parapharyngeal fat pads are depicted in Fig. 97-3, which shows an axial MRI of a normal subject in the retropalatal region. In a patient with sleep apnea, collapse of the upper airway occurs most commonly in the retropalatal and retroglossal regions. Although the location of collapse varies among subjects, within a subject it tends to be reproducible from episode to episode. The surrounding tissue and craniofacial structures in the retropalatal and retroglossal regions contribute to the specific morphology of the airway of a given individual. The main contributors of the airway boundaries include the soft palate and tongue anteriorly, the pharyngeal constrictor muscles, lymphoid tissue, parapharyngeal fat pads, and mandibular rami laterally and the pharyngeal constrictor muscles posteriorly. Unfortunately, we do not completely

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Figure 97-3 Axial MR image at the retropalatal level in a normal subject. The relevant soft tissue and bony structures surrounding the upper airway are highlighted. The tissues immediately lateral to the airway are the lateral pharyngeal walls and the parapharyngeal fat pads.(Reproduced with permission from Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleepdisordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152:1673–1689.)

understand the biomechanical relationships between upper airway size and these surrounding structures. In regard to elucidating the mechanisms leading to obstructive apnea, the focus has been on anatomic and neural factors that influence upper airway patency during wakefulness and sleep.

Anatomic Features That Predispose to Apnea Airway patency is modulated by physical characteristics and neural mechanisms. The upper airway, unlike the lower respiratory tract, lacks a robust support framework of cartilaginous rings and therefore is at risk for collapse due to: (1) extraluminal tissue pressure exerted by circumferential craniofacial and soft tissue structures; and (2) negative pressure associated with inspiration. The pharyngeal dilator muscles help to maintain upper airway patency. Changes in pharyngeal transmural pressure, defined as the difference between the pressure in the airway lumen and the pressure exerted by tissues surrounding the site of collapse, modulates upper airway size. An array of imaging techniques including cephalography, nasopharyngoscopy, fluoroscopy, acoustic reflection, computed tomography (CT), MRI, and optical coherence

tomography have been employed to better understand the pathogenesis of OSA. Such imaging modalities have examined the upper airway during wakefulness, respiration, and during sleep. OSA subjects demonstrate an excess of upper airway soft tissue for the space within the craniofacial structures that envelop the pharyngeal lumen. Upper airway caliber during wakefulness, in general, is smaller in patients with sleep apnea compared with normal subjects, and the configuration of the upper airway is different in apneics than normals. Patients with sleep apnea have larger tongues and longer soft palates than normal subjects (Fig. 97-4). Habitual snorers with or without OSA also have a generalized narrowing of the pharyngeal lumen compared with normal subjects, whether or not they are obese. Length of the upper airway, using cephalometric and MRI techniques, has been demonstrated to be of significance in men with OSA: A longer airway confers a greater risk of airway lumen collapse compared with normal subjects. The major axis of the normal airway is oriented in the lateral, horizontal dimension. In apneics there is considerable reduction in the lateral diameter of the airway with relative preservation of the anterior-posterior diameter. Thus, in contrast to normals, the apneic patient’s airway is oriented more in the anterior-posterior dimension. This configuration has been hypothesized to adversely affect upper airway muscle

Figure 97-4 Mid-sagittal magnetic resonance imaging (MRI) of a normal subject on the left and a patient with sleep apnea on the right. The upper airway is smaller in both the retropalatal and retroglossal region in the apneic patient. The soft palate is longer in the apneic patient. The tongue is bigger in the retroglossal region in the patient with sleep apnea. The amount of subcutaneous fat (white area at the back of the neck) is greater in the apneic. (Reproduced with permission from Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152:1673–1689.)

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Figure 97-5 Axial magnetic resonance imaging (MRI) in the retropalatal region of a normal subject (left) and a patient with sleep apnea (right). The upper airway is smaller in the lateral dimension in the patient with sleep apnea. The lateral pharyngeal walls are larger in the patient with sleep apnea compared with the normal subject. The apneic patient has more subcutaneous fat than the normal subject. (Reproduced with permission from Schwab RJ, Gupta KB, Gefter WB, et al: Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152:1673–1689.)

activity and therefore predispose the apneic subject to airway closure during sleep. This lateral narrowing of the airway indicates that soft tissue structures lateral to the airway (lateral pharyngeal walls and lateral parapharyngeal fat pads) may be important in modulating airway dimensions (Figs. 97-3 and 97-5). Enlargement of the parapharyngeal fat pads solely explaining the obesity-related narrowing of the airway in apneics, has fallen out of favor based on detailed MRI and CT studies. However, increased thickness of the lateral pharyngeal walls has been reported to explain narrowing of the apneic airway by imaging studies (Fig. 97-5). Fat deposition in the parapharyngeal fat pads, in the tongue, and under the mandible in the submental region may all be important in reducing upper airway caliber. Imaging studies have also demonstrated that the total volume of fat surrounding the airway is greater in apneic than in BMI-matched normal subjects, suggesting that fat deposition in the neck plays a role in the pathogenesis of OSA. Indeed, neck circumference is a strong predictor of sleep apnea based on population studies. A number of other soft tissue abnormalities also have been shown to narrow the upper airway in patients with sleep apnea when compared with normals, including an increase in the volume of the tongue, soft palate, and lateral walls surrounding the pharynx. The larger the volume of the lateral pharyngeal walls, tongue, and total soft tissue (Fig. 97-6), the greater is the likelihood of developing OSA. Other factors important in mediating upper airway narrowing/soft tissue enlargement in apneics include genetics, gender, pharyngeal dilator muscle dysfunction, soft tissue edema (secondary to snoring/apnea-related trauma), airway tissue properties (surface tension), vascular perfusion, and posture of the individual (supine versus lateral). Recumbency decreases lung volume and traction on the airway. Muscular dysfunction and soft tissue edema are thought to be consequences rather than primary causes of OSA. Finally, variation in craniofacial morphology influences upper airway configuration. For example, retroposed mandible and reduced hyoid-mandibular plane distance have been associated with higher risks of apnea. This is further discussed under Risk Factors for Sleep Apnea, below.

The upper airway’s static characteristics during wakefulness in relation to apnea risk have been discussed. However, the dimensions of the airway are dependent on the phase of respiration. Dynamic upper airway imaging with CT, MRI, and nasopharyngoscopy has characterized the airway’s geometrical changes into three phases (Fig. 97-7). In inspiration upper airway area is relatively constant, inferring a balance between muscle dilator activity and negative airway lumen pressure. In early expiration, the activity of airway dilator muscles decreases, intraluminal pressure rises, and the airway maximally widens. At end-expiration upper airway dimensions decrease. Therefore, the upper airway is at risk for collapse in both inspiration and expiration.

Neural Modulation of Upper Airway Patency During sleep, the balance in transpharyngeal pressure shifts toward collapse as a consequence of reduced upper airway dilator muscle activity in both normals and patients with sleep apnea. MR images indicate that the upper airway of normal subjects without sleep apnea narrows during sleep (Figs. 97-8 and 97-9). The neural control of these muscles is complex and involves several neurotransmitters (serotonin, noradrenaline, thyroid releasing hormone, Substance p, and aminobutyric acid) that are also influenced by sleep. The most widely studied upper airway muscle is the genioglossus. Three neural mechanisms have been shown to be operative with regard to genioglossus muscle activity. First, negative airway pressure detected by laryngeal mechanoreceptors activates the genioglossus via increased hypoglossal nerve discharge. Second, genioglossus activation has been observed to precede diaphragmatic activation and development of negative intraluminal pressure due to input received from the respiratory control center in the medulla via respiratory neurons. Therefore, loop gain, a measure of stability or instability of a system controlled by feedback loops, can induce obstructive apneas. If central respiratory drive waxes and wanes, so does the pharyngeal muscle activity. Third, neural mechanisms modulating arousal (serotonergic and noradrenergic neurons) have a tonic excitatory influence on the genioglossus activity.

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Figure 97-6 Volumetric reconstruction of axial magnetic resonance (MR) images in a normal subject (top panel) and a patient with sleep apnea (bottom panel). The mandible is depicted in gray, the tongue in orange/rust, the soft palate in purple, the lateral parapharyngeal fat pads in yellow and the lateral/posterior pharyngeal walls in green. Both subjects had an equivalent body mass index (32.5 kg/m2 ). Upper airway caliber is greater in the normal subject than in the patient with sleep apnea. The tongue, soft palate, and lateral pharyngeal walls are all larger in the patient with sleep apnea than in the normal subject. (Reproduced with permission from Schwab RJ, Pasirstein M, Pierson R, et al: Identification of upper airway anatomic risk factors for obstructive sleep apnea with volumetric magnetic resonance imaging. Am J Respir Crit Care Med 2003;168:522â&#x20AC;&#x201C;530.)

To summarize the neural modulation of pharyngeal muscle activity, there exists local input (negative intraluminal pressure), respiration-related input (medulla), and arousal state input (serotonin raphe cells). During NREM sleep, both the tonic and phasic activation of airway dilator muscles decreases during inspiration: This is a consequence of diminished local mechanoreceptor feedback loop activity. In REM sleep, these changes in the airway dilator muscle activity can be further depressed. In fact, during phasic REM activity, muscle action can be completely suppressed. Therefore, it is not unexpected that airway closures (or apneas) occur more commonly during REM sleep.

The Apneic Event Occlusion of the airway results in a range of immediate physiologic disturbances. The continued ventilatory efforts in spite of episodic reduction/cessation in ventilation, combined with repetitive, intermittent hypoxemia and arousals form the basis for a cascade of downstream perturbances. Breathing efforts during an obstructive apnea create large swings in intrathoracic pressures that compromise left ventricular (LV) filling in consequence to rising afterload and preload. Intermittent hypoxemia is associated with increased production in reactive oxygen species, oxidative stress, and an inflammatory state. Surges in the sympathetic nervous system that occur secondary to apnea, hypoxia, hypercapnia, and arousal

result in increased peripheral resistance and cardiac stimulation, which in turn lead to increases in blood pressure and heart rate. Cessation of apnea occurs with an arousal to a lighter stage of sleep or wakefulness. The factors responsible for arousal most likely involve chemical (hypoxia) and mechanical stimuli (increased respiratory effort against an occluded airway). Arousal mechanisms, when adversely affected by alterations in chemosensitive systems or ingestion of alcohol and hypnotics, can lead to prolongation of apnea.

EPIDEMIOLOGY AND RISK FACTORS Estimations of prevalence of OSA in the general population are variable and dependent on the population studied, methods used to measure sleep, and threshold employed to define normal from abnormal. In the United States, the prevalence has been reported to be 4 percent (up to 9 percent) in men and 2 percent (up to 4 percent) in women between the ages of 30 and 60. The prevalence of moderate to severe OSA associated with sleepiness has been estimated to be 0.5 to 1.5 percent in middle-aged men with an average BMI of 24.9 to 27.1. A Spanish study of a sample of 38- to 70-year-old subjects (male and female) noted a prevalence of 7 and 14 percent, respectively; however, the current actual prevalence may be substantially

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Figure 97-7 Changes in upper airway area as a function of tidal volume during the respiratory cycle using cine CT (computed tomography). Airway caliber is relatively constant in inspiration. Airway size increases in early expiration and decreases in late expiration. (Reproduced with permission from Schwab RJ, Gefter WB, Hoffman EA, et al: Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep-disordered breathing. Am Rev Respir Dis 1993;148:1385â&#x20AC;&#x201C;1400.)

higher. Young et al. estimated that among middle-aged adults, 93 percent of women and 82 percent of men with OSA have not been clinically diagnosed. Thus, sleep apnea is exceedingly common and is a significant public health issue that will likely continue to become more common in parallel with its increasingly prevalent risk factors, notably obesity and older age. By consensus, the following criteria are used to define mild, moderate, and severe sleep apnea. (However, it should be noted that this classification system does not use oxyhemoglobin desaturation nadir or EEG arousals.) Mild sleep apnea, AHI: 5 to 15 events per hour Moderate sleep apnea, AHI:15 to 30 events per hour Severe sleep apnea, AHI greater than 30 events per hour

Risk Factors for Sleep Apnea Several risk factors exist for OSA (Table 97-1). Epidemiologic studies demonstrate the prevalence of OSA to be two to three

times higher in men than women. The reasons are not entirely clear but appear to be related to hormonal influence. Postmenopausal women are at higher risk for OSA than are premenopausal women. Hormone replacement therapy may reduce the risk of OSA in postmenopausal women; however, this therapy is problematic due to the increased risk of cardiovascular disease and carcinoma of the breast and uterus. Comparing men with postmenopausal women, the incidence of OSA is reportedly similar. Gender differences in the prevalence of OSA may also be related to body fat distribution. Men exhibit a more central fat distribution, including the neck, thereby increasing the risk for narrowing and closure of the upper airway. However, it is not clear that men have larger parapharyngeal fat pads surrounding their upper airway than women. Numerous studies have shown correlations between the prevalence of OSA syndrome and obesity. The majority of these investigations were cross-sectional. Important longitudinal studies have demonstrated that obesity increases

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Table 97-1 Risk Factors for Obstructive Sleep Apnea Gender (male/female 2:1) Obesity (>120% ideal body weight) Neck size (collar size >17 inches in males, >15 inches in females)

Figure 97-8 State-dependent magnetic resonance imaging (MRI) in the retropalatal region of a normal subject (AHI = 0 events/hour). Airway area is smaller during sleep in this normal subject. The state-dependent change in airway size is secondary to reductions in both the lateral and anterior-posterior airway dimensions. (Reproduced with permission from Trudo FJ, Gefter WB, Welch KC, et al: State-related changes in upper airway caliber and surrounding soft-tissue structures in normal subjects. Am J Respir Crit Care Med 1998;158:1259–1270.)

Upper airway anatomy Macroglossia Lateral peritonsillar narrowing Elongation/enlargement of the soft palate Tonsillar hypertrophy Nasal septal deviation Retrognathia, micrognathia Narrowing of the hard palate Class III/IV modified Mallampati airway Specific genetic diseases, e.g., Treacher Collins, Downs syndrome, Apert’s syndrome, Achrodorophsia, etc. Genetic factors Endocrine disorders—hypothyroidism, acromegaly

the rate of progression of OSA, and weight gain further accelerates disease progression. Although obesity is the most common risk factor for OSA, sleep apnea also occurs in non-obese subjects. In non-obese patients craniofacial features such as retroposed mandible, micrognathia, and narrowing of the hard palate are the primary risk factors for apnea. The importance of craniofacial morphology’s contribution to apnea risk is supported by observations in Asian patients with apnea who have shorter maxillae and mandibles and smaller anterior-posterior facial dimensions, and lower BMI than whites. Soft tissue abnormalities such as tonsillar and adenoidal hypertrophy are important risk factors for apnea in children. Nasal abnormalities, including septal deviation and allergic rhinitis, also increase apnea risk.

Alcohol, sedative or hypnotic use

The effect of age is complex. Population studies illustrate higher prevalence of OSA with increasing age, peaking in the fifties and sixties. However, older individuals have lower rates of apnea and snoring. Reduced recognition of sleep problems by the elderly and a survivor effect are potential reconciling explanations for this paradox. Evidence is accumulating that genetic factors may be involved in the pathogenesis of sleep apnea. The phenotypic risk factors arise from changes to upper airway structure: (1) alteration in craniofacial structures; (2) enlargement

Figure 97-9 Volumetric state-dependent airway imaging in a normal subject using magnetic resonance imaging (MRI). Airway volume during sleep is smaller in the retropalatal (RP) region but not the retroglossal (RG) region. Such images suggest that the upper airway during sleep does not narrow as a homogenous tube. Nonetheless such images indicate that the upper airway of subjects without sleep apnea narrows during sleep. (Reproduced with permission from Trudo FJ, Gefter WB, Welch KC, et al: State-related changes in upper airway caliber and surrounding soft-tissue structures in normal subjects. Am J Respir Crit Care Med 1998;158:1259–1270.)

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of important upper airway structures (tongue, soft palate, and lateral pharyngeal walls); and (3) modification to regional fat distribution. These factors may operate in concert or alone to increase the risk of apnea. On a chromosomal level, several disorders (Treacher-Collins syndrome, Down’s syndrome, Apert’s syndrome, and Pierre Robin syndrome) are associated with craniofacial and/or upper airway soft tissue abnormalities that confer increased risk of sleep-disordered breathing. In the Cleveland Family Study, inheritance patterns of sleep apnea in whites and blacks have demonstrated a recessive mode of inheritance, with a single major gene accounting for 20 percent of the variance. Absent of specific chromosomal or mendelian genetic disorders, familial clustering of OSA has been reported such that first-degree relatives of index cases with sleep apnea are significantly more likely to have SDB than first-degree relatives of controls. Furthermore, heritability of craniofacial abnormalities (retroposed mandible, inferior displaced hyoid bone) and upper airway soft tissue structure (volume of the tongue, lateral pharyngeal walls, and total soft tissue) has been demonstrated in first-degree relatives and siblings, respectively. Heritability accounts for 40 to 70 percent of the variance in body mass index based on studies of population, twins, and adoption. Moreover, regional fat distribution also has a genetic component. The close association of obesity and OSA and the well-known genetic basis of obesity lead to the following questions. First, is the familial aggregation of OSA simply related to the genetics of obesity? Second, do both these conditions share common susceptibility genes? The former is clearly not the case based on a persistence of significant familial aggregation after controlling for BMI. The latter may be partially true, although it is unlikely that susceptibility genes for OSA are exclusively the same genes mediating obesity. The strong effect of obesity on OSA pathogenesis suggests that any genetic alteration predisposing to obesity might also be regarded as an “apnea gene.” Endocrine disorders can also be accompanied by apnea. Hypothyroidism, especially myxedema, is associated with an increased prevalence of obstructive and central sleep apnea via alteration in muscle function and blunted ventilatory response, respectively. Macroglossia associated with hypothyroidism contributes to the higher frequency of sleepdisordered breathing in this population. Sleep apnea syndrome is more common and often severe in acromegalic patients, presumably related to a large tongue narrowing the upper airway. Alcohol, which reduces the upper airway tone, and sedatives or hypnotics, which reduce the arousal mechanism, also exacerbate OSA. Each of these risk factors needs to be considered in the assessment of a patient with OSA. It is important address why an individual has developed sleep apnea. Routine testing with fiberoptic techniques, radiological airway imaging, and thyroid function testing is not recommended for every patient. However, they should be considered in patients in whom the origin of the sleep apnea is not entirely clear.

Sleep Apnea Syndromes

Table 97-2 Clinical Presentation of Obstructive Sleep Apnea Loud, habitual snoring Witnessed apneas Nocturnal awakening Gasping or choking episodes during sleep Nocturia Unrefreshing sleep, morning headaches Excessive daytime sleepiness Automobile or work-related accidents Irritability, memory loss, personality change Decreased libido Impotence

Clinical Presentation The diagnosis of sleep apnea is not difficult to make and can be suggested from the history. Patients with sleep apnea complain of symptoms during the daytime and/or nighttime (Table 97-2). Although not common, patients may report difficulties falling asleep at night. Frequent nocturnal awakenings related to repetitive airway obstruction leads to sleep fragmentation. Patients may report snorting or gasping, choking, diaphoresis, and restlessness related to airway obstruction. Nocturia is fairly common and thought to be secondary to atrial naturetic peptide release in response to apnea-related right atrial stretch. A sensation of choking or dyspnea is reported in up to 30 percent of patients and may be due to increased pulmonary wedge pressure associated with enhanced right heart filling amid apneic events. Bed partners are crucial informants of nocturnal events. A detailed history from bed partners is imperative in all cases of suspected or undiagnosed sleep apnea. Snoring is the cardinal complaint reported by the bed partner. Typically, the snoring is loud, nightly, and has existed for many years. Snoring may be so disruptive that partners may be driven to sleep in another room. A bed partner may report a witnessed apnea that is often followed by loud snorts or gasps at the end of apneic episodes. This can be extremely concerning to the partner and serve as the trigger to seek medical attention. Occasionally, during the arousal that terminates the apneic event, the bed partner may witness arm flailing, other gross movements, or strange behavior.

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Repetitive apneic events are not conducive to restorative sleep. OSA patients experience a reduction in slow wave sleep (stage 3 and 4 or delta) and REM compared with normal age-matched controls due to apnea-related sleep fragmentation. Thus, individuals with sleep apnea are not refreshed upon waking in the morning. Morning headache is a less common manifestation of sleep apnea. If reported, one must consider the possibility of hypercapnia secondary to obesityhypoventilation syndrome. Excessive daytime sleepiness is a chief clinical consequence among patients with OSA. Typically the excessive daytime sleepiness of apneics occurs following meals, while sitting in a car as a passenger, watching television, reading, and during conversation. Driving is particularly problematic in patients with sleep apnea. It is imperative to inquire about drowsy driving. It is not only risky to the patient but also to others on the road. Such patients may report falling asleep at red lights, drowsiness while driving, and in extreme cases motor vehicle accidents. In general, daytime sleepiness directly relates to the severity of sleep apnea. A standard instrument (Epworth Sleepiness Scale) is a useful tool to assess the degree of self-rated sleepiness (Table 97-3). A value above 10 is considered abnormal. The Epworth Sleepiness Scale (scored 0–24) is usually elevated in sleep apnea patients, indicating a propensity to fall asleep. The scale has been reported to correlate with the degree of physiologic sleepiness as measured by the multiple sleep latency test if the score is greater than 16. It is important to appreciate that the presence of excessive daytime sleepiness is neither a necessary nor sufficient condition for OSA: Many patients with AHI greater than 5 do not report daytime sleepiness and many subjects report sleepiness in the absence of sleep apnea (often secondary to sleep deprivation). Sleep apnea can also manifest symptoms related to cognitive impairment. Inattention and deficits in memory and concentration often affect ability to function at work. Fear of sleepiness may limit an individual’s willingness to integrate socially. Moreover, patients with sleep apnea and/or spouses can report irritability, depressive symptoms, and personality change. Sexual dysfunction, either decreased libido or impotence, is a common complaint for men. Physical examination of the patient with suspected OSAS focuses on neck circumference, obesity (BMI greater than 28 kg/m2 ), visualization of the pharynx to assess crowding, and soft tissue dimension (enlargement of the tongue, tonsils, lateral peritonsillar tissue, uvula, and palate), abnormalities of the shape and size of the craniofacial structures (retrognathia, micrognathia, cross-bite, narrowing of the hard palate, and dental malocclusion), and measurement of blood pressure. Neck circumference greater than 40 cm predicts OSA with a sensitivity of 61 percent and specificity of 93 percent, regardless of gender. In a historical cohort analysis of 422 subjects presenting to a sleep clinic, anatomic abnormalities were assessed by physical examination using predefined criteria. Analysis showed increased risk of OSA in patients with lateral narrowing of the airway (odds ratio equals 2.5; 95 percent confidence interval 1.6 to 3.9), tonsillar enlarge-

Table 97-3 Epworth Sleepiness Scale In contrast to just feeling tired, how likely are you to doze off or fall asleep in the following situations? (This refers to your usual life in recent times. Even if you have not done some these things recently, try to work out how they would have affected you.) Use the following scale to choose the most appropriate number for each situation: 0 = Would never doze 1 = Slight chance of dozing 2 = Moderate chance of dozing 3 = High chance of dozing Situation

Chance of dozing

Sitting and reading Watching TV Sitting inactive a public place (i.e. a theater or a meeting) As a passenger in a car for an hour without break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after lunch without alcohol In a car, while stopping for a few minutes in traffic Source: Johns MW: A new method for measuring daytime sleepiness: The Epworth sleepiness scale. Sleep 14:540–545, 1991.

ment (odds ratio 2.0; 95 percent confidence interval 1.0 to 3.8), and enlargement of the uvula (odds ratio equals 1.7; 95 percent confidence interval 1.2 to 2.9).

Screening for Sleep Apnea Inexpensive tools have been developed to assess the likelihood of apnea. Standardized questionnaires such as the multivariable apnea prediction (MAP) and simple tests, such as overnight pulse oximetry, have been evaluated. Three questions in the MAP pertaining to nighttime events have been shown to have excellent predictive power for the presence of sleep apnea. The three questions follow the same form. During the past month, have you had, or have you been told about, the following symptom: snoring or gasping; loud snoring; or breathing stops, choking or struggling for breath? The frequency of occurrence is indicated as follows: never (0); rarely, less than once per week (1); once or twice per week (2); three or four times per week (3); five to seven times per week (4); or don’t know. The total symptom score

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Table 97-4 Conditions in which Sleep Apnea Should be Suspected Systemic hypertension Obesity Myocardial infarction

Sleep Apnea Syndromes

Oximetry (Fig. 97-10) also can be used to screen for sleep apnea. Typically, patients with sleep apnea manifest a sawtooth pattern on nocturnal oximetry. However, overnight oximetry does not detect apneas, hypopneas, or arousal in the absence of significant oxygen desaturation, rendering the sensitivity of the test suboptimal. In addition, it has been shown that abnormal ambulatory overnight oximetry testing based on initial suspicion by general internists frequently does not lead to a sleep medicine referral or patient visit in the sleep clinic.

Cerebrovascular accident Pulmonary hypertension Type II diabetes mellitus Nocturnal cardiac arrhymthmias Driver involved in a sleep-related automobile crash Preoperative anesthesia evaluation

is computed and then combined with age, sex, and BMI to calculate a pretest likelihood of apnea. Such questionnaires are extremely useful to screen for sleep apnea, especially when coupled with further sleep apnea questioning and measurement of neck circumference. The situations where sleep apnea should be considered in evaluating patients are outlined in Table 97-4. Questions pertaining to sleep disorders should be performed in the review of systems of all patients.

DIAGNOSIS The diagnosis of OSA is established by polysomnography, i.e., a sleep study. Four types of polysomnography (PSG) based on supervision and diagnostic equipment can be employed. An â&#x20AC;&#x153;attended PSG,â&#x20AC;? a level I study, records the following variables while the subject is asleep: electroencephalogram (EEG) to monitor sleep states, electrooculogram (EOG) for monitoring eyes, electromyogram (EMG) for muscle tone (all three of these variables help to distinguish REM [muscle atonia, rapid eye movements, saw tooth waves on the EEG] from NREM sleep); respiratory airflow by nasal probe and differential pressure transducer; respiratory effort (e.g., by bands placed around the chest and abdomen); arterial oxygen saturation; and EMG of the anterior tibialis muscles to monitor for the presence of periodic leg movements during sleep (Fig. 97-11). Measurements obtained from such instruments are integrated to record sleep stage and the presence of apneas, hypopneas, and snoring-related arousals. The AHI is calculated from the number of apneas plus hypopneas per hour. Level II and III studies are unattended studies and are

Figure 97-10 Nocturnal oximetry pattern in a patient with obstructive sleep apnea. This patient manifests recurrent oxyhemoglobin desaturations which are most severe in REM sleep. Oximetry calibrated from 0 to 100 percent. Paper speed each small line one minute; each dark black line 5 minutes.

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Figure 97-11 Example of an obstructive apneic episode in a patient with sleep apnea syndrome in stage 2 sleep. The polysomnography traces from the top down are as follows: three EEG channels (C3-A2, C4-A2, OZ-A2); two EOG channels (R and L); submental electromyogram (EMG); right and left anterior tibialis EMG (RAT, LAT), electrocardiogram (EKG); nasal and oral airflow; chest and abdominal motion (chest & abd). During the apneic episodes, there is abnormal airflow (both oral and nasal) with paradoxical motion of the rib cage and abdomen. At the end of the apneic episode there is a burst of EMG activity at the arousal. Following the arousal, respiration resumes with synchronous movements of the rib cage and abdomen.

differentiated by the number of variables measured. The former is a complete non-attended home study and measures the same parameters as a level I study. The latter is a partial home study that typically includes measurement of airflow, respiratory effort, pulse, and sleep position. No information is available on sleep staging; therefore, stage-related events are not detectable. A level IV study is a very limited home study that may measure only one or two parameters, such as pulse rate and oximetry. A typical diagnostic polysomnogram (PSG) entails a whole night of recording during sleep. Patients found to have sleep apnea return on a subsequent night for a second sleep study during which the level of CPAP (continuous positive airway pressure) necessary to abolish SDB events is determined by titration. A “split night” study combines the diagnostic and treatment studies into one night (Figs. 97-12 and 97-13). The scientific rationale for split-night polysomnography is that the AHI in the first half of the night is indicative of the whole night of study; in addition, split-night studies are more cost effective and efficient than two-night studies. The evidence assessing the split-night strategy is comprised predominantly of case series and case control studies in severe OSA patients. Based on this current evidence,

split-night polysomnography appears to be a legitimate alternative to full-night titration studies in specific settings. Patients with a high pretest probability for OSA are more likely to be accurately diagnosed and titrated with a splitnight study, especially if greater than 3 hours of sleep are recorded. An absence of REM sleep and/or less than 3 hours of sleep recorded during a split-night study can lead to significant underestimation of sleep apnea severity. Split-night polysomnography is effective in approximately 78 percent of patients. Certain patients may require a second night study to optimize CPAP therapy. Concerns over suboptimal CPAP titration and poorer CPAP adherence, due to reduced contact with sleep staff, have been expressed with regard to split-night studies. To increase patient access and reduce costs related to diagnosis, portable polysomnography has been designed so that studies may be performed unattended in the patient’s home. Many investigators have reported comparable results with portable studies to “in-lab” polysomnography. However, specific comparisons between in-lab and portable studies are difficult because of variation in definition of events, parameters measured, and threshold of events to diagnose sleep apnea. The portable monitor often

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Figure 97-12 Example of a sleep study epoch from a split night sleep study in a patient with severe apnea. The epoch is viewed at 300 seconds. This patient has recurrent apneic events associated with oxyhemoglobin desaturations (recurrent dips in the red line). At the bottom of the figure is a hypnogram displaying the sleep data from the entire night. The black arrow in the hypnogram shows the time frame for the specific epoch displayed in the top portion of the figure. Later on in the night the patient is started on CPAP and the recurrent apneas and oxyhemoglobin desaturations are abolished (the recurrent desaturations: red lines noted in the hypnogram resolve). C4 and OZ are EEG leads; ROC and LOC are the right and left ocular leads); RAT and LAT are the right and left anterior tibialis electromyograms; SaO2 is the oximetry lead.

does not measure several elements that may be recorded by polysomnography: sleep stage, sleep position, and respiratory-related arousals. The underestimation of RERAs reduces the sensitivity of the portable study: A negative study cannot confidently exclude OSA. The American Sleep Disorder Association (ASDA) states that unattended recordings are acceptable only when the following conditions are met: 1. Clinical symptoms are severe and indicative of sleep apnea, and the initiation of treatment is urgent and standard polysomnography is not available. 2. The patient cannot be studied in the sleep laboratory. 3. Recordings are intended for follow-up studies in which the diagnosis has been previously established and therapy has been initiated. Although unattended studies (levels II and III) may prove to be cost effective and more patient friendly, Medicare and Medicaid do not recognize portable systems as legitimate means of testing at this point in time, even though

some health maintenance organizations have begun to recognize these portable monitoring systems in their diagnostic algorithms. Many different portable monitoring devices are available; however, a majority has only been validated in patients with a high pretest probability of sleep apnea. Most devices correlate closely with in-lab polysomnogram findings, although concerns about misclassification and failure in detecting sleep apnea have been reported. In-lab polysomnography represents the gold standard for diagnosing sleep apnea. However, excessive focus on the significance of elevations in AHI to diagnose OSA hampers the assessment and diagnosis of such patients. Patients may exhibit similar AHI, but experience dramatically different quality of sleep and outcomes. Oxygen desaturation, number of arousals, and apnea/hypopnea length are examples of other important variables not reflected by the AHI. Furthermore, it is not the AHI itself but the consequences (hypertension, myocardial infarction, stroke, cardiac arrhythmias, excessive daytime sleepiness) of sleep apnea that are of paramount importance.

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Figure 97-13 Split night hypnogram in a patient with obstructive sleep apnea. The patient has frequent hypopneas with recurrent oxyhemoglobin desaturations until he is started on CPAP at midnight. The CPAP was titrated to 14 cm H2 O, which abolished the hypopneas and oxyghemoglobin desaturations.

The AHI events can be stratified by a subjectâ&#x20AC;&#x2122;s position of sleep and stage of sleep (NREM vs. REM). In general, obstructive events are most severe in the supine position and during REM sleep. REM-related apnea is common in premenopausal women.

CONSEQUENCES OF SLEEP APNEA The number of recognized associations with sleep apnea has increased considerably and can be categorized broadly into neurocognitive and cardiovascular consequences. Fig. 97-14

is a simplified representation of three principal disturbances associated with apnea during sleep, the proposed downstream pathophysiological mechanisms, and reported clinical consequences. We acknowledge that this is not a complete depiction of all that is known, and that many factors operate in a complex interplay that can jointly augment health risk. For instance, hypertension is known to increase the risk of stroke and coronary artery disease. In addition, hypoxia and compromised breathing efforts during apnea are also believed to be stimuli for arousal from sleep. Nevertheless, the scheme provides a basic framework for the reader to understand the operative sequelae of apneic events and how they may interact.

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Sleep Apnea Syndromes

Apnea/Hypopnea

Sleep fragmentation

Hypoxemia

Negative intrathoracic pressure

•Sympathetic surge •Hemodynamic effects on CV system •Oxidative stress •Inflammation •Endothelial dysfunction •Hypercoagulability •Endocrine dysregulation

Sleepiness -crashes -QOL

Neurocognitive effects -cognitive function -executive function -QOL

Cardiovascular disease -Htn -Arrhythmia -CAD -CVA -CHF -Pulm htn

Endocrinopathy -DM -Insulin resistance

Figure 97-14 Flow chart of the proposed pathophysiologic mechanisms and consequences of obstructive sleep apnea. Abbreviations: CV, cardiovascular; QOL, quality of life; Htn, hypertension; Pulm htn, pulmonary hypertension; CHF, congestive heart failure; CVA, cerebrovascular accident; DM, diabetes mellitus.

Neurocognitive Consequences of OSA

Cardiovascular Consequences of OSA

Excessive daytime sleepiness and sleep fragmentation associated with sleep apnea lead to diminished cognitive function affecting attention/alertness, learning and memory, and executive function. Such adverse effects lead to a poorer quality of life as revealed by general instruments, such as the Short Form-36. Treating such patients is associated with improvement in vitality using the SF-36. A dramatic consequence of sleep apnea and its associated daytime sleepiness is the increased risk of motor vehicle accidents. A recent meta-analysis reported the average odds ratio for subjects with sleep apnea syndrome for having a crash at 2.5. Sleep apnea patients have been shown to be as impaired in driving skills as are those with blood alcohol concentrations in excess of legal limits. These findings raise important issues for practitioners in deciding about driving safety. A majority of the United States lacks explicit laws stating that such patients should be reported to the department of transportation. Texas, California, and all Canadian provinces require physicians to notify state motor vehicle authorities of patients diagnosed with sleep apnea. It is unclear if such a reporting system will have the desired effect of reducing crashes or whether it will discourage persons with sleep apnea from seeking treatment for fear of losing their drivers’ license. The ATS (American Thoracic Society) recommends that patients be reported to their state department of transportation only if they have been involved in a motor vehicle accident caused by falling asleep at the wheel or if they refused treatment for sleep apnea. Documentation of appropriate counseling to patient about the dangers of driving is also recommended. Transfer of responsibility to the patient is imperative after recommendations for treatment and safe driving practices have been undertaken.

A number of cardiovascular consequences of sleep apnea have been reported. These are discussed individually, although they share common and complex pathophysiology. Obstructive apneas result in intermittent but recurrent hypoxia, repetitive arousal, and large swings in pleural pressure. These processes lead to an array of maladaptive mechanisms: sympathetic surges, oxidative stress, inflammation, vascular endothelial dysfunction, metabolic dysregulation, and mechanical effects on the heart and vessels. Each of these physiologic responses to apnea has been the focus of detailed research and requires further reading beyond the scope of this chapter. Nevertheless, it is evident that sleep apnea can induce physiological processes that are conducive to the development of cardiovascular disease. Markers of inflammation such as tumor necrosis factor-α and C-reactive protein are also elevated in OSA. Overall, currently available literature supports a strong relationship between sleep apnea and cardiovascular disease. Hypertension Data for the cardiovascular risk of OSA are most compelling for systemic hypertension. A canine model of sleep apnea demonstrated that intermittent occlusion of a tracheostomy leads to the development of hypertension. Large cross-sectional studies have showed that OSA is associated with hypertension. In the Sleep Heart Health Study, the odds ratio for the presence of hypertension in the highest category of AHI (greater than 30 events/hour) was 1.37 compared with the lowest category AHI (less than 1.5 events/hour). The Wisconsin Sleep Cohort Study, a prospective populationbased study conducted by Peppard et al., demonstrated an

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Figure 97-15 Example of Cheyne-Stokes respiration, a pattern of periodic breathing in which intervals of hyperpnea alternate with intervals of apnea. Respiration waxes and wanes in a crescendodecrescendo pattern. Normally the hyperpneic phase of Cheyne-Stokes respiration is longer than the apneic phase.

increased risk of incident hypertension in patients with OSA, even at low levels of severity (AHI 5–15 events/hour). Independent of BMI, the odds ratio was 2.0 for mild (AHI 5–15 events/hour) and 2.9 for more severe sleep apnea (AHI greater than or equal to 15 events/hour) over a 4- to 8-year follow-up period. The prevalence of sleep apnea is high in patients with drug-resistant hypertension. Logan studied subjects with hypertension who were all taking optimal doses of at least three antihypertensive agents and found an OSA prevalence of 83 percent, with a mean AHI of 25 events per hour. There are also data showing improvements in blood pressure in randomized trials with CPAP. In these studies blood pressure was significantly lowered not only in patients with resistant hypertension, but also in patients with relatively mild hypertension. Two randomized placebo-controlled trials in which placebo consisted of subtherapeutic levels of CPAP, demonstrated that several weeks to months of CPAP resulted in a significant reduction in daytime blood pressure between 1.3 to 5.3 mmHg. This may appear to be a modest improvement; however, drawing upon literature using conventional antihypertensive agents in the non–sleep apnea population, a 5 mmHg drop in diastolic blood pressure is associated with a 42 percent reduction in stroke and 14 percent reduction in coronary artery disease within a 5-year period. The beneficial effects of CPAP on hypertension, however, should not detract from emphasis on conventional pharmacologic methods of lowering blood pressure. Other Cardiovascular Consequences of Sleep Apnea A number of cardiovascular outcomes are adversely affected by sleep apnea. The Sleep Heart Health Study, a study of approximately 6000 subjects, demonstrated that the presence of OSA (AHI greater than 11 events/hour) was associated with a 2.39 odds ratio ( p = 0.002) for congestive heart failure, 1.27 ( p = 0.004) for coronary artery disease, and 1.58 ( p = 0.03) for stroke. The Nurses Health Study demonstrated that selfreported snoring at baseline was an independent risk factor for the development of coronary artery disease 8 years later, after controlling for confounding variables. Marin and associates reported data from a non-randomized controlled observational study of sleep clinic subjects and a community sample of healthy subjects without OSA with a mean followup 10 years. Untreated severe (AHI greater than or equal to

30 events/hour) OSA patients had a 2.9-fold increased rate of fatal cardiovascular events after adjusting for confounding variables. Gami reports an alteration in the day-night pattern of sudden cardiac death in individuals with obstructive sleep apnea, i.e., more deaths occurred at night from midnight to 6 am as compared with the general population. In fact, the risk of sudden death was increased with increasing severity of sleep apnea; individuals with an AHI greater than pr equal to 40 events/hour were more than 2.5 times more likely to experience sudden cardiac death during these nighttime hours than those without OSA. OSA is also associated with systolic and diastolic heart failure. Among CHF patients with diastolic dysfunction and preserved systolic function, OSA was found in 35 percent of subjects. Cheyne-Stokes respiration (Fig. 97-15) and central sleep apnea (CSA-CSR) is a less common form of sleepdisordered breathing usually demonstrated in patients with congestive heart failure. Cheyne-Stokes respiration (CSR) is characterized by periodic breathing in which apnea and hyperpneas alternate with ventilatory periods. Sympathetic neural drive is increased when compared with heart failure patients without CSA. CSA occurs as a result of CHF-related fluctuation in alveolar ventilation, changes in sleep state and hypoxemia. Such physiologic circumstances lower the PaCO2 below a highly sensitive apnea threshold leading to breathing cessation that persists until PaCO2 rises above the threshold required to stimulate breathing. This is typically 4 to 5 mmHg above normocapnia. CSR-CSA is important, as it has been shown to be associated with poorer outcome in CHF patients. It should be noted that the prevalence of CSA is less now than in the past. This is most likely related to the relatively recent widespread use of beta-blocker agents in the management of heart failure patients. Sleep apnea is also associated with arrhythmias. A majority of the arrhythmias are benign (bradycardia/tachycardia [bradycardia during the apnea and tachycardia during the arousal], atrial and ventricular ectopy), especially if the cardiac substrate is normal. However, all types of cardiac arrhythmias (e.g., heart block, nonsustained ventricular tachycardia, atrial fibrillation) have been reported. Data from the Sleep Heart Health Study have shown that patients with OSA had a higher prevalence of non-sustained ventricular tachycardia, complex ventricular ectopy, and atrial fibrillation. Using a validated screening tool, a high prevalence of OSA in patients

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with atrial fibrillation has been reported. These results support an earlier study by that showed higher 1-year recurrence rates of atrial fibrillation in untreated OSA patients compared with subjects who were treated with CPAP. OSA is common in patients who suffer a stroke, with a prevalence of 60 to 80 percent. The largest trial examining the relationship demonstrated that those subjects with an AHI greater than 11 events/hour were 1.58-fold more likely to have reported a history of stroke compared with those with an AHI less than 1.4 events/hour. More recently, an observational cohort study that excluded subjects with prior history of stroke or myocardial infarction, reported that OSA patients had a statistically significant increased risk (hazard ratio, 1.97; 95 percent confidence interval) for stroke or death, after adjusting for demographic and vascular factors. Investigations of OSA patients at night have demonstrated elevations of transmural pulmonary artery pressure at the termination of apneas. The mechanisms postulated are hypoxia, hypercapnia, and intrathoracic pressure swings related to apnea. Therefore, the question is: Do nighttime elevations lead to pulmonary hypertension in the daytime? Pulmonary hypertension has been reported to be a complication of OSA, although studies are disparate with respect to their inclusion criteria. In general, patients with OSA and pulmonary hypertension tended to be older, heavier, and have worse lung function compared with patients with OSA and without pulmonary hypertension. A majority of studies employ a lower threshold (mean pulmonary artery systolic greater than 20 mmHg) for diagnosis of pulmonary hypertension, thereby overestimating the true association. Sleep apnea appears to be associated with, at worst, mild daytime pulmonary hypertension. However, in patients with pulmonary hypertension sleep apnea needs to be investigated since the nocturnal hypoxemia associated with the apneas can exacerbate the pulmonary hypertension. Treatment of OSA with CPAP likely is associated with a decrease in pulmonary artery pressures, but randomized trials need to be performed to confirm this. Finally, the relationship between SDB and metabolic derangements such as insulin resistance has received increasing attention. A ninefold increase in the prevalence of metabolic syndrome has been reported in OSA subjects compared with controls. A subgroup matched by BMI with controls demonstrated an approximately 40 percent absolute increase in the prevalence of metabolic syndrome ( p < 0.001). OSA and the metabolic syndrome share common pathophysiologic profiles; OSA is associated with disturbance in all of the main components of the metabolic syndrome: central obesity, hypertension, insulin resistance, and dyslipidemia. The relationship, whether synergistic or one syndrome leading to the other, remains to be clarified. However, considerations of OSA as a fifth component of the metabolic syndrome merit future work. Type II diabetes has been associated with sleep apnea also. Several cross-sectional and case-controlled studies report an association between SDB and the development of diabetes. Treatment with CPAP has not uniformly been shown

Sleep Apnea Syndromes

to improve glucose tolerance or insulin resistance. Although these studies suggest an association, the question remains whether diabetes is a cause and/or consequence of SDB. CPAP therapy for OSA patients has been examined in multiple studies for various cardiovascular disorders. Intervention trials employing CPAP have shown improved outcomes with respect to hypertension, left ventricular ejection fraction, diastolic dysfunction, cardiovascular events, and mortality. Further supporting evidence can be derived from improvements in serum markers, such as C-reactive protein and interleukin-6, which have been associated with cardiovascular morbidity.

Economic Consequences of OSA Sleep apnea poses a sizeable economic burden on society. It is a common condition, under-recognized and under-treated. OSA subjects have been demonstrated to utilize health care resources at approximately twice the rate of controls as far back as 10 years prior to diagnosis. Estimates of the total economic cost that sleep apnea confers upon society are sparse, however, a recent analysis estimated the burden of sleep disorders in the United States to be $109 billion based on a US population of 293 million in 2004. Limited numbers of sleep laboratories, sleep physicians, and sleep technologists coupled with cost of equipment and reimbursement issues have created a â&#x20AC;&#x153;bottleneckâ&#x20AC;? effect in which global demand for sleep medicine services exceeds capacity. Nevertheless, cost-effective ratio analysis by Ayas shows that addressing diagnosis and treatment of sleep apnea is economically attractive.

TREATMENT First-line therapy for sleep apnea syndrome remains medical. The medical treatment options are listed in Table 97-5.

Table 97-5 Medical Treatment of Obstructive Sleep Apnea General measures Avoidance of alcohol, sedatives, and hypnotics Weight loss Specific measures to increase upper airway caliber Position therapy Positive airway pressure CPAP Bilevel systems Auto-CPAP Oral appliances

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General Measures Patients with sleep apnea should avoid alcohol, sedatives, and hypnotics. Alcohol and benzodiazepines reduce upper airway muscle tone and increase the severity of snoring and apneas. Hypnotics and sedatives also depress the arousal mechanisms, thereby prolonging the apneas and causing greater oxygen desaturations. Maintaining a consistent bedtime and wake-up time as part of good sleep hygiene also is important in sleep apnea patients. Sleep deprivation can reduce hypoxic and hypercapnic respiratory drive and prolong apnea duration. Sleep fragmentation can be minimized by avoiding ingestion of stimulants (e.g., caffeine), alcohol, sedatives, and night exercise.

Weight Loss Weight loss should be recommended in all overweight patients with OSA. Decreasing body weight is a logical target to reduce OSA burden but also to improve a range of health outcomes and quality of life. Weight loss theoretically mitigates the collapsibility of the airway by reducing the extraluminal pressure associated with excess soft tissue and by reducing the encroachment conferred by enlarged airway structures such as the tongue and soft palate. The extent of weight loss and degree of improvement are not always directly related, although it has been shown that a 1 percent change in weight is associated with a 3 percent change in AHI. In cases of dramatic weight loss by extreme dieting or surgery, OSA severity is improved and in some patients abolished. Dietary weight loss remains challenging; therefore, achieving and maintaining a target body weight is difficult. Bariatric surgery, as a potential treatment modality for sleep apnea, has shown impressive short-term improvement in OSA severity and should be considered in apneics with a BMI greater than 35 mg/kg2 . However, recurrences of OSA after several years have been described in the setting of only modest weight gain.

(Theo-Dur), doxapram (Dopram), and almitrine (Doxil) have been investigated. These agents are primarily centrally acting, except theophylline and medroxyprogesterone, which are arguably the most widely studied. Theophylline is reported to confer salutatory effects on the airway musculature and diaphragm at lower doses and central respiratory center stimulation at higher doses, indicating a differential effect on the respiratory system based on the dose. When compared with CPAP treatment, both theophylline and medroxyprogesterone, have demonstrated inferior efficacy. Nevertheless, many authors have reported variable improvement in apnea index with use of these agents. Caffeine, modafinil, nicotine, and cannabinoids have been studied based on their actions on various central excitatory pathways; however, there are no data supporting improvement in apnea index. The key point is that pharmacotherapy does not significantly improve apnea index, but several agents (hypnotics, benzodiazepines, narcotics) are well known to worsen sleepdisordered breathing. Inquiry about these medications, especially benzodiazepines, is important when evaluating patients with sleep apnea.

Oxygen Therapy Oxygen has a limited role in the treatment of sleep apnea syndrome. Although oxygen desaturation may be mitigated by the delivery of oxygen, arousal threshold consequently may be delayed, thereby prolonging apnea and exacerbating the overall sleep fragmentation. Patients with coexisting obstructive lung disease can manifest respiratory acidosis as a consequence of supplemental oxygen. Thus, oxygen alone does not have a role in the treatment of OSA. However, it can be useful in patients who experience significant reductions in nocturnal oxyhemoglobin independent of apneas to avoid cardiovascular complications.

Pharmacologic Treatment

Nasal Dilators

An extensive list of pharmacologic agents has been investigated with obstructive sleep apnea, including antidepressants, respiratory stimulants, central nervous system stimulants, and hormones. Most results have been inconclusive, based on the strength of data or disappointing outcomes. Selective serotonin reuptake inhibitor agents such as paroxetine (Paxil) and fluoxetine (Prozac) have been shown to increase genioglossal muscle activity and decrease REM sleep (apneas are more common in REM), although this has not translated to a reduction in AHI in apnea patients. Protriptyline (Vivactil), an agent that decreases the amount of REM sleep, has inconsistently shown positive effects on symptoms and apnea burden. Anticholinergic side effects such as dry mouth, constipation, and urinary retention can be troublesome and limit its consideration to the occasional patient whose apnea is primarily REM related. Several respiratory stimulants, including acetazolamide (Diamox), medroxyprogesterone (Provera), theophylline

External and internal nasal devices have been proposed as a treatment for snoring and sleep apnea by increasing nasal cross-sectional area and reducing nasal resistance. However, since snoring and apnea originate predominantly in the retropalatal or retroglossal region, nasal dilators are not effective in treating patients with OSA. Existing data do not support their use; however, treatment of nasal congestion symptoms with humidification and nasal steroids is important in patients who develop rhinitis associated with nasal CPAP treatment.

Specific Medical Therapies Position Therapy Sleep in the supine position is more conducive to airway obstruction by virtue of gravityâ&#x20AC;&#x2122;s effect on the tongue. Polysomnography often demonstrates position-dependent sleep apnea with a high AHI in the supine position but not

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in the lateral position. For patients with position-dependent sleep apnea, symptoms may be alleviated by promoting sleep in the lateral decubitus position. This can be accomplished by sewing pockets for tennis balls to the back of night attire. Devices to train people to sleep in the lateral position have been described. Raising the head of bed angle to between 30 and 60 degrees has been studied; however, it is unclear if its effects reach beyond promoting airway stability to actually reducing AHI. Pharyngeal Muscle Stimulation This treatment modality is still in the developmental research stage. The strategy is to electrically stimulate the hypoglossal nerve to enhance phasic activity of the upper airway pharyngeal dilator muscles, thereby increasing airway patency during sleep. More studies need to be performed with this modality. CPAP Sullivan first described the use of nasal CPAP to treat OSA (see examples of subject wearing CPAP in Fig. 97-16), and it has remained the treatment of choice for patients with sleepdisordered breathing. CPAP can be applied through a nasal mask, nasal inserts, or a full-face mask (covers the nose and mouth). The full-face mask should be used in patients who breathe through their mouth during sleep. (Typically these patients complain of a dry mouth in the morning.) CPAP has the advantage of being noninvasive and has been shown to reduce the number of apneic and hypoxic episodes during sleep. It also reduces daytime sleepiness and improves neuropsychiatric function in patients with OSA. CPAP is indicated in all patients with an AHI greater than 30 events/hour and in those patients with an AHI of 5 to 30 events/hour with associated symptoms, including excessive daytime sleepiness,

Figure 97-16 Examples of subjects connected to a CPAP unit wearing three different CPAP interfaces: A. the subject is wearing a nasal inserts which fit directly into the nostrils; (B) the subject is wearing a nasal CPAP mask; and (C) the subject is wearing a full face mask (nose and mouth are both covered). With all three types of interfaces it is essential to ensure a good seal with minimal leaks.

impaired cognition and mood disorders, insomnia, and cardiovascular disorders (hypertension, ischemic heart disease, CVA). CPAP operates by providing a pneumatic splint for the airway, thereby preventing collapse during sleep, when upper airway muscle dilator activity is reduced. The effect of CPAP on upper airway caliber and the surrounding soft tissue structures is shown in Figs. 97-17 to 97-20. CPAP increases airway caliber in the retropalatal and retroglossal regions; in particular, it increases the lateral dimensions of the airway and thins the lateral pharyngeal walls. Technologists determine the optimal pressure during a titration polysomnography. Typically, 5 to 20 cm H2 O is the pressure needed to abolish apneas, snoring, and oxyhemoglobin desaturation in all positions and during REM sleep. CPAP is usually applied through a nasal mask or nasal pillows, which insert into the nostrils (Fig. 97-16). It is important to ensure that the patient has a well-fitting interface with the CPAP machine absent of air leaks. Mouth leaks render CPAP ineffective, since the high flow through the nose generated by the CPAP unit escapes through the mouth. In such situation, full-face masks that cover the mouth and nose can be helpful (Fig. 97-16). Heated humidity is used very frequently with the prescription of CPAP therapy. It has been shown to successfully ameliorate side effects of CPAP listed in Table 97-6, but this has not translated into uniform improvements in adherence to CPAP. Over the last 15 to 20 years, the CPAP equipment and masks have become increasingly user friendly. The machines are smaller, portable, and quieter, and also allow data capture of patient adherence and CPAP efficiency. It is important that CPAP adherence is followed. CPAP masks have improved profoundly so the prospect of using CPAP has become much less daunting. It is important to note that patients

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Figure 97-17 Three-dimensional surface renderings of the upper airway from magnetic resonance images in a normal subject with progressively greater continuous positive airway pressure (CPAP) (0–15 cm H2 O). Upper airway volume increases significantly in both the retropalatal (RP) and retroglossal (RG) regions with higher levels of CPAP. (Reproduced with permission from Schwab RJ, Pack AI, Gupta KB, et al: Upper airway and soft tissue structural changes induced by CPAP in normal subjects. Am J Respir Crit Care Med 1996;154:1106–1116.)

often have a preconceived prejudice against CPAP therapy, as they may have previously seen or used older masks. Hospital CPAP masks are often few in choice and usually of the older type. Other strategies to improve patient comfort include the ramp device and devices that reduce pressure in expiration, such as C-flex (Respironics, Murrysville, PA) or EPR (expiratory pressure relief, ResMed Corp., Poway, CA). CPAP units with a ramp device achieve target CPAP pressures with grad-

ual increases over 15 to 45 minutes, allowing sleep onset at a more comfortable pressure level; however, improvement in CPAP use has not been demonstrated. Furthermore, overuse of this option by repeated resetting of the ramp during the night has been reported. C-flex or EPR are algorithms designed to improve patient comfort by reducing CPAP during early exhalation. Some institutions operate “mask clinics” concomitantly with sleep clinics so that patients with OSA can be fitted for a CPAP mask immediately after the sleep

Figure 97-18 Axial retropalatal magnetic resonance imaging in a normal subject (same subject as Fig. 97-17) at two levels of continuous positive airway pressure (CPAP) (0 and 15 cm H2 O). Airway area is significantly greater at 15 cm H2 O than without CPAP. The increase in upper airway caliber with the application of CPAP is predominantly in the lateral dimension. (Reproduced with permission from Schwab RJ, Pack AI, Gupta KB, et al: Upper airway and soft tissue structural changes induced by CPAP in normal subjects. Am J Respir Crit Care Med 1996;154:1106–1116.)

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Figure 97-19 Axial retropalatal magnetic resonance imaging (MRI) in a normal subject (the same subject as in Figs. 97-17 and 97-18) with continuous positive airway pressure (CPAP) ranging from 0 to 15 cm H2 O. With increasing CPAP there is a progressive increase in the size of the upper airway, particularly in the lateral dimension (the anteriorposterior dimensions of the airway do not change significantly with CPAP). There is little movement of the parapharyngeal fat pads (white structures lateral to the airway) but progressive thinning of the lateral pharyngeal walls. (Reproduced with permission from Schwab RJ, Pack AI, Gupta KB, et al: Upper airway and soft tissue structural changes induced by CPAP in normal subjects. Am J Respir Crit Care Med 1996;154:1106â&#x20AC;&#x201C;1116.)

specialist consultation. No outcome data are available on this emerging strategy. CPAP use is associated with few serious side effects. Common side effects are listed in Table 97-6. Most of these side effects can be alleviated. Nasal irritation and rhinitis are treated with heated humidification and consideration of a nasal steroid spray. Claustrophobia may be relieved by in some case by changing the type of mask. Aerophagia can be amelio-

rated by altering body position or mask type. Serious adverse effects are uncommon but include reports of severe epistaxis, meningitis, and pneumocephalus. Adherence to CPAP therapy is variable and ranges in most studies from 60 to 85 percent. Estimates from a number of studies suggest that patients use the treatment, on average, for 4 to 5 hours per night. Weaver et al. have reported that patterns of CPAP usage declare themselves within the first weeks

Figure 97-20 Mid-sagittal magnetic resonance imaging of a normal subject (the same subject as in Figs. 97-17 to 97-19) at two levels of continuous positive airway pressure (0 and 15 cm H2 O). There is very little increase in airway caliber with the application of CPAP since CPAP does not significantly affect the anteriorposterior structures. (Reproduced with permission from Schwab RJ, Pack AI, Gupta KB, et al: Upper airway and soft tissue structural changes induced by CPAP in normal subjects. Am J Respir Crit Care Med 1996;154:1106â&#x20AC;&#x201C;1116.)

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Table 97-6 Complications Associated with CPAP Nocturnal arousals Rhinitis, nasal irritation, and dryness Aerophagia Mask and mouth leaks (dry mouth in morning) Facial skin discomfort Difficulty with exhalation Claustrophobia Chest and back pain

of therapy with “consistent users” (CPAP greater than 90 percent of nights per week) and “intermittent users” (skipped CPAP use 1 or more nights per week). This pattern, established in the first week, has been reported to remain stable at 1 to 3 months for both groups of patients. Reported predictors for long-term CPAP therapy include snoring history, AHI, and Epworth Sleepiness Score. Regular use in the first 3 months of CPAP therapy appears to be strongly indicative of long-term use. The appropriate CPAP dose (duration and pressure level of CPAP therapy) required for an acceptable outcome remains to be clarified. It is imperative that patients continue to be followed regularly even though they may be long-term users of CPAP. “Perceived benefit” has been shown to be a strong predictor of CPAP use; therefore, it is the health care provider’s responsibility to re-emphasize this. In addition to CPAP, positive airway pressure can be delivered via bi-level systems and automatically titrating systems. Bi-level machines may be used when patients report difficulty with exhaling against positive airway pressure. Bi-level systems allow independent adjustment of inspiratory and expiratory pressure. However, the bi-level systems are more expensive and evidence is lacking in terms of better adherence and treatment outcomes when compared with CPAP. There is limited evidence that patients with coexisting lung disease or respiratory acidosis demonstrate improved gas exchange with the use of bilevel positive airway pressure compared with CPAP. Autotitrating CPAP, or auto-CPAP, adjusts CPAP throughout the night by detection of airway flow, snoring, apneas, inspiratory flow limitation (Fig. 97-21), and airway vibration (snoring). Each auto-CPAP unit uses a different algorithm for abolishing apneas. Currently auto-CPAP devices are used in patient homes as treatment or the sleep laboratory to determine the ideal CPAP setting to be used at home by the patient’s conventional fixed-pressure CPAP unit. Pop-

Figure 97-21 Schematic diagram showing the normal pattern of airflow during inspiration and that which occurs when there is inspiratory flow limitation. In the latter the flow quickly reaches a level that is maintained relatively constant throughout inspiration. This pattern of airflow can be detected by computers built into auto-CPAP units.

ularity for their use is growing among patients and physicians since the auto-CPAP units can be used to evaluate patients who are having difficulty tolerating conventional CPAP. The auto-CPAP devices can determine the optimal CPAP setting, quantify a mask leak, and measure patient adherence. Nonetheless, patient adherence does not appear to be significantly improved with chronic use of auto-CPAP. However, the cost of one auto-CPAP unit is one-third the cost of one in-laboratory study, and investigators have reported effective therapy with empirical pressures set between 8 and 12 cm H2 O. Intraoral Devices Although CPAP represents the gold standard for treating OSA, many patients are intolerant of it because of the described side effects. During the last decade, increasing attention has focused on the intraoral devices as an alternative treatment to CPAP. Dentists have become more attuned and involved in the treatment of OSA, resulting in the growth of research in this field and the formation of the Academy of Dental Sleep Medicine (ADSM). From a patient perspective, based on randomized trials, the oral appliance is a reasonable option. The effectiveness compared with CPAP appears to be the central issue, particularly for patients with severe OSA. A recent report by the AASM updated recommendations for the use of oral appliances for the treatment of snoring and OSA based on the literature. The oral appliances have undergone considerable evolution in their design, comfort, and effect on airway structures in the past three decades. The tongue retaining device (TRD) developed in the 1980s by Samelson was designed to maintain the tongue in a forward position during sleep. Two other types of devices are palatal lifting devices and mandibular advancing devices, the latter being the most studied (see example of mandibular advancing device, Fig. 97-22).

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Figure 97-22 Example of an adjustable mandibular repositioning device (Klearway appliance, University of British Columbia, Vancouver, Canada). This device fits on the upper and lower teeth; it is worn during sleep and results in anterior motion of the mandible with consequent enlargement of the airway. The appliance is adjusted until the sleep disordered breathing improves.

Oral devices aim to alter the position of the upper airway structures, thereby enlarging airway caliber or reducing its collapsibility. Cephalometry has confirmed that mandibular advancing devices increase upper airway dimensions, and it has been proposed they may also increase the tone of the upper airway, thereby opposing its tendency to collapse. The devices produce downward rotation and advancement of the mandible to increase the size of the posterior airway space predominantly in the anterior-posterior orientation. However, recent studies have reported increases in the lateral dimension of the upper airway, suggesting that the biomechanical changes induced by oral appliances are complicated. A number of devices are presently available for snoring and/or sleep apnea and only some these are approved by the Food and Drug Administration (FDA). Many devices are custom-made for the client following a dental or maxillofacial surgery consultation. In choosing an oral device, attention to its adjustability (modifiable over time), titratability (ability to alter jaw position by adjusting the appliance), and provisions for temporomandibular joint support, tooth coverage, and jaw mobility are important.

The effectiveness of oral devices on treating snoring and OSA has been investigated in a multitude of studies. In general, snoring is improved or eliminated; however, this is mostly based on subjective reporting by the bed partner. The degree of improvement in apnea is variable when assessing outcome in terms of AHI. In patients with AHI greater than 20 events/hour, a substantial percentage do not benefit at all. Approximately 50 to 70 percent of all patients with sleep apnea may respond. Response, although indicative of a significant (50 percent) decrement in AHI, does not necessarily mean abolishment of apnea. Success with these devices appears to be heavily related to attention to the adjusting and titrating of the device once in situ. Achieving adequate mandibular advancement influences the extent of improvement in respiratory events. When compared with CPAP, oral devices have demonstrated inferior outcomes, although patient adherence has been higher in many cases. Studies indicate that oral devices may provide better outcomes when compared with surgery, and therefore should be considered as a less invasive option. Side effects of the oral devices include excessive salivation, dental misalignment, and jaw pain or damage. Jaw

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pain, a consequence of muscular activation in response to mandibular repositioning, is of concern but usually subsides with time. Mandibular repositioning devices should be used cautiously in patients with temporomandibular joint syndrome. At present, oral devices are indicated for patients with primary snoring, or mild-to-moderate OSA where weight loss and CPAP have not been viable options, and for those who are not surgical candidates. Severe OSA patients should have a trial of CPAP first based on lower success rates with oral appliances. Patients treated with an oral device are recommended to have follow-up polysomnography and dental visits.

Surgical Treatment of OSA Nasal CPAP, as discussed, is the first-line treatment for OSA. However, tolerance of CPAP, particularly in the long term, is challenging for many patients. Weight loss, a strategy known to decrease or eliminate apnea in obese patients, is difficult to maintain. Oral appliances may not be effective or tolerated. Surgery becomes a reasonable consideration when the preceding scenarios are present or the patient presents with particular anatomic defects, such as tonsillar hypertrophy. A variety of surgical options are available to correct abnormalities in the upper airway that lead to obstruction during sleep (Table 97-7). It is important to appreciate that opting for surgery represents a difficult undertaking. The upper airway is an extremely complex structure with a variety of soft tissue and bony structures contributing to the overall airway morphology. The upper airway not only facilitates exchange of gas between the lungs and atmosphere, but is also

Table 97-7 Surgery for Obstructive Sleep Apnea Nasal surgery (septoplasty, sinus surgery, and others) Tonsillectomy ± adenoidectomy Uvulopalatopharyngoplasty (UPPP) Laser assisted uvulopalatoplasty (LAUP) Radiofrequency volumetric tissue reduction Linguaplasty Genioglossus and hyoid advancement (GAHM) Sliding genioplasty Maxillo-mandibular advancement osteotomy Tracheostomy

crucial in the functions of speech and deglutition. Alterations in airway structure, by nature of surgery and its associated inflammation and scarring, can alter the ability of the airway structures to maintain these vital functions. Therefore, selecting the appropriate sleep apnea patient and suitable surgical approach are critical. Selection of a suitable candidate can be achieved through evaluations examining clinical, fiberoptic, and radiologic information. Height, weight, and neck circumference are thought to influence the surgical outcome. Physical examination of the head and neck region is often supplemented with nasopharyngolaryngoscopy to assess for anatomic abnormalities such as deviated nasal septum, turbinate hypertrophy, palatal/uvula elongation, tonsillar enlargement, and enlargement of the tongue/lateral walls. Craniofacial abnormality, such as retrognathia and narrowing of the hard palate, should also be noted on examination. The use of the Muller maneuver (voluntary inspiration against a closed mouth and obstructed nares) permits visualization of the upper airway structures during a simulated apneic event. CT and MRI can also be employed to provide detailed information about structural dimensions preoperatively and postoperatively. Lateral cephalography offers a less costly imaging technique to provide information concerning craniofacial structures prior to and after upper airway surgery. The leading objectives for presurgical evaluation are to identify the primary site of obstruction (although obstruction may not be in only one site) and assess the risk of surgery and anesthesia. Compromise of the airway in the perioperative period is potentially a serious complication. Sedatives (e.g., benzodiazepines), opioid analgesics, inhalation anesthetic agents, and propofol are examples of medications commonly used in the pre-, peri or postoperative period that inhibit upper airway muscle activity and can worsen sleep disordered breathing. Tracheal intubation may prove challenging by virtue of the anatomical features of apneic subject’s pharyngeal configuration (patients with sleep apnea usually have a high Mallampati score, making intubation difficult). The supine position during surgery potentiates airway obstruction secondary to the effect of gravity on the tongue and soft palate position. In addition, surgery of the upper airway may compromise the upper airway caliber due to edema, hematoma, and inflammation. The postoperative transitioning period when a patient emerges from general anesthesia, and is extubated requires extra vigilance in OSA patients. Residual effects of neuromuscular blockade and sedatives, and ongoing postoperative narcotics for pain are capable of compromising airway patency. CPAP should be immediately available postoperatively and used in the postoperative period. Regular CPAP therapy should be strongly emphasized along with an instruction to bring patient’s own CPAP equipment into the hospital. The level of obstructive site influences the type of surgical procedure to be performed (Table 97-7). Fiberoptic laryngoscopy or imaging can be used to classify the obstruction of the airway at the oropharyngeal (type I), oropharyngeal

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and hypopharyngeal (type II), and hypopharyngeal (type III) levels. Surgical Approaches UPPP is the most common surgical procedure for adult OSA. It was introduced into the United States in 1981 by Fujita and colleagues. UPPP entails removal of excessive mucosa and tissue from the palate and palatopharyngeal arch. The underlying musculature of the palate is left intact, and uvula is shortened or amputated. The tonsils, if present, are removed at the time of this procedure, and the remaining mucosa is trimmed and sutured together. The overall aim is to widen the oropharyngeal aperture. Successful treatment is reported in only approximately 40 to 50 percent of patients. The surgical outcomes are better in patients with retropalatal obstruction compared with retroglossal obstruction. Therefore, patients with obstruction in the hypopharyngeal region would not experience large benefits from this procedure. Potential complications of UPPP include velopharyngeal insufficiency related to over-resection, odynophagia, dysphagia, disturbance in taste, numbness of the tongue, pharyngeal discomfort, and nasopharyngeal stenosis. Hemorrhage after UPPP occurs in 2 to 4 percent of patients. Despite the wide range of complications and side effects, in practice UPPP is generally well tolerated and uneventful. However, patients who undergo UPPP often have a difficult time tolerating CPAP after surgery because surgical reduction of the soft palate can lead to mouth leaks at relatively low levels of CPAP. A modified version of the UPPP is the uvulo-palatal flap procedure. This involves suspending the uvula superiorly toward the hard-soft palate junction following a limited resection of the uvula, lateral pharyngeal wall, and mucosa. The intended result is a widening of the oropharyngeal airway similar to the UPPP. The uvulo-palatal flap is reported to be as efficacious as the UPPP and associated with less pain. Laser assisted uvuloplasty (LAUP) is an office-based procedure that addresses snoring. The procedure involves removal of the uvula and a part of the soft palate with a carbon dioxide laser. The procedure is conducted under local anesthesia and lasts approximately 15 minutes. Although painful, overall it is well tolerated by patients and has a low reported incidence of complications. Nonetheless LAUP can result in dysphagia and the creation of the “silent” (nonsnoring) apneic. A success rate of 90 percent is reported in reducing snoring. Many studies have examined LAUP as a treatment for OSA patients; however, these studies are hindered by methodologic and statistical limitations. Currently, LAUP is not recommended as a treatment option for OSA by the American Academy of Sleep Medicine. Radiofrequency volumetric tissue reduction, a minimally invasive technique, has been employed to treat turbinate hypertrophy and reduce the size of the base of the tongue. Long-term results limited to one study of 18 patients with OSA showed mixed outcomes. It may be useful as an adjunctive treatment to other surgical techniques.

Sleep Apnea Syndromes

Genioglossus advancement (GA) with hyoid myotomy, sliding mortise genioplasty, mandibular osteotomy, and maxillo-mandibular advancement osteotomy are among the procedures that can be used in patients whose examination and cephalometric analysis are consistent with abnormalities of the craniofacial skeleton. All of these procedures effect an anterior advancement of the “bony cage” (maxilla, mandible, hyoid) to enlarge the upper airway. Therefore, the leading aim is to achieve a larger-caliber airway. It is common for genioglossus advancement to be performed concurrently with other OSA surgical therapies, for example UPPP, to optimize upper airway caliber. The success of such combinations has been variable ranging from 23 to 77 percent. Risks associated with GA include the potential need for tracheostomy perioperatively, fractured mandible, infection, hematoma, and injury to the genioglossal muscle. Maxillomandibular advancement has been shown to be an effective surgical treatment for OSA in selected patients (i.e., those with retrognathia, and base of tongue obstruction), but this surgery is extensive. Maxillomandibular expansion, distinct from maxillomandibular advancement, is a procedure consisting of a series of limited osteotomies. The aim, using a technique of distraction osteogenesis, is to widen the constricted maxilla and mandibles by performing osteotomy followed by a process of bone lengthening. This technique is a less invasive surgery than maxillomandibular advancement and has been shown to reduce the severity of OSA. However, patients must endure the requirement of having the distractors in situ for several months. Other procedures listed in Table 97-7 are designed to increase airway caliber or to improve CPAP compliance. Treatment of nasal obstruction by surgical means has proved helpful in some patients, especially by allowing the patient to better tolerate CPAP. The most common nasal surgical procedure is septoplasty and turbinate reduction. These procedures can lead to subjective improvement in nasal patency and a reduction in nasal CPAP requirement. Selected patients who demonstrate macroglossia are candidates for a tongue reduction, although this procedure is usually performed in conjunction with another surgical procedure. Tracheostomy is virtually 100 percent effective in eliminating apnea. Its use in bypassing the upper airway was first described in “Pickwickian” patients. Despite its high efficacy, it requires changes in lifestyle and is associated with negative impact on patients’ quality of life. Tracheostomy is generally reserved for patients with severe OSA who have failed medical or surgical therapy and who manifest severe complications such as malignant arrhythmias without treatment. Tracheostomy can be performed as a temporary measure for high-risk subjects undergoing surgery. Surgery represents a viable therapeutic option for the carefully selected OSA patient (those who fail CPAP/oral appliances, have tonsillar hypertrophy, or nasal septal deviation). Meticulous preoperative assessment by examination, nasopharyngoscopy, and radiologic imaging can help to identify the likely area of upper airway obstruction. Many surgeons have adopted a staged approach performing limited

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procedures such as UPPP and/or GA before proceeding to maxillomandibular advancement. This may be fruitful for some patients by sparing them initial extensive surgery. However, staging may add the unnecessary burden of surgical procedures when the abnormality could have been corrected with a single operation from the outset. The role of surgical treatment of OSA is likely to evolve in the near future. Improvements in our understanding of airway anatomy should allow better selection of candidates. State-dependent airway imaging technology should increasingly allow the surgeon to view the patientâ&#x20AC;&#x2122;s airway configuration during sleep, thereby enhancing their ability to target the upper airway structures causing the apneas.

MANAGEMENT OF OTHER DISORDERS Obesity-Hypoventilation Syndrome The definition and presentation of the obesity hypoventilation syndrome (OHS) has been discussed. A majority of patients with OHS have concomitant OSA. Recent evidence reports significant morbidity and likely early mortality associated with OHS if left untreated. The prevalence is anticipated to increase in parallel with the obesity epidemic; therefore, it is important to recognize the disorder since effective treatment modalities exist. In order to establish the diagnosis, it must be demonstrated in the appropriate clinical setting, that a patient develops nocturnal increments of greater than 10 mmHg in PaCO2 (for diagnostic features, refer to Table 97-8).

Table 97-8 Diagnostic Features of Obesity-Hypoventilation Syndrome Morbid obesity Daytime symptoms of hypercapia Chronic fatigue Morning headache Right sided congestive heart failure/cor pulmonale with lower extremity edema unresponsive to diuretics Laboratory findings Hypercapnia during wakefulness (PaCO2 > 45 torr) Hypoxemia during wakefulness and sleep (SaO2 < 90%) Greater than a 10 torr increase in PaCO2 during sleep Respiratory acidosis during sleep (pH < 7.3) Nocturnal oximetry demonstrating persistent oxyhemoglobin desaturation Polysomnography demonstrating concomitant obstructive sleep apnea or evidence of hypoventilation

Oxyhemoglobin desaturations detected by nocturnal pulse oximetry can provide a clue to the diagnosis, particularly the pattern (Fig. 97-23). In a morbidly obese patient, the diagnosis of OHS can be missed if attention is only focused on the oxygen saturation. During wakefulness patients with OHS manifest hypercapnia and can be confused with patients with COPD. Patients with sleep apnea do not manifest daytime hypercapnia. Further diagnostic clues include compensatory metabolic alkalosis in response to chronic hypercapnia and hypoxia-related secondary erythrocytosis. The pathophysiology of OHS is multifactorial and appears to involve a complex interplay of abnormalities in central respiratory drive, respiratory mechanics, sleep-disordered breathing, and leptin sensitivity. Patients with OHS usually have evidence for right-sided heart failure (lower extremity edema), cor pulmonale, and pulmonary hypertension. The treatment strategy for OHS begins with weight loss, which improves pulmonary function, central ventilatory drive, and concomitant OSA. However, it should not be used as the only strategy, as it is difficult to achieve and maintain. Nocturnal non-invasive ventilation, the treatment of choice, has been demonstrated to correct daytime and nighttime hypoxemia and hypercapnia, ameliorate sleep fragmentation, allow for respiratory muscle rest, reduce pulmonary artery pressures, and improve right ventricular function. These physiologic improvements have been shown to translate to improvement in symptoms, notably excessive daytime somnolence, headache, energy levels, dyspnea, and leg edema. Noninvasive ventilation (NIPPV) may be delivered via volume- or pressure-cycled modes such as bilevel systems. The former appears to be the preferred modality, as it ensures adequate minute ventilation. Regardless, the goal is to achieve normocapnia, preferably over several nights to avoid acute metabolic alkalosis. Use of oxygen alone in OHS patients may worsen hypoxemia and hypercapnia. CPAP therapy may not achieve the required goals in OHS patients due to a failure of airway patency, inadequate inspiratory pressures, patient intolerance, and most importantly an absence of necessary ventilatory support. Other medical therapy for OHS includes the use of progesterone to stimulate hypercapnic sensitivity, and improve ventilation. The routine use of progesterone is not recommended due to an absence of effect upon apnea index and sleepiness, and the lack of long-term data showing efficacy. However, gastric bypass surgery should be considered in OHS patients with a BMI greater than 35 kg/m2 . Bariatric surgery has been shown to improve postoperative weight, sleep apnea, and pulmonary physiology.

Central Sleep Apnea Central sleep apnea (CSA), characterized by repetitive episodes of apnea in the absence of respiratory effort, is caused by an altered ventilatory motor output (Fig. 97-24). CSA has been described as a physiologic process in normal subjects (especially children and the elderly), as a manifestation of breathing instability in a number of medical conditions

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Figure 97-23 Example of typical tracings of oxygen saturation in a patient with obesity-hypoventilation syndrome (left panel) and obstructive sleep apnea (right panel). The former shows an episode of sustained desaturation. In obstructive sleep apnea there are frequent episodic desaturations (saw tooth pattern) that are more profound in REM sleep and abolished by CPAP.

(e.g., Cheyne-Stokes respiration in congestive heart failure and high altitude), or as an association with a variety of neurologic diseases, including Shy-Drager syndrome, CVA, myasthenia gravis, neuromuscular disease, bulbar poliomyelitis, brain stem infarction, and encephalitis. In general, the neurologic disorders associated with CSA lead to the hypercapnic type of CSA in contrast to the non-hypercapnic periodic breathing associated with heart failure, high altitude

or hypothyroidism. The latter group manifests an increased chemo-responsiveness that elicits instability of the ventilatory control system. The initiation of a central apneic event, in most patients, commences with a decrement in arterial PCO2 below the â&#x20AC;&#x153;apneic thresholdâ&#x20AC;? (below 35 mmHg), resulting in reduced ventilatory motor output. The causes of hypocapnia include: sleepstate changes, hypoxia, and fluctuation in minute ventilation

Figure 97-24 Example of a central apnea. The polysomnography traces from the top down are as follows: three EEG channels (C3-A2, C4-A2, OZ-A2); two EOG channels (NAS-RLC and LLC-NAS); submental EMG (EMG); right and left anterior tibialis EMG (RAT, LAT), oxyhemoglobin saturation (O2 SAT), electrocardiogram (EKG); snoring channel (SNORE), nasal and oral airflow; chest and abdominal motion (chest and abdomen). During the apneic episodes, there is abnormal airflow (both oral and nasal) without rib cage and abdomen motion. At the end of the apneic episode there is a burst of EMG activity at the arousal.

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that may be related to heart failure. In patients with hypercapnic CSA, the central drive to breathe is reduced. With sleep onset, a loss of already compromised wakefulness drive to breathe leads to central apnea. Clinical presentation of CSA patients depends on the type. In the more common non-hypercapnic form, associated sleep fragmentation leads to symptoms that are similar to OSA patients: sleep fragmentation, daytime sleepiness, and poor nocturnal sleep. In patients with hypercapnic CSA, presenting symptoms may include those associated with the underlying disease, sleepiness, morning headache, leg edema, and dyspnea. Hypoxemia due to respiratory failure in these patients can lead to secondary polycythemia or cor pulmonale. Diagnosis of CSA is established by polysomnography demonstrating repetitive apnea in the absence of thoracicabdominal excursion. A range of therapeutic options exists depending on the etiology and comorbidity. Oxygen therapy has been shown to improve Cheyne-Stokes respiration in patients with congestive heart failure; however, long-term data showing improved outcomes are lacking. CPAP may be successfully employed in patients who suffer mixed apnea (central and obstructive) or central apneas associated with congestive heart failure. Pharmacologic therapy with heart failure regimens, including beta blockade and angiotensin-

converting enzyme inhibitors, improves heart failure status and reduces CSA. The hypercapnic CSA patient is likely to require nocturnal noninvasive ventilation in the form of pressure-cycled mode with a bi-level system and a backup respiratory rate. Although this approach in such a patient appears intuitive, there is a paucity of evidence that supports its use. Pharmacologic approaches to patients with CSA include the use of acetazolamide and theophylline. Although both agents demonstrate improvements in CSA without adverse effects, an absence of high-level evidence precludes their routine use.

Upper Airway Resistance Syndrome The UARS is characterized by abnormal respiratory effort, nasal airflow limitation, minimal or no oxygen desaturation (greater than 90 percent oxygen saturation), and frequent sleep arousals in the absence of obstructive apneas (Fig. 9725). Controversy regarding its status as a distinct entity has existed since its first description in adults. It is believed by some experts that physicians are overlooking the syndrome since esophageal monitoring is usually necessary to diagnose this syndrome. UARS is thought to be part of the spectrum of sleep-related disordered breathing beginning with snoring and ending with apnea. The UARS patient in contrast to

Figure 97-25 Example of an episode of upper airway resistance in a patient with upper airway resistance syndrome. The traces are similar to those in Fig. 97-24. Particular attention should be paid to snoring channel (SNORE). At the beginning of the trace there is snoring present on each inspiration. Toward the end of the trace there is an obvious arousal with movement artifact on the EEG/EOG traces and activity recorded on both right (RAT) and left (LAT) anterior tibialis EMG. With the arousal there is some increase in airflow but the most obvious change is the abolition of snoring as a consequence of the reduction in upper airway resistance.

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an OSA subject may present with somatic symptoms such as headaches, insomnia, irritable bowel syndrome, psychiatric morbidity such as depression, attention deficit disorders, and a tendency to feel light-headed. Although relatively invasive, the esophageal balloon remains the gold standard for detecting periodic increases in respiratory effort (UARS) as an indirect measure of airflow obstruction. Other noninvasive strategies are currently being developed. Based on a recent retrospective cohort study, diagnosing UARS is important. Untreated diagnosed UARS patients over a 4-year period were found to have increased symptoms of daytime fatigue, insomnia, depression, increased sleep disturbance reported by patient and polysomnogram, and increases in the use of hypnotic medication. A majority of UARS patients were denied CPAP by third-party payers during the period of the study (1995–1998). First-line treatment for UARS patients is CPAP, although Medicare does not currently recognize UARS alone as an indication for it. Most patients with UARS also manifest some level of sleep apnea. Patients with concomitant complaints of chronic insomnia or psychosomatic symptoms have benefited from concurrent cognitive behavioral therapy. Other therapeutic modalities for UARS include oral appliances, radiofrequency reduction, nasal septoplasty, and upper airway or craniofacial surgery. Further work is required to understand the medical outcomes of treating UARS patients.

Pulmonary Diseases during Sleep Pulmonary disorders can deteriorate during normal sleep and especially in patients with concomitant sleep apnea. Normative circadian changes elicit increases in bronchial hyperresponsiveness (increased vagal tone), airway inflammation, and a decrement in lung function, which can contribute to asthma. Supine posture during sleep, interruptions in medication administration, exposure to bed allergens, and gastroesophageal reflux disease (GERD) are also factors that can precipitate asthma. Snoring may trigger bronchospasm by irritation of receptors at the glottic inlet and laryngeal area that are believed to effect bronchoconstrictive reflex activity. Furthermore, snoring or apnea is likely to worsen gastroesophageal reflux, which in turn, is known to exacerbate asthma. Studies addressing subjects with nocturnal asthma and OSA have shown symptom improvement with CPAP use. In fact, asthmatic patients who fail expectant improvement with optimal medical therapy or who manifest primarily nocturnal asthma should be considered for evaluation of sleep apnea, particularly if snoring is present. In regard to patients with COPD, hypoxemia and hypoventilation can both develop during normal sleep. Normal subjects may experience a decrement in up to 10 mmHg of PaO2 during sleep. However, COPD patients who exhibit daytime hypoxemia, experience profound declines in PaO2 , especially in REM, that are proportional to the baseline wakeful oxygen partial pressure. Hypoxemia is multifactorial, and mechanisms include reduced functional residual capacity (decreasing oxygen reserve), increased airway resistance,

Sleep Apnea Syndromes

decreased respiratory muscle function, altered chemosensitivity, alveolar hypoventilation, and ventilation-perfusion mismatch. The coexistence of COPD and OSA is relatively common. In this so-called overlap syndrome, patients are at increased risk of pulmonary hypertension and respiratory failure related to progressive nocturnal hypoxemia. It is important to recognize that a wide variety of lung diseases, including interstitial lung disease, cystic fibrosis, restrictive lung disease, and chest wall disease, can place patients at risk for hypoxemia during sleep. This is related to operating on the steep segment of the sigmoid-shaped oxygen dissociation curve while awake. Polysomnography is not recommended in COPD patients unless clinical features implicate coexistent OSA. Oxygen therapy is unlikely to be sufficient in patients who suffer the overlap syndrome: Either CPAP with oxygen or nocturnal ventilation is usually required. The latter is appropriate when there is concomitant hypercapnia, although its use remains controversial in the literature.

CONCLUSION The field of sleep medicine has undergone a period of great change in the last few years. In particular, significant advances have been made in the diagnosis, consequences, and management of sleep apnea. Prospective studies such as the Sleep Heart Health Study have provided stronger evidence for OSA as a causal element in a variety of cardiovascular disorders. The economic ramifications of undiagnosed subjects with sleep apnea are beginning to be understood. An “access” issue for patients to sleep services now looms: Greater public and medical attention to sleep disorders have resulted in a 12-fold increase in the volume of referrals for sleep studies over the last decade in the United States. However, in spite of the steep growth of infrastructure to diagnose and treat OSA, access to such services remains a sizable problem, and demand overwhelms capacity. Strategies (including portable systems, auto-titrating CPAP, and day CPAP titration) are rapidly being developed to expedite sleep study throughput and subsequent therapy. In spite of the encouraging progress, we acknowledge that many subjects remain undiagnosed and untreated for a variety of reasons. It is our hope that continued high-quality research and practice will engender further understanding and treatment of patients with OSA.

SUGGESTED READING Arzt M, Bradley TD: Treatment of sleep apnea in heart failure. Am J Respir Crit Care Med 2006;173:1300–1308, 2006. Ayas NT, FitzGerald JM, Fleetham JA, et al: Cost-effectiveness of continuous positive airway pressure therapy for moderate to severe obstructive sleep apnea/hypopnea. Arch Intern Med 166:977–984, 2006.

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Bailey DR: Dental therapy for obstructive sleep apnea. Semin Respir Crit Care Med 26:89–95, 2005. Coughlin SR, Mawdsley L, Mugarza JA, et al: Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 25:735– 741, 2004. Duran J, Esnaola S, Rubio R, et al: Obstructive sleep apneahypopnea and related clinical features in a populationbased sample of subjects aged 30 to 70 yr. Am J Respir Crit Care Med 163:685–689, 2001. Gami AS, Howard DE, Olson EJ, et al: Day-night pattern of sudden death in obstructive sleep apnea. N Engl J Med 352:1206–1214, 2005. Gami AS, Pressman G, Caples SM, et al: Association of atrial fibrillation and obstructive sleep apnea. Circulation 110:364–367, 2004. George CF, Boudreau AC, Smiley A: Simulated driving performance in patients with obstructive sleep apnea. Am J Respir Crit Care Med 154:175–181, 1996. Guilleminault C, Abad VC: Obstructive sleep apnea syndromes. Med Clin North Am 88:611–630, viii, 2004. Guilleminault C, Kirisoglu C, Poyares D, et al: Upper airway resistance syndrome: A long-term outcome study. J Psychiatr Res 40:273–279, 2006. Hillman DR, Murphy AS, Pezzullo L: The economic cost of sleep disorders. Sleep 29:299–305, 2006. Hirshkowitz M, Sharafkhaneh A: Positive airway pressure therapy of OSA. Semin Respir Crit Care Med 26:68–79, 2005. Kanagala R, Murali NS, Friedman PA, et al: Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 107:2589–2594, 2003. Kushida CA, Morgenthaler TI, Littner MR, et al: Practice parameters for the treatment of snoring and Obstructive Sleep Apnea with oral appliances: An update for 2005. Sleep 29:240–243, 2006. Li KK: Surgical therapy for adult obstructive sleep apnea. Sleep Med Rev 9:201–209, 2005. Marin JM, Carrizo SJ, Vicente E, et al: Long-term cardiovascular outcomes in men with obstructive sleep apnoeahypopnoea with or without treatment with continuous positive airway pressure: An observational study. Lancet 365:1046–1053, 2005. Mehra R, Benjamin EJ, Shahar E, et al: Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 173:910–916, 2006. Nieto FJ, Young TB, Lind BK, et al: Association of sleepdisordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA 283:1829–1836, 2000. Olson AL, Zwillich C: The obesity hypoventilation syndrome. Am J Med 118:948–956, 2005. Pack AI: Advances in sleep-disordered breathing. Am J Respir Crit Care Med 173:7–15, 2006.

Patel NP, Ahmed M, Rosen I: Topics in practice management: Split-night polysomnography. Chest 2007, in press. Patel NP, Rosen I: Sleep apnea and cardiovascular disease: Association, causation and implication. Clin Pulm Med 14:225–231, 2007. Patel NP, Schwab RJ: Upper airway imaging, in Kushida DCA (ed), Obstructive Sleep Apnea: Diagnosis, and Treatment. Boca Raton, FL, Taylor & Francis, 2007. Peppard PE, Young T, Palta M, et al: Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 284:3015–3021, 2000. Peppard PE, Young T, Palta M, et al: Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 342:1378–1384, 2000. Ronald J, Delaive K, Roos L, et al: Health care utilization in the 10 years prior to diagnosis in obstructive sleep apnea syndrome patients. Sleep 22:225–229, 1999. Schellenberg JB, Maislin G, Schwab RJ: Physical findings and the risk for obstructive sleep apnea. The importance of oropharyngeal structures. Am J Respir Crit Care Med 162:740–748, 2000. Schwab RJ, Pasirstein M, Kaplan L, et al: Family aggregation of upper airway soft tissue structures in normal subjects and patients with sleep apnea. Am J Respir Crit Care Med 173:453–463, 2006. Shahar E, Whitney CW, Redline S, et al: Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 163:19–25, 2001. Sleep-related breathing disorders in adults: Recommendations syndrome definition and measurement techniques in clinical research. The Report of the American Academy of Sleep Medicine Task Force. Sleep 22:667–6689, 1999. Stradling JR, Davies RJ: Sleep. 1: Obstructive sleep apnoea/hypopnoea syndrome: Definitions, epidemiology, and natural history. Thorax 59:73–78, 2004. Weaver TE, Kribbs NB, Pack AI, et al: Night-to-night variability in CPAP use over the first three months of treatment. Sleep 20:278–283, 1997. White DP: Pathogenesis of obstructive and central sleep apnea. Am J Respir Crit Care Med 172:1363–1370, 2005. Yaggi HK, Concato J, Kernan WN, et al: Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 353:2034–2041, 2005. Young T, Evans L, Finn L, et al: Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middleaged men and women. Sleep 20:705–706, 1997. Young T, Peppard PE, Gottlieb DJ: Epidemiology of obstructive sleep apnea: A population health perspective. Am J Respir Crit Care Med 165:1217–1239, 2002. Young T, Shahar E, Nieto FJ, et al: Predictors of sleepdisordered breathing in community-dwelling adults: The Sleep Heart Health Study. Arch Intern Med 162:893–900, 2002.

98 Differential Diagnosis and Evaluation of Sleepiness Charles F. P. George

Meir H. Kryger

I. THE PHENOMENON OF SLEEPINESS II. QUANTIFYING SLEEPINESS Subjective Measures of Sleepiness Objective Measures of Sleepiness Performance and Vigilance Tests

Circadian Rhythms Medications IV. PREVALENCE OF EXCESSIVE DAYTIME SLEEPINESS V. EVALUATING THE SLEEPY PATIENT Approach and Differential Diagnosis

III. FACTORS AFFECTING SLEEPINESS Sleep Quantity Sleep Quality

Excessive daytime sleepiness is a common problem affecting large segments of the population. Although estimates depend on how sleepiness is defined (e.g., sleeping too much vs. falling asleep in the daytime), about 16 percent of adults experience sleepiness that affects their daytime function, and there is increasing evidence that sleepiness plays a part in both industrial and road traffic accidents. The National Highway Traffic Safety Administration estimates that 100,000 automotive crashes per year are fatigue related. These sleepiness-related accidents contribute to 71,000 injuries and 1500 deaths per year. Over the past two decades, research has provided increased understanding of obstructive sleep apnea (OSA), among other sleep disorders. With the recognition that symptomatic sleep apnea alone affects about 1 in 20 people, and increasing awareness of sleep disorders by the general public, respiratory physicians, by necessity, are dealing more and more with sleep apnea and other sleep disorders. In recognition of the need for training pulmonary physicians in sleep disorders, in 1994 the American Thoracic Society published recommendations for training in sleep medicine (available through the ATS office, currently in revision by the American Thoracic Society 2006). It is clear, therefore, that pulmonary physicians need to better understand and treat excessive daytime sleepiness whatever its cause.

THE PHENOMENON OF SLEEPINESS Sleepiness is both a subjective and an objective phenomenon, a constellation of sensations and a physiological state with stereotypical behaviors. As such, it is sometimes difficult to define, and its measurement (see below) depends on the circumstances. Sleepiness may be expressed as feeling sleepy, fatigued, or tired; sleeping too much; or fighting to maintain alertness. Sleepiness can be reflected by any or all of the following: heaviness of the eyelids, mild burning or itching of the eyes, difficulty keeping the eyes open, heaviness in the arms or legs, reluctance to move, loss of initiative, loss of interest in surroundings, and difficulty with concentration. These sensations are accompanied by behavioral changes such as rubbing the eyes, yawning and stretching, and nodding the head, and by generally reduced motor functions such as speech, facial expression, and body movement. Indeed, the average sleepy person often exhibits a face with a glazed, blank, or even “dopey” expression. Sleepiness may also be considered a physiological state like hunger or thirst. Just as hunger and thirst are physiological states that occur with fasting and are satisfied by eating and drinking, sleepiness is produced by sleep restriction or

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deprivation and is reversed or satisfied by sleep. The factors that produce and influence sleepiness are detailed below; they include such obvious factors as time since last asleep, previous amount of sleep, continuity of sleep, and normal 24-hour circadian influences. Environmental stimuli influence this state and can determine, up to a point, whether or not this sleepy tendency will be manifested. For example, heavy meals, warm rooms, boring lectures, or monotonous tasks are usually considered soporific activities or situations. In these situations, a person might feel sleepy and, perhaps, might fall asleep. Yet the environmental factors themselves do not cause the sleepiness; they only allow it to be expressed. Equally, the same degree of physiological sleep tendency might go unnoticed when environmental stimulation occurs in the form of a life-threatening situation. In other words, the degree to which sleepiness is experienced or evident in behavior is determined by the underlying physiological sleep tendency (or the need for sleep) and environmental factors, which interact to make manifest the sleep tendency or sleep propensity. While it is accepted that sleepiness is a physiological state, the physiological substrates of this state have not been identified. Neurotransmitters such as serotonin, acetylcholine, histamine, and the catecholamines have been implicated in the sleep/wake mechanism along with a variety of other sleep-inducing substances, including adenosine through its inhibition of wakefulness-promoting neurons. While much research is ongoing, the understanding of the neurochemicals responsible for sleep, sleepiness, and loss of alertness are still far from clear.

QUANTIFYING SLEEPINESS The sensation of sleepiness is often difficult to quantify, as are other subjective symptoms, such as pain or shortness of breath. All of these subjective sensations mean different things to different people, and are modified by factors including motivation, external stimulation, and competing needs. What constitutes extreme sleepiness for one person may be only mild sleepiness for another and depend on the situation in which it occurs. Sleepiness has different dimensions with both feelings of perceived sleepiness as well as self-estimates of sleepy behavior, which are different in passive vs. active situations. The notion of a sleepiness trait, a composite of sleep need, sleepability, and other individual difference factors has been proposed to explain individual dissimilarities in sleepiness. This idea is supported by the finding of a hereditary component to self-reported overall alertness that is independent of self-reported sleep timing and duration.

Subjective Measures of Sleepiness Subjective reports may be used to quantify sleepiness, but statements such as “I feel sleepy” and “I feel very sleepy” often do not distinguish between feelings caused by a high physiological sleep tendency and those resulting from muscular

fatigue, depressed mood, or a general lack of energy. Thus, several subjective sleepiness scales have been developed. The Stanford Sleepiness Scale (SSS), the first to receive widespread use, is a seven-point self-rating scale ranging from 1 (alert, wide awake) to 7 (almost in reverie, sleep onset soon). It is brief, simple to use and measures current degree of sleepiness. It has been shown to correlate with the performance of mental tasks and demonstrate changes in sleepiness with sleep loss. However, there are no normative data and results often depend on the duration of prior sleepiness. For example, unlike normal persons who are experimentally sleep deprived, patients with more chronic sleep deprivation (e.g., sleep apnea) cannot be accurately tested with the SSS. Some patients who have an obvious overwhelming physiological sleep tendency may claim to be only mildly sleepy, yet fall asleep before your eyes. This was first observed in the early 1970s, and was a stimulus for that group to develop more objective measures of sleepiness (see below). It is clear that over a period of months or years, many sleep apnea patients lose their frame of reference with regard to normal alertness and cannot distinguish major changes in sleepiness. Thus, the subjective report of sleepiness (using the SSS) by people who are chronically and severely sleep deprived is not reliable. The Karolinska Sleepiness Scale (KSS) is a nine-point scale ranging from 1 (very alert) to 9 (very sleepy, fighting sleep, making an effort to keep awake), with verbal descriptions of every second point. Like the SSS, the KSS requires the subject to integrate and translate a number of sensations to a continuum that is fairly abstract despite the verbal description. Ratings obtained with these scales may be affected by the situation in which the scale is presented (at rest or during performing a task) and how the subject relates his or her perception to that particular time or place. Nonetheless, both the SSS and KSS show high correlations with performance. The KSS was also found to be strongly related to EEG and electro-oculographic signs of sleepiness. The Epworth Sleepiness Scale (ESS; Table 98-1) was designed to measure sleep propensity in a single, standardized way and is based on questions relating to eight situations, some known to be very soporific. The questions are self-administered, and subjects are asked to rate on a 0 to 3 scale how likely they are to doze off in the situation based on their usual habits. The ESS tries to overcome the fact that people have different daily routines, some facilitating and others preventing daytime sleep. ESS scores have shown significant correlations with mean sleep latency in the MSLT (see below) and have distinguished groups of patients with disorders of excessive sleepiness such as narcolepsy, OSA, and idiopathic hypersomnolence. It has also correlated significantly with the apnea/hypopnea index (AHI). The ESS has a high test-retest reliability and a high level of internal reliability in normals and patients with sleep apnea. Further work examining the utility of measuring sleepiness in different situations using the ESS suggests that individual measurements of sleep propensity (i.e., sleepiness) entail three components of variation: a general characteristic of the subject (the average sleep propensity), a general characteristic of the situation

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Table 98-1 The Epworth Sleepiness Scale NAME: Todayâ&#x20AC;&#x2122;s Date: Your age (years) Your sex (male = M; female = F) How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation. 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing Situation Sitting and reading Watching TV Sitting inactive in a public place (e.g., in a theater or at a meeting) As a passenger in a car for an hour without a break Lying down to rest in the afternoon when circumstances permit Sitting and talking to someone Sitting quietly after a lunch without alcohol In a car, while stopped for a few minutes in the traffic

in which the sleepiness or sleep propensity is measured (its soporific nature), and a third component that is specific for both subjects and situation.

Objective Measures of Sleepiness The Multiple Sleep Latency Test (MSLT) has been developed and standardized as an objective, reliable, and reproducible measure of physiological sleep tendency. Performed at intervals throughout the day, the MSLT measures the time to sleep onset, as determined by the EEG. This test is based on the assumption that, given the proper surroundings, physiological sleep tendency will be expressed; it has an intuitive appeal in that if one patient is more sleepy than the other, the sleepier patient should fall asleep more quickly. Patients are instrumented to record the EEG, electro-oculogram (EOG), and electromyogram (EMG); they are put in a quiet, darkened, temperature-controlled room, and are asked to lie quietly, close their eyes, and try to fall asleep. Naps are scheduled at 2-hour intervals, with 20 minutes allowed for sleep to occur; the average sleep latency of the naps represents the result of the MSLT. Both clinical and research protocols exist for conducting the MSLT. Since sleepiness follows a circadian rhythm (see below), one nap is insufficient to document and quantify daytime sleepiness. Accordingly, a minimum of four and a maximum of six naps are recommended. The MSLT is a reliable, reproducible test that has been validated in a number of sleep deprivation experiments in normal subjects and a variety of clinical conditions with patients who have disorders such as narcolepsy and sleep apnea and is useful for

Chance of dozing

documenting treatment response. An important advantage of the MSLT is that patient motivation cannot counteract the effects of previous sleep loss on sleep latency. That is, while most people can be motivated to compensate for reduced performance after sleep deprivation, motivation cannot overcome an increased pressure for sleep, particularly when the patient is in bed in a darkened room. An alternative to the MSLT is the Maintenance of Wakefulness Test (MWT). This is a variation on a theme in which subjects sit in a chair in a darkened room and are requested to remain awake for 20 (or 40) minutes. This test was developed on the assumption that the ability to fall asleep and the ability to stay awake are two separate phenomena. The MWT has undergone further tests of validity, but has been criticized for lack of a standardized protocol with 20-, 30-, and 40-minute tests reported. Recent practice parameters suggest using a 40-minute four-trial protocol when assessing whether or not a patient can stay awake in a situation of personal or public safety. While both MSLT and MWT require observer recognition of EEG changes, quantitative computerized analysis of EEG have been proposed as an alternate and more sensitive objective measure of sleepiness. Increased EEG delta activity with sleep deprivation and decreased alpha activity just before sleep onset are two possible metrics. However, these have yet to be translated into clinically useful tests. The Alpha Attenuation Test (AAT) has been validated in sleep-restricted normals and in patients with narcolepsy and correlates strongly with the MSLT. Compared to the MSLT, the AAT has the advantage of being fast (it requires only 6 minutes of recording),

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minimally intrusive, easily administered, and a purely objective measure of sleepiness. While these features make the AAT a valuable tool in lab and field research, its utility in clinical settings has yet to be determined. The Oxford SLEep Resistance Test (OSLER test) was designed as a low cost alternative designed to reproduce many of the features of the MWT, but without the labor-intensive, continuous technician monitoring of EEG. Subjects respond to a light-emitting diode mounted on the wall, which flashes for 1 second every 3 seconds. If there is no response after seven consecutive stimuli, the subject is deemed to be asleep and the test is ended. Limited data are available for this metric. The original study compared OSLER sleep latency with MWT latency in 10 OSA patients and 10 control subjects, done on separate days. Two other studies involving small numbers of sleep disorders center patients and/or normal subjects before and after sleep deprivation have demonstrated excellent agreement between the two measures and suggest that the OSLER could be an alternative to measuring sleepiness. In a study of heart failure patients receiving adaptive ventilation for treatment of Cheyne-Stokes respiration, improvement in OSLER scores followed improvement in nighttime sleep. Despite these promising results, there are no large-scale studies using the OSLER, and the main limitation of this test is its dependence on patient cooperation.

Performance and Vigilance Tests Measurements of performance after sleep loss reflect daytime sleepiness, since most people report decreased performance after a sleepless night. Previously it was felt that only performance tests that were prolonged and monotonous were sensitive to sleep loss. However, the work of Dinges—using his Psychomotor Vigilance Task (PVT)—demonstrates that if the signal rate is high and the response measure sufficiently sensitive, repetitive tasks of only 10-minute duration will expose the limits of performance in sleepy persons. Performance decrements resulting from sleep deprivation (or sleep disorders such as sleep apnea) can be observed in such a task if results are analyzed over time. This time-on-task or vigilance decrement may be observed as evidence of fatigue even in well-motivated subjects with adequate prior sleep, and it manifests itself as a shallow decline in performance as timeon-task increases. When the subject is sleep deprived, it is impossible to sustain attention long enough to maintain peak performance throughout the entire task. Sleep loss increases the rate of decline in and number of lapses in performance and the PVT has become the most widely used measure of neurobehavioral performance. It has been validated with the SSS and MSLT. Recent work using this test has demonstrated consistent individual differences in neurobehavioral deficits from sleep loss, which suggest differential trait vulnerability to sleepiness. Other tests of sustained attention and performance have been developed, many to assess simulated driving performance. Using a divided attention driving task, sleep apnea patients have been shown to perform poorly, and in some

cases, equal to or worse than normals impaired by alcohol. Nonetheless sleepiness as measured by MSLT accounts for less than 25 percent of the variance in tracking performance. Thus, while the effects of sleepiness on performance may occur in a dose-dependent fashion in normals, performance decrements in patients who are sleepy because of an underlying sleep disorder may be accounted for by factors other than sleepiness.

FACTORS AFFECTING SLEEPINESS Sleepiness is determined by the quantity of sleep and the quality and type of sleep, interacting with circadian rhythms or drugs that patients may be taking.

Sleep Quantity The amount of nocturnal sleep has a strong relationship to the degree of daytime sleepiness. Partial or total sleep deprivation is followed by increased daytime sleepiness in normal persons. Furthermore, sleep restriction will become cumulative over time and lead to increasing daytime sleepiness. The effect of sleep restriction on sleep latency is shown in Fig. 98-1. When the sleep of young adults was reduced by 2 hours a night on consecutive nights, sleepiness (as measured by the MSLT) progressively increased over 7 days. Even as little as 1 hour per night of sleep loss will accumulate over time and lead to daytime sleepiness—a fact generally not appreciated. Each person has a certain biologic sleep need, and the specific amount varies from one subject to the next. Regardless of cultural or environmental factors, most adults sleep 7 to 8 hours per day, but the old adage that we must sleep 8 hours each night is not true for everyone. Some people require more than 8 hours, and others less; even conjoined twins show an independence of sleep needs. In the absence of pathology, normal human sleep length varies between 6 and 9 hours, although some people require less. It would be ideal to require a minimum amount of sleep to allow maximum productivity in work and adequate time for social pursuits. Indeed, some investigators believe that Western society predisposes to sleep deprivation. With economic and social constraints—the latter leading to voluntary sleep restriction—the sleep period is the time most encroached on, potentially leading to daytime sleepiness. This is highlighted in the National Sleep Foundation’s annual Sleep in America Poll. Voluntary sleep restriction or insufficient sleep causes daytime sleepiness. Among all prominent features differentiating this group of patients with insufficient sleep from those with narcolepsy was the report, obtained from the sleep history, of a disparity between the amount of sleep on weekdays and that on weekends. People with insufficient sleep typically have a much longer sleep period on weekends (by 2 hours or more). Most patients consider their weekly sleep loss trivial and assume that it is recovered on weekends. However, while

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Figure 98-1 Average daily sleep latency test scores for young adults when nighttime sleep was reduced by 2 hours a night for 7 consecutive nights. (Adapted from Dement WC, Carskadon MA: An essay on sleepiness, in Boldy-Moulinier M (ed), Actualities ´ en Med ´ ecine ´ Experimentale, ´ en Hommage au Prof D Passouant. Montpellier, Euromed, 1981, pp 47–71.)

recovery from a single experimental sleep restriction occurs in a couple of nights, it is not likely that repeated episodes of sleep deprivation can be compensated for in just one night. A study of a large group of normal subjects without complaints of daytime sleepiness has shown that young subjects (particularly college students) had shorter sleep latencies than did older subjects. Within the group of 120 young subjects, 12 healthy, nonsmoking men aged 21 to 35 years, had a mean sleep latency of less than 6 minutes on MSLT testing, while another 12 had an MSLT of greater than 16 minutes. These subjects had baseline testing and then extended their sleep period time from 8 to 10 hours over 6 days. Repeat testing on days 1, 3, and 6 showed stepwise increases in MSLT and performance testing for both subgroups. These data support the notion that chronic voluntary sleep restriction produces objective sleepiness that may or may not be perceived by the subject.

Sleep Quality Sleep quality is perceived to be abnormal when sleep is decreased or discontinuous. Disrupting sleep continuity—i.e., causing arousal from sleep, either experimentally or by sleep disorders—affects the quality of sleep and results in increased physiological sleep tendency. An arousal can be defined as a brief (3 to 15 seconds) speeding up of the EEG, or as a burst of alpha activity occasionally accompanied by transient increases in skeletal muscle tone. These typically do not result in awakening as defined by standard sleep staging criteria or behavioral indicators. Sleep studies can identify various causes of arousal, such as recurrent obstructive apnea, leg movements, or pain, in some but not all cases. A common

exception is the patient with chronic obstructive pulmonary disease (COPD) who has frequent arousals from sleep in the absence of obstructive apnea or leg movements. Patients with COPD often experience oxygen desaturation during sleep, and this is a potential stimulus for arousal. However, arousal frequency is unchanged when supplemental oxygen is given and desaturation is prevented, so the stimulus is still undefined. Nonetheless, compared with age-matched controls, COPD patients have discontinuous sleep and poor sleep efficiency (defined as percentage of time actually asleep in bed). This might be expected to lead to daytime sleepiness, but the sleep latency of COPD patients has not yet been measured systematically. Auditory stimuli presented externally to normal subjects during sleep can produce arousal; repetitive presentation of such stimuli can produce daytime sleepiness. Several studies have shown decreased performance and increased sleepiness the day after repetitive arousal, with the degree of daytime sleepiness related to the frequency of nocturnal sleep disruption. Not surprisingly, the shortest sleep latency occurred after the most fragmented nocturnal sleep. This increased sleepiness will result even if the stimulus is only sufficient to produce EEG signs of arousal, without full wakefulness.

Circadian Rhythms If sleep latency is measured every 2 hours over a complete 24hour day, a biphasic pattern of sleep tendency becomes obvious (Fig. 98-2). This demonstrates that there are two peaks and troughs of sleepiness over a 24-hour period. Not surprisingly, the times of increased sleepiness are during the nocturnal hours and during the daytime hours (in the midafternoon

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Figure 98-2 Sleep latency (mean) as a function of time of day for young subjects (filled circles) and elderly subjects (open circles). Stippled area denotes nighttime sleep period. (Adapted from Richardson GS, Carskadon MA, Orav EJ, et al.: Sleep 5:882â&#x20AC;&#x201C;92, 1982.)

between 2 and 4 p.m.). This circadian rhythm of sleepiness is present in all age groups, although the time of the peak rhythm may vary. The circadian rhythm of sleepiness is similar to other circadian rhythms in that it possesses an endogenous periodicity that can be affected by environmental influences that fine tune or entrain the rhythm. Even in the absence of these environmental cues (e.g., awakening time, alarm clock, degree of light or darkness, food and stimulants, social contact), rhythms show a persistent periodicity. The circadian rhythm of temperature is extremely stable. Temperatures fall in the late afternoon, are lowest during the middle of the sleep period, and rise before morning awakening. The temperature rhythm synchronizes most closely with sleepiness. Although the amplitude of body temperature and sleep latency rhythms differ considerably, no other biologic rhythms correlate so well in time. Two other examples of the influence of circadian rhythms on sleepiness are obvious. The first is that associated with shift work, and the second is due to transcontinental travel (jet lag). Workers with a normal nocturnal sleep period and a previously stable circadian sleepiness rhythm suddenly will have a trough of sleepiness during the middle of their night work period. They will attempt to stay awake, while the circadian influences will promote sleep. Not surprisingly, performance may suffer.

Medications Drug effects on sleep can be significant and can either promote sleep and sleepiness or increase wakefulness and alertness. Not surprisingly, sedative drugs increase sleepiness.

Benzodiazepine hypnotics are widely used to help people get to sleep at night. Many objective studies confirm the ability of hypnotics to shorten sleep latency at bedtime. When given during the day, they will promote sleep. However, the daytime carryover effect of nocturnal sedation is not always recognized. This effect occurs most commonly with longacting benzodiazepines, but it may occur with other medications as well. Alcohol consistently shortens sleep onset and produces sedation, whether given at night or during the day. Drugs that produce sleepiness include antihistamines, which are used in allergy and pulmonary practice. Many of the early H1 antihistamines, such as diphenhydramine and chlorpheniramine, have been shown to reduce the MSLT. Some newer antihistamines, such as terfenadine and astemizole, do not produce objective sleepiness. The more lipid-soluble drugs (e.g., diphenhydramine and chlorpheniramine) penetrate the central nervous system more easily and therefore are more likely than less lipid-soluble drugs to produce sedation. Other medications with high lipid solubility have been reported to produce daytime sedation; the most common of these are the beta blocker drugs. There are no controlled, objective studies of sleep latency with this type of drug, and sleepiness from these medications is based on reports of side effects. The effect of a particular drug in producing sleepiness also depends on the background level of sleepiness or alertness. When ethanol or caffeine is given to normal sleeping young men in the morning, one might expect ethanol to produce daytime sleepiness and caffeine to increase sleep latency during the day. Subjects are consistently sleepier after ethanol than after caffeine ingestion, but fully rested subjects (those

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having spent 11 hours in bed) do not show sleepiness after taking ethanol. In other words, the sedative effects of drugs such as alcohol can be enhanced by increased background sleepiness. Thus, a driver who is sleepy to start with may be as vulnerable after just one or two drinks as a previously alert driver who has become legally intoxicated. Stimulants such as amphetamine, methylphenidate, and modafinil increase alertness. These are most often used in the treatment of narcolepsy but are also used, quite inappropriately, by truck drivers trying to keep awake when driving over long distances. It is our anecdotal experience that many sleepy truck drivers actually have sleep apnea and are not particularly helped by stimulant medications. Caffeine, probably the most widely used stimulant, can reduce daytime sleepiness and transiently increase alertness. Excessive caffeine intake also paradoxically may cause a degree of daytime sleepiness. This occurs when caffeine levels persist into nocturnal hours and promote difficulties with sleep onset and increased awakenings during sleep.

PREVALENCE OF EXCESSIVE DAYTIME SLEEPINESS Prevalence rates for sleepiness depend greatly on the type of questions addressing sleepiness. Are you sleeping too much vs. are you falling asleep during the daytime vs. does your sense of sleepiness impair your daytime activities all result in widely different prevalence rates. Also men tend to report sleepy behavior while women report feelings of excessive daytime sleepiness, again contributing to variable prevalence. Prevalence of sleepiness also varies with the population examined. Of 2552 Finnish army recruits, 9.5 percent answered affirmatively when asked, “Do you consider yourself more sleepy during the daytime than your friends or work mates?” In addition, “daytime sleepiness” was reported by 16.2 percent of 1138 male subjects aged 18 to 23 years in a questionnaire distributed in Milan. The prevalence of excessive daytime somnolence was investigated in 58,162 draftees in the French army; 14.1 percent reported occasional daytime sleep episodes, 3.8 percent reported one or two daily episodes, and 1.1 percent reported more than two daily episodes. Of the total sample, 5 percent considered the sleep periods to be affecting their lives. A multivariate analysis showed five independent factors related to excessive daytime sleepiness: use of hypnotics, sleep difficulties, irregular sleep/wake schedule, snoring, and hours of sleep. In a recent study of 1066 Brazilian residents, sleepiness causing impairment at least three times per week was 10 percent in men and 21 percent in women, with rates increasing in low-income and unemployed. The Wisconsin Sleep Cohort study was the first to formally determine the prevalence of sleepiness as a function of sleep apnea. This landmark study demonstrated that at least 2 percent of middle-aged women and 4 percent of middle-aged men had OSA and symptoms of excessive daytime sleepiness.

Differential Diagnosis and Evaluation of Sleepiness

More recent estimates suggest that about 1 in 20 (5 percent) have symptomatic sleep apnea. While there may have been other causes for the daytime sleepiness besides OSA, it is clear that sleep apnea is responsible for a great deal of the daytime sleepiness in North America.

EVALUATING THE SLEEPY PATIENT Approach and Differential Diagnosis Keeping in mind the factors that determine daytime sleepiness, the sleep history can be individualized and can be very helpful in narrowing the differential diagnosis (Table 98-2). One should always question the patient about his or her nocturnal sleep, looking specifically at sleep onset time, sleep period time, number of awakenings, and time of rising in the morning. Sleep onset phenomena such as sleep paralysis and hypnagogic hallucinations often suggest a diagnosis of narcolepsy, although these sometimes occur in apneics who are severely sleep deprived. A history of loud snoring or stopped breathing during sleep is suggestive of sleep apnea, particularly if the snoring is cyclical rather than continuous, with periods of loud snoring or snorting alternating with quiet intervals. Since insufficient sleep may be the cause of sleepiness, it is important to ask if there is any difference in the amount of sleep required during the week compared with

Table 98-2 Common Causes of Persistent Daytime Sleepiness Obstructive sleep apnea and other sleep-disordered breathing conditions (e.g., neuromuscular weakness with nocturnal respiratory failure) Narcolepsy/cataplexy syndrome Sleep-related movement disorders (e.g., periodic limb movement disorder, bruxism, etc.) Depression Postviral fatigue Head injury Metabolic, toxic, and drug-induced hypersomnolence Idiopathic hypersomnolence Insufficient sleep Circadian rhythm sleep disorders

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that on weekends. Equally important is whether the patient has any changes in subjective sleepiness on weekends or holidays compared with weekdays. In some instances, more information will be obtained from the spouse (or bed partner) or from a sleep/wake diary, since not all people are aware of the severity of their sleepiness. Moreover, patients may not understand the importance of good sleep hygiene; the diary can serve as a reminder for patients to be diligent about it. In estimating the degree of daytime sleepiness, it is useful to ask when and during what activities the patient experiences sleepiness. Is the patient sleepy on awakening in the morning, or is it only by midday? Does the patient fall asleep while doing things or only when inactive? Driving to and from work are important times when sleepiness may become obvious, particularly while the person is waiting at a railroad crossing or stoplight. Episodes of automatic behavior, related to “microsleeps,” often occur while one is driving. Do patients nap during the day, and if so, is the nap refreshing? Many patients with sleep apnea are still sleepy or foggy after a nap, whereas patients with narcolepsy most often feel refreshed immediately upon awakening. Since drugs can have a profound effect on sleep and sleepiness, a careful drug history is mandatory in the assessment of sleepiness. The clinician must remember to include queries not only about drugs that specifically affect sleep (hypnotics, sedatives, or other psychoactive medications) but also about substances that may not be considered to have any effect on sleep or waking. In particular, alcohol is a known precipitant or exaggerating factor for sleep apnea; patients will often report that they feel much worse the day after ingesting alcohol despite having had a nonintoxicating dose. Apart from a general physical exam, one should pay particular attention to the size of the jaw, face, and upper airway, looking for obvious skeletal abnormalities—particularly retrognathia or micrognathia. One then carefully examines the upper airway, looking for nasal obstructions such as a deviated nasal septum or inflammatory allergic polyps; then, one examines the oropharynx, looking at the size of the tongue, the position of the soft palate, and the size of the uvula; finally one examines the larynx to rule out upper-airway tumors or other obstructing lesions. While the typical sleep apnea patient will be the obese plethoric man with a thick neck, it is important to remember that examination of the awake, upright airway may bear no relationship to what happens when the patient is supine and asleep. Thus, the diagnosis of sleep apnea usually is confirmed by nocturnal polysomnography. The patient who has a history of snoring and daytime sleepiness but has no sleep apnea during his or her nocturnal study must undergo an objective measure of daytime sleepiness, because some patients who claim to have substantial daytime somnolence are simply looking for compensation. Also, some OSA patients will remain sleepy despite adequate treatment of their apnea, and an additional sleep disorder may coexist. Again, daytime quantification of sleepiness will be necessary. The only disadvantage of the MSLT is that it is

an inefficient test. Compared with objective measurements of airflow (i.e., an FEV1 ), which take seconds to perform and interpret, the MSLT takes almost a whole day and provides only one piece of information. Until better tests are developed and validated, however, the MSLT will continue as a standard, albeit time-inefficient, objective measure of daytime sleepiness.

SUGGESTED READING American Thoracic Society 2006 webpage accessed Jan 21, 2006: http://www.thoracic.org/sections/publications/ statements/pages/respiratory-disease-adults/ sleeptraining1-5.html Arand D, Bonnet M, Hurwitz T, et al.: The clinical use of the MSLT and MWT. Sleep 28:123–144, 2005. Arnedt JT, Wilde GJ, Munt PW, et al.: Simulated driving performance following prolonged wakefulness and alcohol consumption: Separate and combined contributions to impairment. J Sleep Res 9:233–241, 2000. Baldwin CM, Kapur VK, Holberg CJ, et al.: Associations between gender and measures of daytime somnolence in the Sleep Heart Health Study. Sleep 27:305–311, 2004. Basheer R, Strecker RE, Thakkar MM, et al.: Adenosine and sleep-wake regulation. Prog Neurobiol 73:379–396, 2004. Bunn TL, Slavova S, Struttmann TW, et al.: Sleepiness/fatigue and distraction/inattention as factors for fatal versus nonfatal commercial motor vehicle driver injuries. Accid Anal Prev 37:862–869, 2005. De Castro JM: The influence of heredity on self-reported sleep patterns in free-living humans. Physiol Behav 76:479–486, 2002. De Valck E, Cluydts R: Sleepiness as a state-trait phenomenon, comprising both a sleep drive and a wake drive. Med Hypoth 60:509–512, 2003. Dinges DF: Probing the limits of functional capability: The effects of sleep loss on short duration tasks. In Broughton RG, Ogilvie RD (eds), Sleep, Arousal and Performance. Boston, Birkhauser, 1992, pp 177–188. Folkard S, Lombardi DA, Tucker PT: Shiftwork: safety, sleepiness and sleep. Ind Health 43:20–23, 2005. Hara C, Lopes Rocha F, Lima-Costa MF: Prevalence of excessive daytime sleepiness and associated factors in a Brazilian community: The Bambui study. Sleep Med 5:31–36, 2004. Horne JA, Reyner LA, Barrett PR: Driving impairment due to sleepiness is exacerbated by low alcohol intake. Occup Environ Med 60:689–692, 2003. Jones BE: Basic mechanisms of sleep-wake states, in Kryger M, Roth T, Dement WC (eds), Principles and Practice of Sleep Medicine, 4th ed. Philadelphia, Elsevier Saunders, 2005, pp 136–153. Kim H, Young T: Subjective daytime sleepiness: Dimensions and correlates in the general population. Sleep 28:625–634, 2005.

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Krieger AC, Ayappa I, Norman RG, et al.: Comparison of the maintenance of wakefulness test (MWT) to a modified behavioral test (OSLER) in the evaluation of daytime sleepiness. J Sleep Res 13:407–411, 2004. Littner MR, Kushida C, Wise M, et al.: Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 28:113–121, 2005. Mazza S, Pepin JL, Deschaux C, et al.: Analysis of error profiles occurring during the OSLER test: A sensitive mean of detecting fluctuations in vigilance in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 166:474–478, 2002. National Sleep Foundation: Sleep in America Poll. Washington DC, 2005: http://www.sleepfoundation.org/ content/hottopics/2005 summary of findings.pdf Otmani S, Roge J, Muzet A: Sleepiness in professional drivers: Effect of age and time of day. Accid Anal Prev 37:930–937, 2005. Pepperell JC, Maskell NA, Jones DR, et al.: A randomized controlled trial of adaptive ventilation for Cheyne-Stokes breathing in heart failure. Am J Respir Crit Care Med 168:1109–1114, 2003.

Differential Diagnosis and Evaluation of Sleepiness

Priest B, Brichard C, Aubert G, et al.: Microsleep during a Simplified Maintenance of Wakefulness Test: A validation study of the OSLER test. Am J Respir Crit Care Med 163:1619–1625, 2001. Roberts RE, Shema SJ, Kaplan GA: Prospective data on sleep complaints and associated risk factors in an older cohort. Psychosom Med 61:188–196, 1999. Sforza E, Grandin S, Jouny C, et al.: Is waking electroencephalographic activity a predictor of daytime sleepiness in sleep-related breathing disorders? Eur Respir J 19:645– 652, 2002. Van Dongen HPA, Baynard MD, Maislin G, et al.: Systematic inter-individual differences in neurobehavioral impairment from sleep loss: Evidence of trait-like differential vulnerability. Sleep 27:423–433, 2004. Young T, Peppard PE, Gottlieb DJ: Epidemiology of obstructive sleep apnea: A population health perspective. Am J Respir Crit Care Med 165:1217–1239, 2002. Young TB: Epidemiology of daytime sleepiness: Definitions, symptomatology, and prevalence. J Clin Psychiatry 65:12– 16, 2004. Zielinski J, Zgierska A, Polakowska M, et al.: Snoring and excessive daytime somnolence among Polish middle-aged adults. Eur Respir J 14:946–950, 1999.

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XIV Surgical Aspects of Pulmonary Medicine

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99 Perioperative Care of the Patient Undergoing Lung Resection Robert J. Cerfolio

I. PATIENT SELECTION II. MORBIDITY AND MORTALITY III. PREOPERATIVE ASSESSMENT AND OPTIMIZATION Lung Function Optimization of Preoperative Pulmonary Function/Smoking Cessation IV. PERIOPERATIVE FACTORS REDUCING LUNG FUNCTION Bed Rest and Respiratory Function Bed Rest and Cardiac Function Alterations in Lung Function Secondary to Surgery Cardiac Stress Test V. RESECTION Extubation and Postoperative Supplemental Oxygen Pain Control Antibiotics Fluids, Electrolytes, and Oral Intake VI. COMPLICATIONS AFTER LUNG RESECTION Air Leak or Alveolar Pleural Fistula/Chest Tube Management

The postoperative care of any patient who undergoes pulmonary resection starts long before the incision is made and is comprised of three main areas. The first is patient selection, the second is the actual operation itself, and the third is postoperative care. This chapter briefly reviews some of the specific elements that go into these three areas. In addition, it discusses the incidence, prevention, and treatment of some of the most common postoperative problems that continue to vex thoracic surgeons around the world.

Postoperative Chest Tube Management Amount of Chest Tube Drainage High Output Chest Tube States (Chylothorax, Subarachnoid Pleural Fistula) Atrial Fibrillation Pneumonia Postoperative Somnolence from Epidural Analgesia Aspiration Pulmonary Edema Right Ventricular Failure Early Bronchopleural Fistula Postpneumonectomy Pulmonary Edema Empyema Pulmonary Insufficiency Renal Insufficiency Postoperative Hemorrhage Pulmonary Torsion Recurrent Laryngeal Nerve Injury Pulmonary Herniation VII. CONCLUSION

PATIENT SELECTION Perhaps the best way to minimize postoperative complications is to operate only on young healthy patients. Unfortunately, thoracic surgeons like most other surgeons are now presented with older and sicker patients than in the past. The median age of our society has increased and so have their comorbidities. We are increasingly challenged with larger

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tumors in older patients with smaller pulmonary reserve. As the bar for the upper age limit has risen the basement for the acceptable FEV1% and DlC O % has fallen. In the third millennium there are few, if any, absolute contraindications to pulmonary resection based on chronological age or pulmonary function.

MORBIDITY AND MORTALITY During the perioperative period, many factors contribute to pulmonary compromise. Estimates of the overall surgical mortality for pulmonary resection range in large series from 2 to 4 percent. The estimated mortality increases with the size of the resection—from less than 1 percent for a wedge resection of the lung, to 2 to 3 percent for a lobectomy, and 6 to 8 percent for pneumonectomy. The morbidity associated with elective pulmonary resection is also high. Complications have been reported to occur in 36 to 75 percent of patients undergoing pneumonectomy and 41 to 50 percent of patients after pulmonary lobectomy. Most complications are minor and include air leak, atrial fibrillation, and atelectasis. However, a significant number are major; these most commonly include pneumonia, aspiration, respiratory failure, myocardial infarction, bronchopleural fistula, and pulmonary embolus.

PREOPERATIVE ASSESSMENT AND OPTIMIZATION Lung Function Assessment of the patient’s risk for pulmonary resection starts preoperatively in the clinic. One important but difficult factor to quantify is the patient’s desire to undergo the work required to recuperate from a thoracic surgical procedure. The importance of walking and deep breathing after lung resection cannot be overstated. A study performed by the Lung Cancer Study Group suggested that the patient’s attitude toward his or her malignancy was the best indicator of long-term survival. A patient who appears to be unwilling to participate in his recovery should be allowed ample opportunity to explore reasonable alternative therapies, such as radiation. Moreover, if this attitude persists, it may be best not to operate at all. A large number of studies have examined preoperative pulmonary function tests in an attempt to delineate the risk to a patient. In a study of 476 patients operated on over 12 years, only three of seven preoperative risk factors for morbidity and mortality were found to carry a significant association with mortality. These risks included age over 60 years, pneumonectomy, and the presence of ventricular premature contractions on the preoperative electrocardiogram. All risk factors analyzed together accounted for only 12 percent of the risk of mortality.

Figure 99-1 Drilling holes in the bottom rib, thus enabling sutures to be placed through it.

At the time of the initial visit, an attempt to establish the amount and character of sputum production, the presence or absence of an effective cough, and a patient’s ability to climb a flight of stairs of fixed height help provide an idea of a patient’s ability to undergo surgery. Patients with preoperative arterial hypercapnia are apt to have pulmonary hypertension and are poor candidates for pneumonectomy, but they may be able to tolerate a lobectomy. Pulmonary function tests, in particular the FEV1 percent and the DlC O %, in combination with lobar perfusion scans, allow prediction of the postoperative predicted or post-resectional FEV1 % (Fig. 99-1). A post-resectional FEV1 % less than 40 percent of predicted is cause for concern. A study of the DlC O % in 165 patients who underwent lung resection identified it as the most important indicator of postoperative pulmonary complications or death. Another study focused on the maximal oxygen consumption (MVO2 ). A MVO2 of 20 ml/kg per min was associated with the fewest chance of complications, whereas an MVO2 under 15 ml/kg per min was associated with a 75 percent of the postoperative morbidity.

Optimization of Preoperative Pulmonary Function/Smoking Cessation Many patients who are to undergo elective pulmonary resection are current smokers. A variety of medical therapies are designed to improve pulmonary function. Optimization of pulmonary function begins first and foremost with smoking cessation. Even a short period of abstinence from cigarettes can improve the effectiveness of mucociliary transport. Heavy smokers also maintain high levels of carboxyhemoglobin that interfere with oxygen transport and delivery to peripheral tissues. However, the optimal time after smoking cessation for elective thoracotomy is still unknown. Studies of patients undergoing abdominal surgery and coronary artery bypass surgery suggest that 8 weeks of abstinence is necessary to achieve a significant decrease in pulmonary complications,but this type of delay is often not practical in patients with lung cancer.

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In patients with evidence of reversible airway obstruction on pulmonary function tests, or symptoms suggestive of airflow obstruction, nebulized albuterol appears to be of benefit. Mycostasis, if present, may warrant the addition of mucolytics such as N-acetylcysteine. However, this medicine may also lead to certain side effects, such as increased mucus production and bronchoconstriction. Similarly, although the condition of patients with reversible airflow obstruction generally improves with steroids, prednisone or other corticosteroids should be added reluctantly because of their adverse effects on wound healing and wound infection. If steroids are necessary, the dosage in the postoperative period should be minimized. Patients who produce purulent sputum should be treated with oral antibiotics directed at the organism identified and surgery delayed until the infection is eradicated.

PERIOPERATIVE FACTORS REDUCING LUNG FUNCTION Despite the wide variety of pathologies and types of operative procedures performed by thoracic surgeons, the postoperative course is often quite predictable. We have published on the techniques and specific steps that enable patients to be “fast-tracked” after both elective pulmonary resection and esophageal resection. These clinical pathways and/or computerized algorithms lead most importantly to safe results, high patient satisfaction, and only a 3- to 4-day length of stay after pulmonary resection. Early ambulation and aggressive pulmonary rehabilitation are cornerstones for successful fast-tracking. The physiological consequences of decreased activity and lack of changes in posture form a background for the pathophysiological processes caused by the underlying illness and the surgical procedure.

Bed Rest and Respiratory Function In normal adults, mismatches between alveolar ventilation and blood flow are small. In bedridden postoperative patients, however, ventilation and perfusion are badly matched. The zones of the upright lung are considered elsewhere in this volume. Placing a normal patient in a recumbent position leads to changes in all lung volumes except the tidal volume. In a normal person, a change from the upright to supine position decreases the vital capacity by 2 percent, total lung capacity by 7 percent, closing volume by 10 percent, residual volume by 19 percent, expiratory reserve volume by 46 percent, and functional residual capacity (FRC) by 30 percent. The decrements in volume that accompany changes to other than the supine position are small. In normal subjects, the FRC decreases by only 17 percent after a move from the upright to the lateral decubitus position. The closing volume has been shown to be relatively independent of posture. However, the FRC decreases by about 20 percent in the supine position—an amount that may be sufficient to cause the closing volume to exceed the end-tidal volume, thereby resulting in closure of

Perioperative Care of the Patient Undergoing Lung Resection

basilar alveoli. These alveoli remain closed for the initial portions of the next inhalation, while the ventilation is shunted to the open apical alveoli. It is interesting that these changes might be less in patients with chronic pulmonary disease. Thus, in patients with chronic airflow obstruction, a decrease in FRC of only 3.5 percent accompanied a move from the upright to supine position and a decrease of only 1.9 percent accompanied the move from the supine to lateral decubitus position. Finally, although arterial oxygen saturation decreased significantly in supine normal subjects, it did not do so in patients with significant airflow obstruction. The degree to which the described changes affect gas exchange has been only partly studied. In normal young males after 10 days of bed rest, PaO2 decreased by 9 mmHg and the alveolar-arterial difference in Po2 by 10 mmHg, without change in PaCO2 . Such changes, which would probably not be important in normal young people, might take on greater significance in a patient with chronic obstructive pulmonary disease (COPD).

Bed Rest and Cardiac Function Upon standing, approximately 500 ml of blood shifts from the upper to the lower body. When lying down, the central venous return increases, resulting in a decrease in heart rate, peripheral vasodilation, increased renal blood flow, and diuresis. Within an average of 24 hours the diuresis causes a 5 percent decrease in plasma volume, which continues to fall by 10 percent in 6 days and 20 percent in 14 days. A wide variety of experimental subjects and protocols have been used to examine the cardiovascular effects of prolonged immobilization. Orthostatic intolerance is common after prolonged bed rest. This is attributable, at least in part, to the depletion in intravascular volume noted in the preceding. This may be compounded by an increase in venous pooling in the lower extremities because of an increase in venous compliance after bed rest. Prolonged recumbency also blunts cardiac responsiveness to rapid changes in posture. Bed rest increases the resting heart rate by 4 to 15 beats a minute. After prolonged bed rest, the increase in heart rate during exercise is more pronounced. For example, normal volunteers experienced an increase in heart rate to approximately 129 beats a minute during submaximal exercise; after bed rest, the same exercise drove the heart rate to approximately 165 beats a minute.

Alterations in Lung Function Secondary to Surgery In addition to the physiological consequences of inactivity described in the preceding, the thoracic surgery patient also experiences major alterations in chest wall compliance. The pain and discomfort of deep breathing also lead to an increase in the work of breathing that is independent of the amount of resected lung. Manipulation of the lung and re-expansion of the lung leads to pulmonary “bruising.” Microscopic or

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even macroscopic areas of atelectasis persist. Fluid or blood clots in the pleural cavity may compress the lung parenchyma. Inhalational anesthesia depresses mucociliary transport. Mechanical changes alter the work of breathing. Thoracotomy alone was found to decrease chest wall compliance to 47 percent of preoperative levels and to increase work of breathing to 143 percent of preoperative levels. As a result, vital capacity and oxygen saturation fall significantly in the first few postoperative days. Pain, among other factors, leads to diminished cough. Cough pressures were found to decrease to 29 percent of preoperative levels after surgery and to increase only to 50 percent of preoperative levels by the seventh postoperative day.

Cardiac Stress Test Since many patients are smokers and elderly, we prefer to perform a preoperative stress test in most patients prior to thoracotomy. Previously undiscovered or unsuspected coronary artery disease should be determined, anatomically identified, and corrected prior to elective thoracotomy.

RESECTION Extubation and Postoperative Supplemental Oxygen Almost every patient undergoing lung resection should be extubated in the operating room and is brought to the recovery room breathing spontaneously. Reintubation in the immediate postoperative period is rare. If prolonged intubation is anticipated, however, the double-lumen endotracheal tube should be replaced by a single-lumen endotracheal tube of sufficient size to permit the introduction of an adult bronchoscope. For extubation, standard criteria are followed: vital capacity more than 10 ml/kg, respiratory rate less than 30 breaths per minute, and normal arterial blood gases. Supplemental oxygen is supplied in the postoperative period if the patientâ&#x20AC;&#x2122;s arterial oxygen saturation, measured by pulse oximetry, is less than 92 percent, either at rest or during exercise. We prefer sending patients directly to the floor and have not used the intensive care unit after lobectomy since 1998. Many centers have adopted a similar practice; however, patients must have 24-hour cardiac-rhythm and pulse oximetry monitoring in these specialized units. Nurses need to have chest tube training. These types of floors allow the patientâ&#x20AC;&#x2122;s family to stay in close proximity at all times. This offers significant psychological support to most patients; if the family is attentive and intelligent, as most are, they also can act as an invaluable part of the patientâ&#x20AC;&#x2122;s care and add another level of patient protection.

Pain Control A thoracotomy is a painful procedure. This is probably secondary to trauma and/or compression of the intercostal nerve. We have evaluated ways to reduce the pain of

Figure 99-2 Standard pericostal sutures.

thoracotomy using prospective randomized studies. We have completed four such trials and have published three. One study showed that drilling holes in the bottom rib, thus enabling sutures to be placed through it rather than around the ribs, helps avoid entrapment of the lower intercostal nerve (Fig. 99-1) and this simple technique reduces the pain compared with the standard pericostal sutures (Fig. 99-2). Another study examines the use of an intercostal muscle flap. This flap is harvested prior to rib retraction (Fig. 99-3) so as to avoid retractor injury to the intercostal nerve, which runs in the muscle flap. This study also showed significant benefit and further reduction of pain. Both positive studies showed reduction in postoperative pain in the hospital and a lessening of a decrease in the tidal volume immediately postoperatively. In addition, there was less pain at 3 months, both early and up to 12 weeks postoperatively. Simple techniques such as these, as well as video-assisted procedures that help prevent or limit the amount of pain are important. The key to pain control, like all postoperative complications, is prevention. Postoperative pain that is not controlled early reduces the ability to breath and cough and increases respiratory complications. Moreover, the best way to reduce late or chronic pain is to aggressively treat early pain. Most patients should receive a thoracic epidural prior to thoracotomy and/or a patient-controlled analgesic (PCA) intravenous device to help control it. Recently, some surgeons have tried subpleural catheter systems that infuse local anesthetics in the paravertebral area as well. The complications associated with epidural opiates are numerous and include pruritus, ileus, urinary retention, and respiratory depression. Epidural analgesia is most useful in the young patient with poor pulmonary function. We have avoided it in elderly patients, those who become somnolent, or those who have a rising carbon dioxide level on arterial blood gas. The use of nonsteroidal agents such as oral ketorolac in addition to narcotics is helpful as well and should be given immediately in the operating room and continued for a few days to help prevent pain. It should be avoided in those with marginal renal function. After postoperative day 2 or 3, the epidural should be

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Harvesting of ICM flap between the twi ribs

Perioperative Care of the Patient Undergoing Lung Resection

ICM flap transected anteriorly and reflected posteriorly

Figure 99-3 Muscle flap harvested prior to rib retraction.

removed and oral agents such as Tylox or Percocet should be added. Treating pain using a combination of different classes of agents is helpful.

Antibiotics Wound infection following thoracotomy is rare. This may be due to the large amount of musculature contained in the chest wall. However, infectious complications such as pneumonia are not uncommon following lung resection, and prophylactic antibiotics are often given in an attempt to reduce the incidence of these complications. Currently, it is recommended that a broad-spectrum antibiotic, such as cefazolin, be administered within 1 h of the skin incision, and continued for 24 to 48 h. Subsequent antibiotic administration should be based on clinical factors such as fever, radiographic infiltrates, leukocytosis, and sputum Gram stain and culture results. There is no need to provide antibiotic coverage simply because a chest tube is in place. A study that examined the relationship between pulmonary flora and postoperative infections found that Haemophilus influenzae was the most common organism identified from sputum at the time of surgery and that the risk of pneumonia in culture-positive patients was 10-fold that of patients with culture-negative secretions. However, the cultured organisms were sensitive to the antibiotic that was administered, suggesting that the administration of antibiotics may be less important than careful pulmonary toilet in preventing postoperative pneumonia.

Fluids, Electrolytes, and Oral Intake A routine lung resection is not associated with large fluid losses intraoperatively or sequestration of volume in the third

space postoperatively. Most patients should leave the operating room relatively euvolemic. Administration of intravenous fluids consisting of 5 percent dextrose and 0.45 percent normal saline at 50 to 75 ml/h until the patient begins to take oral fluids is usually adequate to maintain intravascular fluid volume. Oral intake should be resumed as soon as the patient is able to take fluids by mouth, but strict aspiration precautions cannot be overemphasized. Urine output should be maintained at 0.5 to 1 ml/kg of body weight an hour to preserve renal function. Oliguria, which is often overtreated by surgical residents, should be tolerated in patients who have undergone elective pulmonary resection. Some surgeons practice aggressive diuresis with the goal of reducing secretions. However, it is not clear that a lower volume of thick, tenacious secretions is preferable to a higher volume of thin secretions that are more readily cleared. Ideally, diuresis should be guided by measurements of intravascular volume. Measurements of central venous pressure correlate poorly with intravascular volume. Many surgeons are reluctant to insert Swan-Ganz catheters into patients after lung resection, particularly after pneumonectomy, because of the possibility of disruption of a pulmonary artery closure. Even if a Swan-Ganz balloontipped catheter has been safely introduced into a patient postoperatively, the data should be interpreted with caution because the inflated balloon may have occluded a significant portion of the remaining pulmonary vascular bed, thereby artificially increasing right ventricular after load and decreasing cardiac output. In our practice the measurement of central venous pressure is rarely if ever used and a Swan is reserved for a patient in the intensive care unit that is hypotensive, oliguric, and hypoxic. Blood transfusion is not necessary unless the patientâ&#x20AC;&#x2122;s hemodynamics and overall clinical scenario call for it. Some

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believe that a hematocrit less than 24 percent is an indication for transfusion, but we prefer to use the Hb level, which is less affected by dilution. A decision should be made on each individual patient’s situation and a knee-flex reaction to any specific level should be avoided. Transfusion of 250 ml of packed red blood cells increases the intravascular volume by 750 to 1000 ml, because of the movement of extravascular volume into the intravascular space due to plasma oncotic forces. The increase in intravascular volume may be more dangerous than a low hematocrit. Furthermore, the intraoperative administration of blood is probably immunosuppressive and may be associated with a decrease in frequency of 5-year disease-free intervals.

COMPLICATIONS AFTER LUNG RESECTION Air Leak or Alveolar Pleural Fistula/Chest Tube Management An alveolar pleural fistula (APF), more commonly known as an air leak, is probably the most common complications after elective pulmonary resection. It is defined as a communication between the pulmonary parenchymal distal to a segmental bronchus and the pleural space. Factors that increase the incidence of air leak include: emphysema, steroids or other medical conditions that slow wound healing, bilobectomy compared with lobectomy, poor chest tube placement, and operations that do not employ techniques that help prevent air leaks. The latter include: pleural tents, pericardial buttressed stapled lines, fissure-less surgery, and checking for air leaks prior to closing. Chest tubes are commonly placed after thoracotomy to drain blood, serum, and air from the pleural space. The ideal number, type, or size of a chest tube to place after elective pulmonary resection is controversial. There are little data to suggest that one practice is better than another; however, recently several prospective randomized studies have shown that one chest tube works as well as two. After routine lobectomy we have changed our practice based on these studies and now only use one chest tube in patients who do not have a large untreatable air leak or a large fixed pleural space deficit after lobectomy. We use a 28-French soft catheter that is difficult to kink. The advantage of one tube is that it may cause less pain and morbidity, but this advantage is theoretical. Recently, a great deal of scientific research has been devoted to the best management of chest tubes after pulmonary resection. Until 1998 there were few if any objective data concerning the best setting (i.e., suction or water seal) for chest tubes after lung surgery and most practices were opinions based on where one trained and who one believed. We and others have studied this process using prospective randomized studies. We have developed a classification system for air leaks so as to be able to study air leaks objectively with scientific rigor. The summary of our work is that we prefer to connect the tubes to suction for the night of surgery and

then convert to water seal the next morning, especially in patients who have an air leak. If patients have no leak but have a pneumothorax, we prefer suction. In patients with an air leak, we prefer water seal unless there is a pneumothorax, in which case we prefer –10 cm of suction (instead of –20). However, Brunelli, who has carefully and critically studied the problems of air leaks after the pulmonary resection process, prefers water seal during the day and some suction at night. Marshall has corroborated our findings in a prospective randomized study of her own and found that air leaks are best treated by placing chest tubes on water seal instead of suction in the postoperative setting. Brunelli did not find a statistical advantage for water seal; however, he did identify a trend in patients who did not undergo pleural tenting favoring water seal over suction. Thus, the best treatment of most air leaks appears to be water seal in most patients so long as they do not develop a pneumothorax or subcutaneous air on seal. We have also studied the use of daily chest radiographs, which most surgeons perform to ensure the effective removal of air and fluid from the pleural space. These films, which are labor intensive, costly, and wake the patient in the early morning hours, are not needed if the patient does not have an air leak or other clinical problems. If the postoperative chest roentgenogram in the recovery room after surgery has no significant pathology and the patient is not hypoxic, an everyday early morning chest x-ray is not needed. If a patient develops subcutaneous emphysema and hypoxia and there is a pneumothorax, then suction should be added. We have also studied the problem of air leaks in patients with a concomitant pneumothorax and found that the least amount of suction (usually –10 cm of water) needed to alleviate the pneumothorax or subcutaneous air is best. Other daily management techniques should include “stripping” the tubes in the attempt to remove clots, examining all connections to ensure their integrity, and maintaining appropriate water levels in all drainage bottles. If the leak continues after postoperative day 4, then the patient may be discharged home on a Heimlich valve or a similar device such as an Atrium Express (Atrium USA, Hudson, NH). The chest tube can be removed after 2 weeks even if the air leak remains. A discharge PA and lateral x-ray should be performed prior to leaving, which serves as an important baseline film for later comparisons. Occasionally, massive subcutaneous emphysema may occur if either the loss of air from the lung into the pleural cavity exceeds the drainage capacities of the chest tube or the tube is positioned away from the site of the air leak (Fig. 99-4). The latter condition is much more common than the former. If this occurs, chest tubes should be examined for patency. Occasionally, a tube will be found to be clamped or twisted by the bed or IV pole, at the skin level or in the subcutaneous fat. If a tube is occluded because of a plug, the tube should be stripped; if this fails to re-establish patency, the tube should be opened and suctioned, using sterile technique, with a nasotracheal suction catheter. Some surgeons irrigate an occluded tube with sterile saline, but because of the possibility of

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tomy balanced drainage system The tube can removed the morning of POD #1 if there is no bleeding.

Amount of Chest Tube Drainage

Figure 99-4 Massive subcutaneous emphysema following a pulmonary resection.

infectious contamination this should only be used as a last resort. If all methods fail to re-establish patency of a chest tube, the tube should be removed and a new one inserted. Although uncomfortable and disfiguring, massive subcutaneous emphysema is rarely life threatening. However, two dangerous situations can arise. First, in patients with tracheostomies, the tube can be displaced into the subcutaneous tissues if the skin is elevated up and away from the tracheal opening. Second, circumferential massive lifting of the skin around the thorax can lead to restriction of normal outward excursions of the rib cage excursion, limiting tidal volume— as in the case of limitation imposed by circumferential eschar in a burn patient. Such emergency situations may require the placement of small skin incisions, usually in an infraclavicular location. We have only had to perform these incisions a few times. In both instances, the patient’s eyelids were so swollen with air that the patient could not see. This technique should be reserved for this scenario when the chest tube is in good position, on high (–40 cm of water) suction and patent, and the subcutaneous air is not decreasing.

Postoperative Chest Tube Management Postpneumonectomy space drainage is managed differently from postlobectomy drainage. After pneumonectomy, the position of the mediastinum is a major concern. Shift of the mediastinal structures either into the pneumonectomy cavity or toward the residual lung can lead to either hemodynamic or respiratory compromise. To allow “balancing” of the mediastinum after a pneumonectomy, most surgeons leave a single chest tube in the pleural cavity. This tube can be removed in the operating room after the patient has been returned to the supine position and is hemodynamically stable. We prefer to leave the tube in overnight attached to a special pneumonec-

For resections other than pneumonectomy, chest tubes are removed when there is no air leak and fluid output has decreased. The maximum amount of drainage per day has not been studied. Many surgeon use less than 200 ml a day, but there are no data that higher volumes cannot be accepted. We currently remove tubes with 450 cc per day and this has been a safe cutoff value in over 4000 thoracotomies. Perhaps even a higher number can be used. One needs to ensure there is no blood, chyle, or cerebrospinal fluid prior to removal of the tube as described in the following sections. Removal is performed while the patient executes a Valsalva maneuver. Some argue that it may be best to remove the tube when the patient takes a deep breath out and holds it, as opposed to a deep breath in and holds it. There are little data to suggest the best way to perform chest tube removal, and we are currently performing a prospective study to help answer this question. An occlusive dressing is maintained over the site for 36 hours. Patients should be advised that it is not uncommon to have additional drainage after tube removal. If the chest tube output in the first several hours after surgery is greater than 200 cc/hour for more than a few hours or if clinically suspected, bleeding must be ruled out. Early surgical re-exploration, before the patient leaves the recovery room, is our preference if the patient’s coagulogram (INR, PTT, and platelet count) is normal.. Each individual patient’s clinical scenario should be considered. Confirmation that the drainage is blood can be obtained by simple visual inspection of the effluent or, if needed, the effluent can be sent for a confirmatory hemoglobin and/or hematocrit level.

High Output Chest Tube States (Chylothorax, Subarachnoid-Pleural Fistula) Chylothorax/Subarachnoid Pleural Fistula A chylothorax is diagnosed when a milky white chylous effusion occurs out of the chest tube in a patient after enteral intake. It consists of intestinal lymphatic fluid (lymphocytes, immunoglobulins, and enzymes) and fat (fat-soluble vitamins, chylomicrons, and triglycerides). Once the patient starts to eat, the diagnosis is obvious. However, the diagnosis should be expected in a patient who is not eating, has a stable hemoglobin and hematocrit, and whose chest tube output is high but the cause is unexplained. The diagnosis is made by sending the effluent for analysis. A triglyceride level greater than 110 mg/dl or a positive Sudan fat stain helps secure the diagnosis. The incidence of a chylothorax has been reported to be about 1 to 2.4 percent after lobectomy, and 0.7 to 1 percent after pneumonectomy. The treatment of a chylothorax depends on the level of the injury. Most commonly after pulmonary resection, a chylothorax occurs from engorged lymphatics in patients who have positive mediastinal (N2) nodal disease who have

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undergone an aggressive nodal dissection. It is also seen in patients who have received neoadjuvant therapy for N2 nodal disease and have undergone a complete thoracic lymphadenectomy. The best treatment of most patients is to make them NPO and ensure the chest tube volume decreases. A medium-chain triglyceride (MCT) diet should then be instituted as well. In this situation re-operation is less helpful, even if fibrin glue is applied to the draining nodal basins, because the lymphatic channels are engorged with obstructed lymphatics from cancer. Radiation has been used successfully in this situation. The patient may be discharged home with the tube in place on the MCT diet for 2 weeks. Finally, we challenge the patient with fatty meals for 2 days. If chest tube output is decreased, the chest tube is removed. However, if the output volume remains high despite compliance on a MCT diet, then complete cessation of all oral intake is needed and total parental nutrient is required. Nutritional parameters should be tested and the white blood cell count monitored. Persistent chylothorax can lead to neutropenia, infection, and malnutrition. Less frequently, a chylothorax following pulmonary resection occurs due to injury to the main thoracic duct. If there is an injury to the main thoracic duct (best determined from a lymphangiogram) or from a high chest tube output greater than 800 c/day, then early re-operation with duct ligation and pleurodesis is best. Subarachnoid Pleural Fistulas Subarachnoid pleural fistulas are unusual. The incidence of a subarachnoid pleural fistula after thoracic surgery is very low, but several cases have been reported. They occur most often after trauma but may also complicate thoracic surgical procedures if dissection in the costovertebral angle or excessive traction avulses a thoracic nerve root from its dural sleeve. The most common setting for this to occur is during resection of malignancies invading either the posterior chest wall or vertebral column. However, retraction of the ribs for exposure during a standard posterolateral thoracotomy may generate sufficient traction to avulse a nerve root. The presence of a communication between the subarachnoid and pleural spaces allows for the bidirectional movement of cerebrospinal fluid and pleural fluid: During inspiration, low intrathoracic pressure draws cerebrospinal fluid into the thorax; during expiration, the elevated thoracic pressure forces air and potentially contaminated material outward into the subarachnoid space. A chest tube placed next to the fistulous tract may increase loss of cerebrospinal fluid. As a result, patients may develop headaches, meningismus, paresis, seizures, hemorrhagic infarcts, and obtundation leading to death. Cerebrospinal fluid analysis may be bizarre, owing to the entry of serosanguineous fluid into the subarachnoid space. The diagnosis of a communication between the subarachnoid and pleural spaces is suggested by visualization of a pneumocephalus on skull radiographs. More specifically, the fistulous communication may be delineated by contrast CT myelography. The time between thoracotomy and clin-

ical diagnosis of the fistula ranges from 5 to 8 weeks. The unpredictable nature of the neurologic sequelae mandates that surgical closure of the dura be carried out as soon as the diagnosis is confirmed via re-operation and application of glues and a muscle flap.

Atrial Fibrillation Atrial fibrillation is another very common complication after pulmonary resection. The incidence varies due to inconsistent definitions. Its incidence ranged from 12 to 20 percent in several large series, with over 500 patients each with a peak onset on postoperative day 2. Risk factors for postoperative atrial fibrillation include advanced age (greatest for those more than 70 years old), amount of lung resected, clamshell incision, history of congestive heart failure, and type of pulmonary resection (rightsided pneumonectomy). The incidence is also dependent on the type of pulmonary resection performed. Other identified risk factors for the development of postoperative atrial fibrillation include male gender, previous cardiac arrhythmia, or intraoperative blood transfusions. The ideal treatment of atrial fibrillation is prevention. A prospective randomized trial from Sloan Kettering showed that prophylactic diltiazem reduced the overall incidence of atrial fibrillation after standard and intrapericardial pneumonectomy. The treatment of postoperative atrial fibrillation depends on the patientâ&#x20AC;&#x2122;s ventricular rate and hemodynamic status. If the patient is unstable, transfer him or her to the intensive care unit and obtain an urgent cardiology consultation. Electrical cardioversion may be needed. However, the vast majority of patients are hemodynamically stable despite a rapid ventricular rate. These patients are best treated with a calcium channel blocker. Often a drip can be used while the blood pressure is carefully monitored. The use of digitalis has fallen out of favor, but this safe and time-tested drug slows the ventricular rate, although it may not restore normal sinus rhythm. More recently, amiodarone has been shown to be effective in the treatment of supraventricular arrhythmias; it is safe even in elderly patients and often restores normal sinus rhythm.

Pneumonia Pneumonia remains a vexing problem following pulmonary resection. Although the incidence at our institution has been reported to be as low (2.2 percent)in one series, we have reported much higher rates (7â&#x20AC;&#x201C;9 percent) in other series. Deslauriers et al. in 1994 and Duque et al. in 1997 reported incidences ranging up to 6 percent. When pneumonia occurs, it wreaks significant morbidity. Risk factors include preoperative hospital stay, immunocompromised state, procedure type (pneumonectomy > lobectomy), compromised pulmonary reserve, smoking, and atelectasis. Atelectasis, a risk factor for the development of pneumonia, is a common complication after pulmonary surgery itself, as shown by Deslauriers and Ginsberg. Fortunately, most

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atelectasis is platelike, discoid, or linear and is subsegmental and has little clinical consequence in the patient with adequate pulmonary reserve. However, atelectasis that is segmental or greater may cause clinical demise and usually requires bronchoscopy. Risk factors for this type of atelectasis are poor cough, impaired pulmonary function, inadequate pain control, diaphragmatic dysfunction, chest wall instability, and sleeve resection. The clinical sequela of this type of atelectasis is ventilation/perfusion mismatch that leads to hypoxemia, impaired alveolar macrophage function, and often pneumonia. Again, prevention is the best treatment. Chest physiotherapy with vibratory percussion, frequent spirometry exercises, ambulation at least three to four times daily, and secretion control is the mainstay of prevention. Ambulation not only decreases the risk of deep venous thrombosis, but also it helps rehabilitate the patient. It changes pulmonary blood flow and helps improve areas of ventilation/perfusion mismatch. Respiratory treatments entail mist inhalation to loosen secretions, inhaled nebulized bronchodilator, and chest percussion with postural drainage. Pain control allows for deep cough and facilitates adequate mobilization of secretions. Despite these techniques, sometimes a new infiltrate develops. Sputum cultures should be obtained and broadspectrum antibiotics started. Although Tobin et al. in 1984 showed that up to 30 percent of new infiltrates in the intensive care unit prove not to be pneumonia, a missed pneumonia in a postoperative patient has high morbidity. Once the culture results are available with a sensitivity panel, the antibiotics should be narrowed to treat the offending organism. This helps prevent the selection of fungus or other resistant organisms. Often there is no evidence of an infiltrate but the patient develops a productive cough, fever, and/or elevated white count. Since the radiological findings of an infiltrate often lag behind a clinical pneumonia, especially in the dehydrated patient, broad-spectrum antibiotics with fungal prophylaxis should be started. If all the cultures are negative, then the antibiotics can be stopped. However, if the infiltrate worsens or if the patient’s clinical course deteriorates, bronchoalveolar lavage should be performed to help identify the pathogen and direct antibiotic coverage.

Postoperative Somnolence from Epidural Analgesia Epidural analgesia has been one of the most important advances in general thoracic surgery in the last decade. It reduces respiratory complications by allowing patients to breathe deeper, walk sooner, and better mobilize secretions. It has allowed us to operate on older and sicker patients. These advantageous effects, however, have resulted in a dual-edged sword. By enabling us to safely operate on older, sicker, and weaker patients with less cardiopulmonary reserve, it has “raised the bar” to such heights that there are now few, if any, patients who cannot tolerate a thoracotomy, wedge resection, or segmentectomy.

Perioperative Care of the Patient Undergoing Lung Resection

Complications from epidural analgesia include accidental entry into the subarachnoid space, hematoma, urinary retention, itching, nausea, and respiratory depression. A “wet tap” can occur when the needle or catheter accidentally enters the subarachnoid space. The former should be immediately recognized by the one placing the epidural. The latter is recognized when the test dose given after insertion results in numbness in the chest area. The most significant and common complication from epidural analgesia is the over-narcotized patient. This is not uncommon and needs to be swiftly recognized and treated. New-onset somnolence may have several etiologies (stoke, intracranial abnormalities, electrolyte imbalances, sundowning, etc.); however, the epidural should not be overlooked as a potential cause. Often, a patient’s family members aggressively deliver the analgesia. Clinical staff should discourage this practice. If the patient cannot deliver his or her own pain medicines or does not understand how to use the machine, he or she is a poor candidate for PCA units and should not have one. In this case, traditional pain medicines should be delivered by the nursing staff. If the patient is somnolent from excessive narcotic analgesia, we prefer to arouse her or him with external stimuli. A chest rub or aggressive bedside maneuvers can quickly wake a patient up, and this helps establish the diagnosis and can eliminate other potential causes. A reliable calm family member in the room can also be helpful, and often one-on-one nursing may be needed. If external stimulation fails, if the patient’s oxygen saturations remain low or an arterial blood gas continues to show hypercapnia despite aggressive pulmonary toilet and incentive spirometry, then we prefer to give onefourth amp of intravenous naloxone (hydrochloride, Endo Labs, Chadds Fords, PA). A higher dose can result in too much rebound pain. If the patient does not awaken after this, a higher dose can be administered after other causes of the newonset somnolence have been ruled out. This patient is best transferred to the intensive care unit. If the patient arouses with Narcan, we eliminate the epidural basal rate and/or remove the epidural altogether, depending on the situation and postoperative day.

Aspiration Aspiration is a devastating complication after pulmonary surgery. The incidence is often underestimated because pneumonia may be caused by silent (unsuspected) aspiration. Risk factors for an acute aspiratory event include age (the incidence is greater in elderly patients), altered mental status, and weak and/or sleepy patients. It commonly occurs in the CT scanner because patients are often febrile, weak, and sick (which is why they are often sent to the scanner) and then have to lie flat for considerable lengths of time. It can also occur in a healthy patient who is preparing to go home following an uncomplicated postoperative course. It can take this type of joyous moment and within a few days end with sepsis, multiorgan system failure, and death. Therefore, one’s guard against aspiration can never be lowered; its occurrence

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must be aggressively avoided. Patients should be instructed to eat only when wide awake and sitting upright at 90 degrees in bed or a chair. Family members should be discouraged from “helping feed the patient to get him or her stronger,” especially if the patient is sleepy. Once aspiration occurs, patients quickly desaturate. Continuous pulse oximetry monitoring until discharge helps signal this event and leads to a quick diagnosis. The diagnosis can be made by history if the patient is still alert or by a family member if he or she was present at the time of the aspiration event. Treatment depends on the patient’s clinical status. Most patients should have a nasogastric tube placed, a chest radiograph taken, an arterial blood gas drawn, and other lab work performed. If the patient is in extreme respiratory distress, immediate intubation with bronchoscopy with lavage and cultures should be performed. Broad-spectrum antibiotics should be started immediately, hemodynamics maximized to help perfuse and protect end-organs, and patient should be transferred to the intensive care unit.

Pulmonary Edema One of the biggest obstacles facing the surgeon who has performed a pulmonary resection is convincing inexperienced anesthesiologists, nurses, residents, and fellows that patients do not require and should not have the “traditional” amount of fluids that most other postsurgical patients need. Pulmonary surgery does not cause large fluid shifts, as does intraperitoneal surgery. Moreover, expansion and deflation of the lung secondary to double lumen tube anesthesia, intraoperative barotrauma and volutrauma to the alveoli, and surgical manipulation of the lung all lead to pulmonary damage and edema. Therefore, the guiding standard to treat pulmonary edema is the principle of prevention. The true incidence is difficult to gauge because of the different etiologies and definitions. The tendency to give the patient large volumes of fluids after epidural placement because of hypotension from the sympathectomy effect must be avoided. This difficult task is only accomplished by continued communication among the surgeons; the rest of the surgical service; and the pain and anesthesia nurses and residents who continually rotate through these services. We prefer the use of alpha agonists such as phenylephrine if mean arterial blood pressure falls after epidural dosing in the patient who is to undergo pulmonary resection after one 250-cc bolus of fluids. However, despite “running the patient dry,” some patients still develop pulmonary edema. Obviously, one needs to ensure that the cause is not cardiac insufficiency. Diuretics remain the mainstay of treatment and the sodium level can be used as a judge of the patient’s fluid status. Other factors that need to be considered include the patient’s weight gain since surgery, the chloride level, and the urinary osmolarity if diuretics have not been given yet. The more commonly used central venous pressure and/or pulmonary capillary pressure are not needed in most patients unless they are “wet” on chest roentgenogram, hypoxic, hypotensive, and oliguric. If the patient continues to deteriorate, echocardiography should be

performed to assess both right and left ventricular function and the patient should be transferred to the intensive care unit for placement of a Swan-Ganz catheter. Blood cultures and appropriate scans should be performed to rule out occult infection and “leaking capillary membranes” from sepsis. If high-dose diuretics are not successful, the patient may have adult respiratory distress syndrome. Management of this complication is discussed elsewhere in this volume.

Right Ventricular Failure It is possible that some patients with postoperative complications after lung resection experience an acute exacerbation of pulmonary arterial hypertension that leads to right ventricular failure and a decrease in cardiac output. Several reports suggest this possibility. One study, based on the use of thermodilution catheters, found that the right ventricular end-diastolic volume increased from 153 to 177 ml, and that the right ventricular ejection fraction decreased from 45 to 36 percent in the first few postoperative days. Another, using echocardiography, found that patients who developed supraventricular arrhythmias after lung resection had a significant increase in the velocity of the tricuspid regurgitant jet, whereas those who underwent lung resection without arrhythmias did not. A third study of patients undergoing pneumonectomy was unable to find any hemodynamic variable or pulmonary function test that augured early morbidity. It did, however, indicate that a right ventricular ejection fraction of less than 35 percent, pulmonary vascular resistance greater than 200 dyne · s/cm5 , and a pulmonary vascular resistance/right ventricular ejection fraction ratio equal to or greater than 5.0 indicated long-term cardiopulmonary disability. No studies have been reported of patients suffering severe complications, such as pneumonia, in the remaining lung after pneumonectomy to determine whether right ventricular failure is a component of cardiopulmonary dysfunction. A better understanding of the alterations in right ventricular function might lead to modification in patient management. For example, the anesthetic technique might be altered. In a recent study concerning ventilation of one lung, the administration of propofol was associated with sustained decrease in right ventricular ejection fraction and mean cardiac output as compared with the administration of isoflurane. The use of proper anesthetic agents might minimize the additive effects of hypoxic pulmonary vasoconstriction and surgical resection of the pulmonary vascular bed. In principle, numerous therapies are available to lessen the burden on the right ventricle in the postoperative period. Among the agents proposed are nitric oxide, adenosine, calcium channel blockers, dopamine, and mechanical devices. However, none of these has yet been put to the test.

Early Bronchopleural Fistula A bronchopleural fistula (BPF) is defined as a communication between a lobar or segmental pulmonary bronchi and

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the pleural space. It is different from an alveolar pleural fistula. This difference is not just one of semantics, but also centers around treatment since an alveolar pleural fistula almost never requires a re-operation, whereas a BPF almost always does. A BPF can present as an early complication but more commonly is a late one. The incidence of a BPF has been reported to be 4.5 to 7 percent after a pneumonectomy(8.6 percent if right pneumonectomy and 2.3 percent for left pneumonectomy), about 1 percent after a lobectomy,and 0.3 percent after a segmentectomy. However, a bronchopleural fistula after lobectomy that was performed for cancer is very rare. Risk factors for a BPF are divided into patient characteristics and intraoperative techniques. The former include: infectious etiology, preoperative radiation, type of procedure (right pneumonectomies have the greatest incidence), immunocompromised state such as history of solid organ transplant, and comorbidities such as diabetes. Intraoperative technique risk factors include: surgeon inexperience, a long stump, leaving lymph nodes on the bronchus, and injuring the arterial blood supply to the bronchus. When a BPF presents as an early complication, the patient develops a new large air leak he or she did not have before. It usually is a continuous leak as described by the RDC classification system of air leaks. Treatment should be immediate recognition, which requires a high index of suspicion any time the air leak suddenly increases. Usually it can be confirmed with bronchoscopy; however, this test can be falsely negative, as a small BPF can be missed. If the diagnosis remains in question, a Xenon ventilation scan can be performed. (This is difficult if the patient is intubated.) The Xenon gas can be seen escaping the airway, traversing the pleural space, and going into the chest tube and drainage system. This secures the diagnosis. Once diagnosed, the BPF should be treated with reoperation using muscle flaps or omentum as further described elsewhere in this volume.

Postpneumonectomy Pulmonary Edema Postpneumonectomy pulmonary edema is a rare but lethal complication of pneumonectomy. For several reasons, the patient who has undergone pneumonectomy is thought to be at increased risk of pulmonary edema. First, although the removal of one lung is well tolerated if the pulmonary vasculature is normal, if preexisting pulmonary vascular disease is present, the reduced pulmonary vascular bed may be unable to accommodate the cardiac output without an inordinate increase in pulmonary arterial pressure. Second, disruption of lymphatics associated with mediastinal lymph node dissection may interfere significantly with the clearance of fluid from the lung. In the presence of these two predisposing factors, overzealous administration of fluid may lead to the formation of lethal pulmonary edema. The clinical presentation of postpneumonectomy pulmonary edema is that of a relatively uneventful initial 24- to 48-h postoperative period, followed by a relentlessly increasing need for respiratory support, usually culminating in death within 24 to 48 h. The pulmonary edema progresses despite

Perioperative Care of the Patient Undergoing Lung Resection

Figure 99-5 Postpneumonectomy pulmonary edema with onset 48 h after extrapleural pneumonectomy. There is a diffuse interstitial infiltrate present that was heralded by the insidious development of hypoxemia in this otherwise healthy 60-year-old woman.

aggressive efforts to effect diuresis and other supportive measures (Fig. 99-5). Current therapy is directed at limiting the administration of fluids perioperatively and providing supportive measures if the complication should arise. Postpneumonectomy syndrome is a rare complication manifested by cough and dyspnea on exertion that usually follows right pneumonectomy. It is due to progressive mediastinal shift with compression of the left mainstem bronchus by the vertebral column. The underlying cause of this complication of pneumonectomy is herniation of the contralateral lung into the vacant pleural space, causing compression of the mainstem bronchus between the aorta, pulmonary artery, or vertebral column (Fig. 99-6). Repair is directed toward repositioning and stabilizing the mediastinum in the midline by a combined procedure of cardiopexy and placement of pliable, variable-volume tissue expanders into the empty pleural space. Cardiopexy alone probably provides insufficient protection against recurrence. Before surgical repositioning, it can be difficult to assess whether significant tracheomalacia is present in the compressed segment. Persistent airway narrowing and symptoms of obstruction following correction of mediastinal shift may require placement of an airway stent or reoperation for resection of the affected bronchial segment.

Empyema Empyema is an uncommon complication after pulmonary resection. It is most often seen in patients who have undergone pneumonectomy. It is estimated to occur in about 2 to 16 percent of post-pneumonectomy patients. In a study by

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operative day 2 or 3 secondary to pneumonia, poor cough effort, or pulmonary edema. The patient often begins to develop signs of respiratory distress prior to seeing an infiltrate on chest roentgenogram. Sputum cultures should be obtained and immediate broadspectrum antibiotics should be started. These should be tailored to the cultures and sensitivities reported later. Pulmonary mechanics must be maximized; this includes minimal intravenous fluids, aggressive chest physiotherapy, continuous respiratory treatments with bronchodilators, incentive spirometry, frequent ambulation with physical therapy, control of secretions, and nutritional support. If the patient can not clear his or her own secretions, then nasal tracheal suction should be used to â&#x20AC;&#x153;encourageâ&#x20AC;? coughing. Nasal tracheal suctioning via a nasal trumpet or even mini-tracheostomy affords the surgeon other methods to help clear the airway and avoid recurrent atelectasis and pneumonia. If the patient is somnolent, she or he needs to be aroused and treated as described in the preceding. Arterial blood gases should be performed to rule out hypercapnia. If this fails, mini-tracheostomy can be performed to manually suction the upper airways, and bronchoalveolar lavage should be used to obtain sputum samples to identify the offending organisms.

Renal Insufficiency Figure 99-6 Marked shift of the mediastinum with hyperinflation of the left lung and tethering of the left mainstem bronchus over the vertebral column, characteristic of postpneumonectomy syndrome.

Varela, empyema was the most common cause of recidivism after pulmonary resection (18/727), 2.5 percent of patients. The primary risk factor has been cited to be pneumonectomy with an associated BPF. Less commonly cited risk factors include anatomic extent of disease (no association with stage I cancer, some association with stages II and III cancer), degree of surgical manipulation, and a compromised immunological host. The treatment is control of the pleural space. This can be established by chest tube placement, video-assisted thoracoscopic approach, or most commonly a redo thoracotomy with a muscle flap. If there is any question that an early BPF is the cause of the early empyema, then redo thoracotomy with muscle or omental harvesting is mandatory to not only drain the empyema and decorticate the lung, but to also buttress the open bronchus.

Pulmonary Insufficiency Despite preoperative tests and pulmonary preserving techniques, pulmonary insufficiency can still occur after pulmonary resection. The inability to extubate a patient immediately after the operation (which should be extremely rare) is a poor prognostic sign. The difficulty usually arises on post-

It is not uncommon for patients to have a increase in their creatinine level after pulmonary resection. Most patients are elderly and thus have reduced renal reserve, and many are hypotensive with the epidural and the low amount of fluids administered. Thus, early recognition of this problem entails checking the creatinine level on all patients who create less than 0.5 mg/kg per hr of urine. Treatment is early recognition, the removal of renal toxic agents such as Toradol (ketoconazole), and the gentle rehydration of the patient.

Postoperative Hemorrhage The incidence of postoperative hemorrhage after elective general thoracic surgical procedures in a non-coagulopathic patient is extremely low, almost unheard of. We, like most general thoracic surgeons, have limited this complication and currently have an incidence of 0.3 percent (7 patients in our last 2400 thoracotomies) that require re-exploration for bleeding. In all circumstances, bleeding was from a small vessel (or the bronchial artery in one patient). This low incidence, shared by many others, is achievable by having the attending surgeon present during the entire opening and closing of the chest. The pulmonary artery should be handled with meticulous care, and it should be carefully dissected. We prefer double ligation or stapling. The vein can be safely handled with a stapler as well. Prior to chest closure, the major vascular structures in addition to all other sites of surgical dissection should also be re-examined to ensure hemostasis. The inferior pulmonary ligament, which usually contains a small artery, should be checked. We perform a complete lymph node resection in all patients with bronchogenic carcinoma;

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therefore, all lymph node stations are potential sites of postoperative bleeding. This is especially true of the #7, subcarinal area. There is a large artery that feeds the subcarinal lymph nodes that comes off the carina. It should be visualized and ligated. This is often difficult to do, especially on the left side. Excessive cauterization should be avoided, especially in the aorta-pulmonary window lymph node area on the left and the paratracheal area on the right, to avoid injury to the recurrent laryngeal nerves. Bleeding can also occur from the pulmonary parenchyma, especially after wedge resection. This area needs to be re-evaluated prior to chest closure. The surface of the undercut rib both anteriorly and posterior should be carefully examined also. Finally, the chest tubes sites and pericostal sutures sites (if used instead of the preferred intracostal sutures) should be examined from inside the chest before closure. The branches of the bronchial artery that can spasm and later bleed should be identified and clipped or tied if dissected. If a patient is having excessive postoperative bleeding of greater than 200 ccs/hr (i.e., blood loss alone; not chyle, cerebrospinal fluid, or transudative effusion) for 2 to 4 consecutive hours, a coagulogram should be preformed. This panel of blood work includes an INR, PT, PTT, and platelet count. Any abnormalities should be corrected. If the mediastinum and/or pleural space do not have retained clots, and the coagulogram is abnormal, reoperation can be avoided if the underlying problem is corrected and the bleeding slows down. However, if there is residual clot in either space, this often leads to a local consumptive coagulopathy and the patient will continue to hemorrhage until the clot is fully evacuated, either via the chest tubes or usually by reoperation.

Perioperative Care of the Patient Undergoing Lung Resection

Figure 99-7 Consolidation of the right middle lobe caused by torsion following right upper lobectomy.

lowed by fixation to surrounding structures. If the lung is not viable, lobectomy or complete pneumonectomy may be required.

Pulmonary Torsion

Recurrent Laryngeal Nerve Injury

During a pulmonary resection, an extensive dissection is usually performed around the hilum for division of the pulmonary vessels. In addition, after an upper lobectomy, the inferior pulmonary ligament is divided to allow the lower lobe to rise within the pleural space to obliterate the residual apical space. Unfortunately, on rare occasions the increased mobility of these structures can lead to torsion of all or part of the residual lung, causing venous outflow obstruction and, possibly pulmonary gangrene. The right middle lobe is at greatest risk, especially after a right upper lobectomy, since the right middle lobe fissure-like connection to the right lower lobe is often diminutive. This complication should be avoidable by the surgeon, who should prevent it by tacking the middle to the lower lobe prior to closing the chest. However, it can still occur. Any portion of residual lung can be affected (Fig. 99-7). To reduce the risk of middle-lobe torsion, sutures or staples are used to secure the middle lobe to the remaining right lower lobe or upper lobe after lobectomy. Pulmonary torsion may be suggested by the radiographic finding of consolidated lung, in association with fever, leukocytosis, and purulent occasionally bloody sputum. Bronchoscopy may be helpful if a twisted bronchus can be demonstrated. The treatment is immediate surgical exploration with re-rotation of the affected lung, fol-

In a patient with lung cancer, the recurrent laryngeal nerves are vulnerable to injury because of either direct invasion by malignancy or injury during surgical dissection. The left vagus nerve is at greater risk than the right because of its course from the neck down into the left aspect of the mediastinum and across the aortic arch before giving off the left recurrent laryngeal nerve at the level of the inferior border of the aortic arch (Fig. 99-8). The nerve passes around the ligamentum arteriosum and â&#x20AC;&#x153;recursâ&#x20AC;? along the left tracheoesophageal groove. If either nerve is injured, unilateral vocal cord dysfunction results in hoarseness, an increased risk of aspiration, and marked decrease in the effectiveness of cough and the ability to clear secretions. Neurapraxia may resolve within weeks or last for 6 to 9 months. For the patient with limited pulmonary reserve who has undergone surgery with its attendant postoperative transient decrease in pulmonary function, vocal cord paralysis can be a devastating problem and may mean the difference between recovery and respiratory failure secondary to aspiration. Surgical correction of unilateral vocal cord paralysis is becoming increasingly popular. Techniques include injection of Gelfoam for temporary medialization, Teflon for permanent medialization, or surgical placement of a hand-crafted silicone elastomer implant. The success rate, as measured by

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Figure 99-8 Location of the left recurrent laryngeal nerve as it takes its origin from the vagus nerve at the level of the aortic arch. Note its position relative to the ligamentum arteriosum.

symptomatic improvement in dysphonia, aspiration, or incidence of pneumonia, exceeds 90 percent.

Pulmonary Herniation Herniation of the lung outside of the chest is uncommon but can occur in immunocompromised thin patients. The patient complains of a bulge with coughing or sneezing and a CT scan diagnoses the pulmonary parenchyma in an extrathoracic position. Treatment is surgical re-closure and approximation of the ribs.

CONCLUSION The key to the management of postoperative complications is full understanding of the cardiopulmonary physiologic changes that occur after pulmonary resection, either using thoracotomy or video-assisted techniques. Despite careful patient selection, meticulous operation, and hypervigilant postoperative care, many of the described complications occur. Early recognition secondary to a high index of suspicion along with prompt treatment leads to the minimization of the morbidity of these unwanted postoperative events.

Acknowledgment The author would like to thank Dr. Steve Goldberg for his contribution of the art work in this chapter.

SUGGESTED READING Adler RH, Plaut ME: Post-pneumonectomy empyema. Surgery 71:210–214, 1972. Amar D, Burt ME, Roistacher N, et al: Value of perioperative Doppler echocardiography in patients undergoing major lung resection. Ann Thorac Surg 61:516–520, 1996. Amar D, Roistacher N, Burt ME, et al: Effects of diltiazem versus digoxin on dysrhythmias and cardiac function after pneumonectomy. Ann Thorac Surg 63:1372–1381, 1997. Amar D, Zhang H, Leung DH, et al: Older age is the strongest predictor of postoperative atrial fibrillation. Anesthesiology 96:352–356, 2002. Asamura H, Naruke T, et al: Bronchopleural fistulas associated with lung cancer operations. J Thorac Cardiovasc Surg 104:1456–1464, 1992. Barbetakis N, Vassiliadis M: Is amiodarone a safe antiarrhythmic to use in supraventricular tachyarrhythmias after lung cancer surgery? BMC Surg 11:4–7, 2004. Bechard D, Wetstein L: Assessment of exercise oxygen consumption as preoperative criterion for lung resection. Ann Thorac Surg 44:344–349, 1987. Bolton JW, Weiman DS: Physiology of lung resection. Clin Chest Med 14:293–303, 1993. Bolton JW, Weiman DS, Haynes JL, et al: Stair climbing as an indicator of pulmonary function. Chest 92:783–788, 1987. Brunelli A, Al Refai M, Monteverde M, et al: Pleural tent after upper lobectomy: A randomized study of efficacy and duration of effect. Ann Thorac Surg 74:1958–1962, 2002.

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Brunelli A, Monteverde M, Borri A, et al: Comparison of water seal and suction after pulmonary lobectomy: A prospective, randomized trial. Ann Thorac Surg 77:1932–1937, 2004. Byrd RB, Burns JR: Cough dynamics in the post-thoracotomy state. Chest 67:654–657, 1975. Calvin SH, Ng SW, Lee TW, et al: Post-pneumonectomy empyema: Current management strategies. ANZ J Surg 75:597, 2005. Cardus D: O2 alveolar-arterial tension difference after ten days recumbency in man. J Appl Physiol 23:934–937, 1967. Cerfolio RJ: The incidence, etiology, and prevention of postresectional bronchopleural fistula. Semin Thorac Cardiovasc Surg 13:3–7, 2001. Cerfolio RJ: Advances in thoracostomy tube management. Surg Clin North Am 82:833–848, 2002. Cerfolio RJ, Allen MS, Deschamps C, et al: Postoperative chylothorax. Ann Thorac Cardiovasc Surg 112:1361–1365, 1996. Cerfolio RJ, Bass CS, Pask AH, et al: Predictors and treatment of persistent air leaks. Ann Thorac Surg 73:1727– 1730, 2002. Chalon J, Tayyab M, Ramanathan S: Cytology of respiratory epithelium as a predictor of respiratory complications after operations. Chest 67:32–35, 1975. Chan TY: Low-dose dopamine in severe right heart failure and chronic obstructive pulmonary disease. Ann Pharmacother 29:493–496, 1995. Craig DB, Wahba WM, Don HF: Airway closure and lung volumes in surgical positions. Can Anaesth Soc J 18:92–99, 1971. Deslauriers J, Ginsberg RJ, Dubois P, et al: Current operative mortality associated with elective surgical resection for lung cancer. Can J Surg 32:335–339, 1989. Deslauriers J, Ginsberg RJ, Piantadosi S, et al: Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 106:329S–330S, 1994. Dietrick JE, Whedon GD, Shorr E: Effects of immobilizations upon various metabolic and physiologic functions of normal men. Am J Med 4:3–36, 1948. Duque JL, Ramos G, Castrodeza J, et al: Early complications in surgical treatment of lung cancer: A prospective, multicenter study. Ann Thorac Surg 63:944–950, 1997. Ferguson MK, Little L, Rizzo L, et al: Diffusing capacity predicts morbidity and mortality after pulmonary resection. J Thorac Cardiovasc Surg 96:894–900, 1988. Fullerton DA, Jones SD, Grover FL, et al: Adenosine effectively controls pulmonary hypertension after cardiac operations. Ann Thorac Surg 61:1118–1124, 1996. Gamsu G, Singer MM, Vincent HH, et al: Postoperative impairment of mucous transport in the lung. Am Rev Respir Dis 114:673–679, 1976. Gerrard JW, Cockcroft DW, Mink JT, et al: Increased nonspecific bronchial reactivity in cigarette smokers with normal lung function. Am Rev Respir Dis 122:577–581, 1980.

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Ginsberg RJ, Hill LD, Eagan RT, et al: Modern 30-day operative mortality for surgical resections in lung cancer. J Thorac Cardiovasc Surg 86:654–658, 1983. Hofstetter Kr, Bjelland JC, Patton DD, et al: Detection of a broncho-pleural subarachnoid fistula by radionuclide myelography. Case report. J Nucl Med 18:981–983, 1977. Hollaus PH, Setinek U, Lax F, et al: Risk factors for bronchopleural fistula after pneumonectomy: Stump size does matter. Thorac Cardiovasc Surg 51:162–166, 2003. Hyman N, Foster RS Jr, DeMeules JE, et al: Blood transfusion and survival after lung cancer. Am J Surg 149:502–507, 1985. Jackson CV: Preoperative pulmonary evaluation. Arch Intern Med 148:2120–2127, 1988. Johnson PC, Driscoll TB, Carpenter WR: Vascular and extravascular fluid changes during six days of bed rest. Aerospace Med 42:875–878, 1971. Kambam JR, Chen LH, Hyman SA: Effect of short-term smoking halt on carboxyhemoglobin levels and P50 values. Anesth Analg 65:1186–1188, 1986. Kellow NH, Scott AD, White SA, et al: Comparison of the effects of propofol and isoflurane anaesthesia on right ventricular function and shunt fraction during thoracic surgery. Br J Anaesth 75:578–582, 1995. Kohman LJ, Meyer JA, Ikings PM, et al: Random versus predictable risks of mortality after thoracotomy for lung cancer. J Thorac Cardiovasc Surg 91:551–554, 1986. Kraus DH, Ali MK, Ginsberg RJ, et al: Vocal cord medialization for unilateral paralysis associated with intrathoracic malignancies. J Thorac Cardiovasc Surg 111:334–341, 1996. Krowka MJ, Pairolero PC, Trastek VF, et al: Cardiac dysrhythmia following pneumonectomy: Clinical correlates and prognostic significance. Chest 91:490–495, 1987. Kucich VA, Villareal JR, Schwartz DB: Left upper lobe torsion producing pulmonary torsion following lower lobe resection. Chest 95:1146–1147, 1989. Kutlu CA, Sayar A, Olgac G, et al: Chylothorax: A complication following lung resection in patients with NSCLC: Chylothorax following lung resection. Thorac Cardiovasc Surg 51:342–345, 2003. Laver MB, Hallowell P, Goldblatt A: Pulmonary dysfunction secondary to heart disease: Aspects relevant to anesthesia and surgery. Anesthesiology 33:161–192, 1970. Lemaire LC, Van Lanschot JM, Stoutenbeek CP, et al: Thoracic duct in patients with multiple organ failure: no major route of bacterial translocation. Ann Surg 229:128–136, 1999. Lewis JW Jr, Bastanfar M, Gabriel F, et al: Right heart function and prediction of respiratory morbidity in patients undergoing pneumonectomy. J Thorac Cardiovasc Surg 108:169– 175, 1994. Lindgren L, Lepantalo M, von Knorring J, et al: Effect of verapamil on right ventricular pressure and atrial tachyrhythmia after thoracotomy. Br J Anaesth 66:205–211, 1991. Marini JJ, Tyler ML, Hudson LD, et al: Influence of headdependent positions on lung volume and oxygen saturation in chronic airflow obstruction. Am Rev Respir Dis 129:101–105, 1984.

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Marshall MB, Deeb ME, Bleier JI, et al: Suction vs water seal after pulmonary resection: a randomized prospective study. Chest 121:831–835, 2002. Martinez FJ, Paine R III: Medical evaluation of the patient with potentially resectable lung cancer, in Pass HI, Mitchell JB, Johnson DH, Turrisi AT (eds), Lung Cancer: Principles and Practice. Philadelphia, Lippincott-Raven, 1996, pp 511–534. Massard G, Wihlm JM: Postoperative atelectasis. Chest Surg Clin North Am 8:503–529, 1998. Merrigan BA, Winter DC, O’Sullivan GC: Chylothorax. Br J Surg 84:15–20, 1997. Miller JI, Landreneau RJ, Wright CE, et al: A comparative study of buttressed versus nonbuttressed staple line in pulmonary resections. Ann Thorac Surg 71:319–322, 2001. Mols P, Huynh CH, Deschamps P, et al: Acute effect of nifedipine on systolic and diastolic ventricular function in patients with chronic obstructive pulmonary disease. Chest 103:1381–1384, 1993. Oliver RM, Fleming JS, Waller DG: Right ventricular function at rest and during exercise in chronic obstructive pulmonary disease. Chest 103:74–80, 1993. Olsen GN, Bolton JW, Weiman DS, et al: Stair climbing as an exercise to predict the postoperative complications of lung resection: Two years’ experience. Chest 99:587–590, 1991. Pairolero PC, Arnold PG, Trastek VF, et al: Postpneumonectomy empyema: The role of intrathoracic muscle transposition. J Thorac Cardiovasc Surg 99:958–968, 1990. Pastorino U, Valente M, Piva L, et al: Empyema following lung cancer resection: risk factors and prognostic value on survival. Ann Thorac Surg 33:320–323, 1982. Peters RM, Wellons HA Jr, Htwe TM: Total compliance and work of breathing after thoracotomy. J Thorac Cardiovasc Surg 57:348–355, 1969. Pollack IF, Pang D, Hall WA: Subarachnoid-pleural and subarachnoid-mediastinal fistulae. Neurosurgery 26:519– 525, 1990. Pryor JA, Webber BA, Hodson ME: Effect of chest physiotherapy on oxygen saturation in patients with cystic fibrosis. Thorax 45:77, 1990. Reed CE, Spinale FG, Crawford FA Jr: Effect of pulmonary resection on right ventricular function. Ann Thorac Surg 53:578–582, 1992. Riveron FA, Adams C, Lewis JW, et al: Silastic prosthesis plombage for right pneumonectomy syndrome. Ann Thorac Surg 50:465–466, 1990. Romero S, Martin C, Hernandez L, et al: Chylothorax in cirrhosis of the liver: analysis of its frequency and clinical characteristics. Chest 114:154–159, 1998. Roselli EE, Murthy SC, Rice TW, et al: Atrial fibrillation complicating lung cancer resection. J Thorac Cardiovasc Surg 130:438–444, 2005. Rossaint R, Falke KJ, Lopez F, et al: Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399– 405, 1993.

Ruckdeschel J, Piantadosi S: Quality of life in lung cancer surgical adjuvant trials. Chest 1066:324S–328S, 1994. Sabanathan S, Eng J, Mearns AJ: Alterations in respiratory mechanics following thoracotomy. J Roy Coll Surg [Edinburgh] 35:144–145, 1990. Sabanathan S, Richardson J: Management of postpneumonectomy bronchopleural fistulae: A review. J Cardiovasc Surg [Torino] 35:449–457, 1994. Schulz V: Preoperative treatment of chronic obstructive lung disease, in: Peters RM, Toledo J (eds), Current Topics in General Thoracic Surgery: An International Series, vol 2: Perioperative Care. Amsterdam, Elsevier, 1992, pp 52–68. Shimizu K, Yoshida J, Nishimura M, et al: Treatment strategy for chylothorax after pulmonary resection and lymph node dissection for lung cancer. J Thorac Cardiovasc Surg 124:499–502, 2002. Siebecker K, Sadler P, Mendenhall J: Postoperative ear oximeter studies on patients who have undergone pulmonary resection. J Thorac Surg 36:88–94, 1958. Slater JP, Goldstein DJ, Ashton RC Jr, et al: Right-to-left venoarterial shunting for right circulatory failure. Ann Thorac Surg 60:978–985, 1995. Sonett JR, Krasna MJ, Suntharalingam M, et al: Safe pulmonary resection after chemotherapy and high-dose thoracic radiation. Ann Thorac Surg 68:316–320, 1999. Stein M, Cassara EL: Preoperative pulmonary evaluation and therapy for surgery patients. JAMA 211:787–790, 1970. Tarkka M, Polela R, Lepojarvi M, et al: Infection prophylaxis in pulmonary surgery: A randomized prospective study. Ann Thorac Surg 44:508–513, 1987. Taylor HL, Henschel A, Brozek J, et al: Effects of bed rest on cardiovascular function and work performance. J Appl Physiol 2:223–235, 1949. Temes RT, Wilms CD, Endara SA, et al: Fissureless lobectomy. Ann Thorac Surg 65:282–284, 1998. Terzi A, Furlan G, Magnanelli G, et al: Chylothorax after pleuro-pulmonary surgery: a rare but unavoidable complication. Thorac Cardiovasc Surg 42:81–84, 1994. Tobin MJ, Grenvik A: Nosocomial lung infection and its diagnosis. Crit Care Med 12:191, 1984. van Migehem W, Tits G, Demuynck K, et al: Verapamil as prophylactic treatment for atrial fibrillation after lung operations. Ann Thorac Surg 61:1083–1086, 1996. Vaporicyan AA, Correa AM, Rice DC, et al: Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: Analysis of 2588 patients. J Thorac Cardiovasc Surg 127:779–786, 2004. Varela G, Aranda JL, Jimenez MF, et al: Emergency hospital readmission after major lung resection: Prevalence and related variables. Eur J Cardiothorac Surg 26:494–497, 2004. Vester SR, Faber LP, et al: Bronchopleural fistula after stapled closure of bronchus. Ann Thor Surg 52:1253–1258, 1991. Vester SR, Faber LP, Kittle CF, et al: Bronchopleural fistula after stapled closure of bronchus. Ann Thorac Surg 52:1253– 1257, 1991.

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Wansbrough-Jones MH, Nelson A, New L, et al: Bronchoalveolar lavage in the prediction of post-thoracotomy chest infection. Eur J Cardiovasc Surg 5:433–434, 1991. Warner MA, Offord KP, Warner ME, et al: Role of preoperative cessation of smoking and other factors in postoperative pulmonary complications: A blinded prospective study of coronary artery bypass patients. Mayo Clin Proc 64:609– 616, 1989. Weissman C, Kemper M, Damask MC, et al: Effect of rou-

Perioperative Care of the Patient Undergoing Lung Resection

tine intensive care interactions on metabolic rate. Chest 86:815–818, 1984. West JB: Ventilation-Blood Flow and Gas Exchange, 3rd ed. Philadelphia, Lippincott, 1977. Wong PS, Goldstraw P: Pulmonary torsion: A questionnaire survey and a survey of the literature. Ann Thorac Surg 54:286–288, 1992. Zeldin RA, Normandin D, Landtwing D, et al: Postpneumonectomy pulmonary edema. J Thorac Cardiovasc Surg 87:359–365, 1984.

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100 Thoracic Trauma Larry R. Kaiser

Francis W. DiPierro

I. INITIAL MANAGEMENT Ensuring Airway Patency and Breathing Emergency Department Interventions II. BLUNT THORACIC TRAUMA Tracheobronchial Injuries Airway Ruptures Pulmonary Contusion Rib Fracture and Flail Chest Sternal Fracture Diaphragmatic Injury

Chest trauma can be classified as either blunt or penetrating. Blunt injury most commonly results from motor vehicle accidents but may also result from falls or beatings. Penetrating injuries are the result of stab or gunshot wounds and occasionally of impalement. The approach to diagnosis and treatment of injuries to the chest depends greatly on the mechanism of injury that influences the incidence and type of associated injuries. Most, if not all, gunshot wounds of the chest require thoracotomy for management, whereas blunt injury usually is managed nonoperatively. The possibility of associated injuries, especially to the abdomen, must also be kept in mind and thoroughly investigated prior to initiating a treatment plan. This is especially important for penetrating injuries that occur in the so-called intermediate zone, in which the chest, abdomen, or both may be involved. An injury of the anterior chest in the fifth intercostal space may not involve intrathoracic structures, but the damage may be confined solely to the abdomen. The type of weapon as well as the site of injury is particularly important. The physician managing a penetrating chest injury needs to know what type of knife was used because it is crucial to know the length of the blade to assess the

This chapter has been slightly modified from the version that appeared in the third edition of Fishmanâ&#x20AC;&#x2122;s Pulmonary Diseases and Disorders.

III. PENETRATING INJURY OF THE LUNG IV. ARDS AFTER CHEST TRAUMA Mechanically Assisted Ventilation High-Frequency Jet Ventilation Extracorporeal Membrane Oxygenator Ventilation of Each Lung Separately V. CONCLUSION

possibility of visceral injury in either the chest or abdomen. Likewise for gunshot wounds, it is important to know the type of gun used to better address the potential extent and severity of the resultant injury. Often a determination of the type of gun may be made based on the appearance of the bullet seen on radiographic studies. Physicians managing patients with chest injuries must be prepared to make quick but accurate judgments and decisions and to act on them. With the development of trauma systems in most cities, more critically injured patients are surviving long enough to make it to the hospital, and the time spent prior to taking the patient to the operating room may make the difference between survival and mortality. The thoracic surgeon should be involved as soon as the patient arrives in the emergency room, although many chest injuries do not require operation.

INITIAL MANAGEMENT Ensuring Airway Patency and Breathing The initial goal in resuscitation of any patient sustaining a traumatic injury is to establish adequate oxygenation and ventilation. Of primary importance is the establishment of a patent airway. Objects commonly found obstructing the

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airway following chest trauma include the patientâ&#x20AC;&#x2122;s tongue, teeth, blood, secretions, or vomitus. Foreign objects as well as intrinsic laryngeal tissue, as in laryngeal fracture, can also obstruct the airway. As initial management, an oropharyngeal or nasopharyngeal airway can be inserted to maintain patency of the airway. Endotracheal intubation may be performed for apnea, to protect the airway from blood or secretions, or for hyperventilation in cases of severe head trauma. In cases of severe maxillofacial injury, a tracheostomy may need to be performed. Once patency of the airway has been established, it must be verified that breathing is adequate. The patientâ&#x20AC;&#x2122;s chest is fully exposed and inspected for evidence of rise and fall with respiration. In the intubated patient, a carbon dioxide monitor can be connected to the endotracheal tube to establish that gas exchange is adequate and that the tube is properly situated. Mechanical ventilation may be instituted as necessary.

Emergency Department Interventions Once adequate oxygenation and ventilation have been established, the primary resuscitation effort must rule out other life-threatening chest injuries. Simple, open, and tension pneumothoraces, hemothoraces, and pericardial tamponade are injuries that require immediate attention. Simple Pneumothorax Simple pneumothorax is created when a tear in the pleura allows entry of air into the pleural space with resultant loss of negativity in intrathoracic pressure. If an injury to the lung parenchyma produces an airleak, the air accumulates in the pleural space with each breath markedly increasing intrathoracic pressure, thereby shifting the mediastinum toward the opposite hemithorax (Fig. 100-1). This so-called tension pneumothorax is immediately life threatening because of the limitation of vena caval blood flow, which results in hypotension, tachycardia, and cardiac arrest. Treatment of simple pneumothorax requires insertion of a chest tube into the pleural space under sterile conditions, usually through the fifth or sixth intercostal space in the anterior axillary line, and connection of the tube to suction. In cases of tension pneumothorax, the pressure is initially relieved by placement of a standard 16-gauge needle in the anterior second intercostal space in the midclavicular line. This maneuver is followed by placement of a chest tube for definitive management. Tension Pneumothorax The diagnosis of tension pneumothorax should always be considered in a patient who has sustained penetrating chest trauma. It is less likely to occur after blunt trauma. In this circumstance, the likelihood of its occurrence increases with the severity of the injury to the chest wall (e.g., when rib fractures puncture the lung parenchyma). A high index of suspicion for tension pneumothorax should be maintained, while remembering that insertion of a large-bore needle into

the second intercostal space may result in injury to the lung if the diagnosis is incorrect. Clinical findings that support the diagnosis of tension pneumothorax include hypotension, absent breath sounds on the involved side with tympany on percussion, tracheal deviation toward the opposite side, and difficulty in mechanically ventilating the patient because of high airway pressures. Once the diagnosis of tension pneumothorax is suspected, treatment should be initiated immediately without waiting for chest radiograph confirmation. A rush of air exiting via the needle confirms the diagnosis as treatment is initiated. It should always be kept in mind that not every pneumothorax that results from trauma is a tension pneumothorax. Pneumothorax and Open Chest Wound When a pneumothorax is associated with an open chest wound after penetrating trauma, initial management is designed to restore a seal to the thoracic cavity. This is accomplished by applying a sterile occlusive dressing to the wound immediately followed by placement of a chest tube. The dressing allows some air to escape from the pleural space but does not allow air from the outside to enter. Hemothorax Both blunt and penetrating injuries of the chest may be associated with hemothorax, but this finding is far more common following penetrating trauma. Absence of breath sounds over the injured hemithorax and dullness to percussion are the characteristic physical findings. When the quantity of blood in the chest is small, the chest radiograph, which is usually taken as an anteroposterior film while the patient is supine, may only show haziness on the involved side (Fig. 100-2). On rare occasion, hemothorax, which is usually the result of injury to the lung parenchyma, can reproduce the physiological

Figure 100-1 Right tension pneumothorax. Note the marked shift of the mediastinum to the left and the total absence of lung markings on the right.

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Many patients with these injuries live long enough to make it to the hospital despite evidence of cardiac tamponade, which can be managed temporarily by massive replacement of blood volume. Cardiac tamponade results when the intrapericardial pressure becomes high enough to impede the low-pressure venous return to the heart resulting in circulatory collapse. Aspiration of as little as 10 to 20 ml of blood from the pericardial space often relieves intrapericardial pressure sufficiently to restore adequate circulation until the patient can be transported to the operating room for definitive repair of the inciting injury to the myocardium, usually the right atrium or ventricle. On rare occasion, blunt chest injury may cause cardiac tamponade. However, although myocardial rupture secondary to blunt trauma is usually fatal, an occasional patient with rupture of the atrium survives to reach the emergency room.

Figure 100-2 Hemothorax following a penetrating wound to the left chest showing the characteristic haziness seen on a supine film. The blood has been incompletely drained despite placement of a large-bore chest tube.

disturbances of a tension pneumothorax by increasing intrapleural pressure. Injury to the pulmonary artery or veins or the aorta is usually fatal before the patient reaches the hospital, but occasionally these patients do reach the emergency room. This type of massive exsanguination is usually obvious because of the clinical findings, and immediate transfer to the operating room is mandatory for any chance to save the patientâ&#x20AC;&#x2122;s life. For the more common type of hemothorax, which is due to lung parenchymal injury, a large-bore (36 Fr or greater) chest tube should be inserted, and blood volume replacement should be initiated simultaneously. Additional therapeutic maneuvers are based on the documentation of continued blood loss. Depending upon the extent of parenchymal injury, bleeding may have ceased by the time the chest tube is inserted. Thus, after the accumulated blood has drained, little if any further drainage will occur. If blood continues to drain, and the patient is hypotensive and tachycardic in spite of volume replacement, exploration of the chest is indicated. An intraabdominal injury should be ruled out; if suspected, the appropriate procedures should be initiated. Even in the hemodynamically stable patient, if blood continues to drain from the chest tube at a rate of greater than 200 ml/h for 2 or 3 h, the patient should be surgically explored. Following chest tube insertion, if the decision is made to observe the patient, a chest radiograph should be repeated within several hours of the insertion to ensure that blood is not accumulating in the chest. Cardiac Injury Penetrating injury to the chest may involve not only the pulmonary parenchyma but also, not infrequently, the heart.

Emergency Room Thoracotomy Occasionally, a patient with a penetrating injury to the chest who arrives at the emergency department loses vital signs soon after arrival. A thoracotomy performed in the emergency room allows immediate control of an exsanguinating thoracic injury and enables open cardiac massage while the patient is being transported to the operating room. The decision to perform an emergency room thoracotomy is a difficult one and requires consideration of the time required to transport the patient to the operating room in the particular hospital. Indications for emergency room thoracotomy vary from institution to institution. In general, emergency center thoracotomy is indicated in patients with exsanguinating chest injury who become pulseless after arrival but in whom some myocardial electrical activity persists. The procedure is rarely indicated in the patient who arrives without vital signs, since the success rate in resuscitating these individuals is dismal. Application of a clamp across the thoracic aorta, open cardiac massage, and simultaneous volume replacement are all performed once the chest is opened to restore blood flow to the brain and heart. If the hemorrhage originates in part from the pulmonary hilum, a vascular clamp or the surgeonâ&#x20AC;&#x2122;s hand can be placed across the hilum. In addition, for penetrating cardiac wounds, the pericardium is opened and the injury repaired. The survival rates for patients undergoing emergency center thoracotomy is less than 10 percent. Feliciano and coworkers reported an 8.1 percent survival rate with 335 emergency center thoracotomies performed over a 7-year period. In most series, the procedure has been successful most often in patients with stab wounds as opposed to gunshot wounds and in patients in whom the injury is confined to the chest.

BLUNT THORACIC TRAUMA Tracheobronchial Injuries Isolated injury to the tracheobronchial tree is unusual because of the proximity of other major structures, specifically,

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the great vessels. However, it does occur occasionally. Tracheal disruption may follow blunt injury to the neck and is usually identified by the presence of subcutaneous emphysema. Intuitively, it is not obvious how an individual can survive after complete disruption of the cervical trachea. However, survival is due to the pretracheal fascia, which ensheathes the trachea and is stout enough to preserve sufficient integrity of the airway to allow air to pass into the distal trachea, albeit with some difficulty. The more common injury to the tracheobronchial tree that results from blunt trauma is disruption of a mainstem bronchus, usually resulting from sudden deceleration either as a result of a motor vehicle accident or fall. Since the left mainstem bronchus and carina are tethered by the aortic arch, sudden deceleration of this fixed structure may result in a tear or total disruption of either the right or left main bronchus. Blunt injuries causing tracheobronchial disruption are often associated with simultaneous injuries to adjacent structures including the great vessels (especially the descending thoracic aorta), esophagus, manubrium, mandible, and cervical spine. Usually such coincident injuries are fatal. Those patients with a tracheobronchial injury who do survive long enough to reach the hospital usually have only the isolated injury, implying individuals with other injuries have already died in the field. The isolated tracheobronchial injury occurs most often in young people in whom the blood vessels, including the aorta, are somewhat more compliant than the tracheobronchial tree, so that these vessels remain intact despite trauma to the chest, which disrupts the tracheobronchial tree. How tracheobronchial injuries present clinically depends on the type of injury. Rupture of the airways resulting from blunt trauma commonly presents with subcutaneous emphysema, although this manifestation may be too subtle to appreciate by clinical examination. Other associated findings include hemoptysis, respiratory distress, change in voice, pneumothorax, or hemothorax. Pneumothorax is only present if the airway rupture communicates with the pleural space, a circumstance that does not always occur because of the dense, fibroconnective tissue around the carina and mainstem bronchi. In fact, more commonly, the only finding, even in the presence of complete bronchial disruption, is the presence of deep cervical or mediastinal air that is only appreciated on the chest radiograph (Fig. 100-3). The diagnosis of airway rupture has to be suspected if the small amount of mediastinal or cervical emphysema displayed by the chest radiograph is to be detected by physical examination. Detection of mediastinal or cervical emphysema is rendered more difficult by the rarity of tracheobronchial injuries (i.e., no more than 2 to 3 per year) seen in major trauma centers. As noted, pneumothorax may follow bronchial disruption, but the evidence of an airway injury is usually not apparent until after a chest tube is placed. When suction is applied to the chest tube, the patient may become significantly more dyspneic, a situation which is only relieved by discontinuing the suction. Also, as a consequence of the large air leak, the lung expands incompletely despite increasing suction. Al-

Figure 100-3 Traumatic rupture of the right main bronchus following a motor vehicle accident. This radiograph demonstrates the classic findings of a pneumothorax that fails to resolve despite chest tube placement and subcutaneous and mediastinal air. Often the findings are more subtle.

though the combination of these findings almost ensures the diagnosis, bronchoscopy should always be done even if suspicion is low that the airway is injured. Bronchoscopy clearly delineates the injury and confirms the location, information that is crucial for planning the operative approach. Management of the patient with tracheobronchial injury begins with making sure that the patient has a reliable airway. In patients with suspected injury to the cervical or mediastinal trachea, intubation of the trachea beyond the injury is performed under direct vision under bronchoscopic guidance. If airway injury is not suspected, blind endotracheal intubation may suffice but may result in further problems. Tracheostomy should be avoided if at all possible. In patients with unilateral bronchial injury, intubation of the opposite main bronchus is desirable.

Airway Ruptures Airway ruptures occur in transverse, longitudinal, or combined directions. The most common tracheal injury occurs between tracheal rings. Longitudinal injuries occur along the membranous portion of the airways. Most tracheobronchial ruptures occur within 2.5 cm of the carina, and the trachea or bronchi may be completely disrupted. The principles of managing airway rupture include debridement of devitalized tissue and primary repair for tracheobronchial injuries. Lesions of the distal trachea, carina, and the right mainstem bronchus are approached via a right thoracotomy. This approach also provides excellent exposure of the proximal left main bronchus, but the way in which an injury on the left should be managed is greatly influenced by the bronchoscopic findings. A partial disruption of the proximal left mainstem bronchus is usually approached by way of a right thoracotomy with mobilization of the carina.

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Complete disruption on the left usually should be managed by way of a left thoracotomy. Exposure of the proximal left main bronchus from the left side is difficult because of the aortic arch. Often the arch must be encircled and retracted superiorly in order to gain adequate exposure. Division of the ligamentum arteriosum also facilitates exposure of the left main bronchus at its origin. The bronchus is either repaired or reanastomosed with sutures so as to be airtight. Rarely is pulmonary resection required, although lobectomy may have to be carried out if a lobar bronchus is involved. Pneumonectomy should never be required unless the lung parenchyma has been virtually destroyed. In cases involving complex injuries to the distal trachea, carina, or mainstem bronchi, providing adequate oxygenation and ventilation during the operation without the use of cardiopulmonary bypass may be difficult, but this is distinctly unusual. Usually the airway is managed just as it is in elective carinal or main bronchial sleeve resections, scrupulously avoiding the use of extracorporeal oxygenation and systemic heparinization.

Pulmonary Contusion Pulmonary contusion occurs during blunt thoracic trauma as the force of impact is transferred through the chest wall to the lung parenchyma. The anatomic manifestation of contusion is disruption of alveolar-capillary interfaces and resultant collection of blood and protein in the interstitium and alveoli. Both the physiologic derangements and the presentation of patients with this type of injury are variable and range from asymptomatic to severe hypoxia and the need for mechanical ventilation. This variability in presentation reflects the fact that contusion often occurs with associated injuries that require resuscitative measures, which can add to the anatomic insult. Also, the extent of the contusion may be quite variable. In a classic series of experiments, Trinkle and colleagues studied the effects of crystalloid versus colloid resuscitation on the severity of pulmonary contusions in dogs. To mimic the clinical situation in which pulmonary injury is often associated with significant blood loss from associated injuries, the dogs also underwent blood loss that called for restoration of blood volume. Crystalloid intravenous fluid resulted in more severe pulmonary damage than did the use of colloidal solutions. In addition, mechanical ventilation and furosemide therapy decreased the severity of the pulmonary lesion. Hence, in patients suspected of having extensive pulmonary contusion, restoration of blood volume using crystalloid should be accomplished carefully to avoid increasing the injury. In addition to associated injuries, preexisting medical conditions greatly influence the course of patients with pulmonary contusions. Patients with chronic obstructive pulmonary disease, heart failure, or renal failure are predisposed to shunting in the involved segment of lung parenchyma and should be mechanically ventilated at the first suggestion of systemic hypoxemia. Similarly, the degree of pulmonary vascular reactivity influences the severity of injury from pul-

Thoracic Trauma

monary contusion and the subsequent clinical course. Pulmonary vasoconstriction occurs after pulmonary contusion, apparently serving to reduce that intrapulmonary shunt created by perfusing injured, poorly ventilated parenchyma. Patients unable to vasoconstrict adequately experience larger shunt fractions than do those with more reactive pulmonary vasoconstriction. Although the value of classifying patients as “good vasoconstrictors” or “bad vasoconstrictors” is not clear, the distinction may help to determine treatment strategies, including the decision to abandon conservative management and proceed with limited pulmonary resection. Pulmonary laceration often complicates pulmonary contusion. In the transfer of energy to the chest wall during blunt trauma, shear forces are often generated that are capable of tearing the lung. Although most lacerations resolve spontaneously, elastic recoil of the lung can extend the laceration and form a cavity or a pulmonary pseudocyst. Potential complications of these cysts include infection, abscess formation, hemoptysis, air leak, adult respiratory distress syndrome (ARDS), and death. Although secondary infection of these pseudocysts is rare, it does occur and is treated in the same way as uncomplicated lung abscesses with sputum culture, directed antibiotic therapy, and pulmonary toilet. Failure of an infected pseudocyst to respond requires either surgical drainage and debridement or drainage via a percutaneous catheter introduced with the guidance of computed tomography (CT). The findings on chest radiograph in pulmonary contusion range from small nodular patchy infiltrates to frank consolidation involving a significant portion of the pulmonary parenchyma (Fig. 100-4). These findings become evident

Figure 100-4 Right pulmonary contusion following blunt chest trauma associated with left-sided rib fractures.

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within a few hours of injury in the classic presentation of pulmonary contusion. The usefulness of the chest radiograph in the management of contused lung is limited by the time lag between the appearance of abnormalities in gas exchange and the appearance of the injury on chest radiograph. Nonetheless, the chest radiograph is valuable in following resolution. Chest CT scans define the extent of injury more accurately than do chest radiographs and can allow rapid classification and quantification of pulmonary parenchymal damage. The management of pulmonary contusion consists mainly of adequate analgesia and pulmonary toilet along with supplemental oxygen as needed. Endotracheal intubation and mechanical ventilation may be required depending on the extent of the contusion and the presence of associated injuries. Avoidance of overhydration is particularly important. Serial chest radiographs can be used to follow the course of a pulmonary contusion until it resolves, although clinical evidence of improved gas exchange is really the bottom line as far as the patient is concerned.

Rib Fracture and Flail Chest Blunt trauma to the chest may fracture ribs or produce flail chest. Rib Fracture The designation â&#x20AC;&#x153;simple rib fractureâ&#x20AC;? usually refers to a nondisplaced fracture of a rib without injury to the lung or pleura. The most common mechanism for simple rib fractures is direct impact such as occurs in a fall or in a motor vehicle accident. Clinically, simple rib fractures may present with manifestations ranging from pain isolated to the involved rib to pneumonia secondary to splinting and hypoventilation caused by the pain. This latter circumstance is more likely in the elderly patient with osteoporosis, obstructive pulmonary disease, or malnutrition. Point tenderness is present over the fracture site, and a step-off may be palpated at the point where the fractured ends overlap. However, the physical findings are often more subtle. Physical examination in the awake patient is usually sufficient to make the diagnosis of rib fracture. Chest radiographs obtained during the initial evaluation of a trauma patient in the emergency room usually are anteroposterior views taken with the patient supine, and rib fractures are often missed. Since the management of isolated simple rib fractures consists of analgesia and pulmonary toilet, attempting to ensure a radiographic diagnosis with oblique views or special rib views may not be necessary. In patients with underlying lung disease, the anteroposterior chest radiograph is most useful in establishing the absence of associated injuries, such as pulmonary contusion and pneumothorax. The management of rib fractures may, at times, be dictated in part by which ribs and how many are injured. Fracture of the first or second ribs requires significant force and can be associated with major vascular or nerve injury as a result of the proximity of these ribs to the subclavian vessels and the brachial plexus. Although fractures of these two ribs are not

necessarily an indication for an arteriogram, certain associated injuries do require angiographic study. Abnormalities in pulse or in the neurologic examination of the upper extremities or a hematoma at the base of the neck should prompt an arteriogram. Other indications include palpable displacement of the first rib and a widened mediastinum on the chest radiograph. Fracture of the lower ribs may be associated with injury to the liver or spleen. Regardless of etiology, all rib fractures caused by trauma require repeated chest radiographic examinations to screen for radiographic evidence of pulmonary contusion or other complication such as hemothorax. Pulmonary complications of rib fractures can result from pain and splinting and include retained secretions, atelectasis, ventilatory failure in patients with limited pulmonary reserve, and empyema. The cornerstone of the management of rib fractures is the management of secretions. This can only be accomplished by adequate analgesia. Options for analgesia with rib fractures include narcotics and intercostal nerve blocks. Rib fractures often accompany other injuries. In a series of 711 patients with rib fractures evaluated over a 5-year period, 94 percent had associated injuries, 32 percent had a pneumothorax or hemothorax, 26 percent had a pulmonary contusion, and 12 percent died. Thus, information underscores the importance of knowing the mechanism of injury and the high likelihood of additional injuries either in the chest or elsewhere. Flail Chest Flail chest is an even better indicator of extensive injury. It occurs when a section of the chest wall becomes unstable because of multiple rib fractures (Fig. 100-5). This segment moves paradoxically with respiration causing respiratory embarrassment. There has been a continuing debate regarding whether the segmental, paradoxical chest wall motion or the underlying lung contusion is responsible for the ventilatory

Figure 100-5 Left flail chest following blunt trauma.

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abnormalities seen in these patients. The force of the injury required to cause a flail segment causes a significant contusion, and it is likely that the contused lung contributes most significantly to the derangement in gas exchange. Because of the evolving views concerning the pathophysiological mechanism, the treatment of flail chest has changed dramatically over the years. The early approach reflected the belief that the chest wall deformity was responsible for the ventilatory compromise and consisted of external stabilization of the chest wall with sandbags. Operations were also performed for internal fixation of the flail segment. Subsequently, internal pneumatic stabilization with positive pressure ventilation was used in a further effort to prevent the paradoxical chest wall motion produced by spontaneous respiration. Patients were intubated and ventilated even when gas exchange was reasonable. In time, more attention was directed toward the underlying pulmonary contusion as the significant pathophysiological mechanism. Trinkle tested this concept by treating one group of chest trauma patients with flail chest using positive-pressure ventilation while treating a second group with a standard pulmonary contusion, which included restriction of fluids and relief of pain. Length of hospitalization was shorter and incidence of complications significantly less in the group treated without mechanical ventilation. Current treatment for flail chest avoids mechanical ventilation until mandated by standard criteria. There is no physiological reason to institute positive-pressure ventilation solely to prevent paradoxical chest wall motion. Management is directed toward the pulmonary contusion and control of pain. Continuous epidural analgesia has proved to be an excellent adjunct in the overall management of these patients, since the relief of pain lessens splinting, improves chest wall mechanics, and decreases the risk of atelectasis and pneumonia. Aggressive pulmonary toilet and secretion management are also important in the overall management of these patients. If a segment of the chest wall is completely disrupted, operative fixation may provide a necessary adjunct. In this injury, the bellows mechanism of the chest is severely disordered by the major skeletal deformity, which consists of complete separation of the ribs from each other with maintenance only of the integrity of the overlying skin. In this injury, the flail is severe, and operative repair with wire stabilization of the flail segment and reconstruction of the chest wall is often necessary for restoration of the bellows.

Sternal Fracture Sternal fracture most commonly occurs during motor vehicle accidents in which there is direct impact of the anterior chest on the steering wheel. Paramedics often report damage to the steering wheel in accidents that produce these injuries. Sternal fractures also are occasionally associated with single or multiple costochondral dislocations. The association of these two injuries can lead to flail chest with paradoxical motion of the sternum during spontaneous respiration. Other injuries associated with sternal fracture include flexion injuries of the

Thoracic Trauma

vertebral column, tracheobronchial rupture, aortic disruption, and myocardial contusion or rupture. Isolated sternal injury is a relatively rare injury, since the force required to fracture the sternum usually results in other injury, which is often fatal. When first seen, the awake, conversant patient with a sternal fracture often complains of pain. Inspection of the chest wall often reveals ecchymosis or abrasion of the skin overlying the sternum; a chest wall deformity may be visible. Palpation of the sternum and costochondral junctions may reveal point tenderness and a crepitance or step-off over the fracture. Sternal fractures are difficult to detect on anterior or oblique films. Patients suspected of having a sternal fracture should have lateral views with a specific request for sternal views. In the patient with multiple injuries who is unable to tolerate many diagnostic studies, the diagnosis can be made based safely on physical examination. Sternal fractures most commonly extend either through the body of the sternum or occur at the junction of the manubrium and body. Simple undisplaced sternal fractures require no treatment. Displaced fractures with overlapping fragments may require operative reduction, debridement, and direct wire fixation. Claviculosternal dislocations may compress the structures traversing the thoracic inlet including the trachea, major vessels, and brachial plexus. Treatment of the sternal fracture may need to be delayed depending on the presence of other associated injuries.

Diaphragmatic Injury Injury to the diaphragm should be considered in any penetrating or blunt injury to the chest, abdomen, or lower back. The injury is easily detectable at the time of laparotomy but is often overlooked in the heat of the moment when dealing with intraabdominal hemorrhage (Fig. 100-6). When a diaphragmatic injury is noted, primary suture repair of the rent usually suffices, but occasionally repair with prosthetic mesh is required. Regardless of etiology, all diaphragmatic injuries should be repaired because there is a significant risk of incarceration and possible strangulation of abdominal viscera through the hernia as well as pulmonary compromise secondary to compression. In those patients who do not undergo emergency laparotomy, the diagnosis can be delayed for several months or even years. Diaphragmatic injuries can occur with penetrating injuries as well as from blunt trauma, although the injuries incurred from a blunt mechanism tend to produce larger rents in the diaphragm. Patients with missed diaphragm injuries often complain of midepigastric pain or symptoms of bowel obstruction as abdominal viscera herniate into the chest. Examination may reveal a scaphoid abdomen without significant tenderness to palpation. Auscultation of the chest may reveal bowel sounds. The chest radiograph shows what appears to be an elevated hemidiaphragm, hydrothorax, hydropneumothorax, an air-fluid level, and evidence of abdominal viscera. These findings are most often seen on the left side because, after right-sided diaphragmatic injuries,

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Figure 100-6 Ruptured left hemidiaphragm following a motor vehicle accident. Note the subcutaneous emphysema and the loss of diaphragm contour on the left. The contents of the left side of the abdomen are in the left chest.

the liver protects the abdominal viscera from herniating into the right chest. Occasionally, the liver itself may herniate after right-sided injuries. An easy diagnostic test is the introduction of a nasogastric tube. If the tube coils into the left chest, the diagnosis of gastric herniation through the diaphragmatic injury is made, and operation is indicated for repair of the diaphragm and restoration of the abdominal contents into the abdomen. Similarly, an upper gastrointestinal series or barium enema can be performed to evaluate the viscera with respect to herniation into the chest. If the diagnosis is made relatively quickly after herniation, the abdominal approach can be used for repair. If the diagnosis is made before incarceration but well after the initial herniation, the repair is performed through the left chest, since there are often adhesions to the lung as a result of chronic inflammation. As mentioned, almost all these injuries occur on the left side with only the occasional diaphragmatic injury seen on the right.

damage than the typical low-velocity missiles used by civilians. High-velocity bullets create a blast effect, producing a large temporary cavity within the tissues hit by the bullet. Although it may not be evident initially, the ultimate extent of

PENETRATING INJURY OF THE LUNG Penetrating injuries of the lung occur from stab or gunshot wounds. An occasional impalement injury may also be seen. The degree of injury sustained by the lung ranges from small lacerations caused by knife injuries to massive destruction with shotgun blasts (Fig. 100-7). In addition, the type of firearm used defines the amount of injury. Specifically, highvelocity missiles such as those used during wartime and, more recently in urban areas, are more likely to produce severe

Figure 100-7 Gunshot wound to the left chest demonstrating a large hemothorax present on admission to the emergency room prior to chest tube placement. The amount of blood in the chest and continued drainage of blood determine whether exploration of the chest is indicated.

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injury caused by such forces is often extensive because of the associated pulmonary contusion from the blast effect. Lowvelocity bullets are more likely to produce wounds that have a cross-sectional area about the size of the bullet and the blast effect is relatively less than that produced by high-velocity bullets. In a series of 1168 patients with penetrating injuries to the thoracic cavity, only 6 percent of these required operative repair of pulmonary parenchymal or hilar injuries. Of 384 patients with gunshot wounds, 283 (74 percent) were managed with chest tubes alone. Similarly, of 784 patients with stab wounds to the thorax, 602 (77 percent) required only a chest tube. Mortality for those requiring only a chest tube was 0.7 percent. In contrast, mortality for those with hilar injuries was 30 percent, and for those with injuries requiring lung resection, mortality was 28 percent. Thus, most civilian penetrating thoracic injuries can be managed with tube thoracostomy alone because of relatively minimal injury to lung parenchyma. Hilar injury or significant parenchymal injury requiring resection carries a high mortality. The management of penetrating thoracic injury begins with placement of a chest tube. One indication for operation in such patients is an initial drainage of 2 L or more of blood. Clinical signs are particularly important. The patient who remains hypotensive following volume replacement should be explored. In those with less initial drainage, continuing drainage of 150 to 200 ml of blood every hour for 3 to 4 h is another indication for operation. Additional indications include hemoptysis, shock, and cardiac tamponade. Options for treatment include direct suture repair of the lung, wedge resection, or formal anatomic resection, such as lobectomy. Great effort is made to preserve pulmonary parenchyma, and resection is reserved for those cases where there is significant destruction of lung tissue or injury to a pulmonary artery. Everything possible is done to avoid pneumonectomy which, in this situation, is associated with mortality greater than 60 percent.

ARDS AFTER CHEST TRAUMA The adult respiratory distress syndrome often complicates chest trauma, and its clinical manifestations are similar to those that occur in patients with adult respiratory distress syndrome (ARDS) after insults that do not involve trauma. Several injuries and their sequelae have been implicated in the etiology of ARDS. Among these are the following clinical factors often found in the chest trauma patient: sepsis syndrome, pulmonary contusion, aspiration of gastric contents, multiple emergency transfusions, and multiple major fractures. In addition, the risk of ARDS has been found to be most closely related to the number of risk factors present (18 percent with one factor, 85 percent with three or more factors). Hence, any chest trauma patient admitted with clinical risk factors of ARDS should be followed closely so that appropriate treatment can be administered promptly. In addition, although

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these risk factors are only associated with ARDS rather than causative, they should receive prompt treatment with the goal of minimizing any potential causative role they could have.

Mechanically Assisted Ventilation As with other etiologies, the mainstay of treatment of ARDS in the patient with chest trauma revolves around the use of assisted ventilation (see Chapter 153), i.e., volume ventilation and positive end-expiratory pressure (PEEP). By increasing the number of ventilated alveoli, thereby increasing the func˙ Qt) ˙ tional residual capacity (FRC), the shunt fraction (Qs/ is decreased, and arterial oxygenation improves. The target ˙ Qt ˙ ratio is less than 0.2. The usually established for the Qs/ goals of this scheme for ventilatory management are to adjust the fraction of inspired oxygen (FiO2 ) and the level of PEEP to the lowest values capable of supporting adequate oxygenation. In the rare patient with severe chronic lung disease, bronchopleural fistula, or such severe ARDS that oxygenation using this approach is not successful, high-frequency jet ventilation, extracorporeal membrane oxygenation (ECMO), and simultaneous independent lung ventilation remain as options.

High-Frequency Jet Ventilation In high-frequency jet ventilation, a small cannula is inserted into the airway and brief high-pressure jets of air are used to ventilate the lungs. As the jet of air enters the bronchus it pulls air along by the Venturi effect, thereby determining the inspiratory volume. Typical ventilator settings include tidal volumes of 1 to 3 ml per kg and rates of 100 to 200 breaths per minute. The advantage of this mode of ventilation is the avoidance of the high-peak airway pressures produced by PEEP. Results obtained with this technique have not been consistent from clinic to clinic. Hurst and colleagues used both high-frequency jet ventilation (HFJV) and the related high-frequency percussive ventilation (HFPV) in trauma patients with injury to multiple organ systems. This combination combines the mechanism of HFJV with the ability to change airway pressure phasically. They found that HFJV improved CO2 elimination more effectively than did the intermittent mandatory ventilation/continuous positive airway pressure (IMV/CPAP) mode of ventilation. In addition, HFPV improved PaO2 and reduced PaCO2 at lower peak, mean, and end-expiratory pressures. In contrast, Albelda and co-workers studied the use of HFJV in patients with bronchopleural fistulae and found no clear benefit with the technique in these patients. The utility of HFJV in chest trauma patients remains to be completely elucidated, but it is available as an option in patients with severe barotrauma from PEEP.

Extracorporeal Membrane Oxygenator Yet another option in the chest trauma patient with recalcitrant ARDS is extracorporeal membrane oxygenator

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(ECMO). This technique is not yet used routinely in adult patients with severe ARDS. One reason that ECMO has produced variable results in this population is that these patients often have major multiorgan system dysfunction in addition to their pulmonary dysfunction. If these other conditions are not corrected, the likelihood of survival is low despite the ability to oxygenate and ventilate using ECMO. The role of ECMO in the adult population with ARDS remains to be defined.

Ventilation of Each Lung Separately Simultaneous ventilation of each lung separately involves the use of one separate ventilator for each lung using a double lumen endobronchial tube. The ventilators can function in either synchronous and asynchronous modes. The technique is used in conditions of unilateral severe lung disease, such as postunilateral lung transplantation or unilateral severe pulmonary contusion.

CONCLUSION For purposes of classification, a distinction must be made between blunt and penetrating trauma to the chest, yet the management of many of these injuries, no matter what the cause, is similar. An injury confined to the chest most often results in a favorable outcome; the difficulty lies in the fact that most chest trauma is associated with other injuries. Many multiple-injury patients with chest trauma never make it to the hospital. Those who do must be managed by a team of individuals consisting of trauma and thoracic surgeons as well as physicians trained in critical care. The initial management of patients with thoracic trauma often requires quick and accurate decision making such as in the case of the patient who presents with a tension pneumothorax. It behooves all physicians who deal with critically ill patients to be familiar with the care of patients with chest trauma.

SUGGESTED READING Albelda SM, Hansen-Flaschen JH, Taylor E, et al.: Evaluation of high-frequency jet ventilation in patients with bronchopleural fistulas by quantification of the airleak. Anaesthesia 63:551–555, 1985. Cohn SM:Pulmonary contusion: review of the clinical entity. J Trauma 42:973–979, 1997. Dee PM: The radiology of chest trauma. Radiol Clin North Am 30:291–306, 1992. DeMuth WE Jr: High velocity bullet wounds of the thorax. Am J Surg 115:606–625, 1968. Easter A: Management of patients with multiple rib fractures. Am J Crit Care 5:320–327, quiz 328–329, 2001.

Feliciano DV, Bitondo CG, Cruse PA, et al.: Liberal use of emergency center thoracotomy. Am J Surg 152:654–659, 1986. Gincherman Y, Luketich JD, Kaiser LR: Successful nonoperative management of secondarily infected pulmonary pseudocyst: Case report. J Trauma 38:960–963, 1995. Gupta A, Jamshidi M, Rubin JR: Traumatic first rib fracture: Is angiography necessary? A review of 730 cases. Cardiovasc Surg 5:48–53, 1997. Habashi N, Andrews P: Ventilator strategies for posttraumatic acute respiratory distress syndrome: airway pressure release ventilation and the role of spontaneous breathing in critically ill patients. Curr Opin Crit Care 10:549–557, 2004. Hudson LD, Milberg JA, Anardi D, et al: Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 151:293–301, 1995. Hurst JM, Branson RD, DeHaven CB: The role of highfrequency ventilation in posttraumatic respiratory insufficiency. J Trauma 27:236–242, 1987. Kavolius J, Golocovsky M, Champion HR: Predictors of outcome in patients who have sustained trauma and who undergo emergency thoracotomy. Arch Surg 128:1158–1162, 1993. Kiser AC, O’Brien SM, Detterbeck FC: Blunt tracheobronchial injuries: Treatment and outcomes. Ann Thorac Surg 71:2059–2065, 2001. Lazrove S, Harley DP, Grinnell VS, et al.: Should all patients with first rib fracture undergo arteriography? J Thorac Cardiovasc Surg 83:532–537, 1985. Maunder RJ: Clinical prediction of the adult respiratory distress syndrome. Clin Chest Med 6:413–426, 1985. Parsons PE: Mediators and mechanisms of acute lung injury. Clin Chest Med 21:467–476, 2000. Pepe PE, Potkin RT, Reus DH, et al.: Clinical predictors of the adult respiratory distress syndrome. Am J Surg 144:124– 130, 1982. Reuter M: Trauma of the chest. Eur Radiol 6:707–716, 1996. Richardson JD, Franz JL, Grover FL, et al: Pulmonary contusion and hemorrhage—crystalloid versus colloid replacement. J Surg Res 16:330–336, 1974. Robison PD, Harman PK, Trinkle JK, et al: Management of penetrating lung injuries in civilian practice. J Thorac Cardiovasc Surg 95:184–190, 1988. Shah R, Sabanathan S, Mearns AJ, et al: Traumatic rupture of diaphragm. Ann Thorac Surg 60:1444–1149, 1995. Sirmali M, Turut H, Topcu S, et al.: A comprehensive analysis of traumatic rib fractures: Morbidity, mortality and management. Eur J Cardiothorac Surg 24:133–138, 2003. Symbas PN, Justicz AG, Ricketts RR: Rupture of the airways from blunt trauma: Treatment of complex injuries. Ann Thorac Surg 54:177–183, 1992.

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Symbas PN, Vlasis SE, Hatcher CR Jr: Blunt and penetrating diaphragmatic injuries with or without herniation of organs into the chest. Ann Thorac Surg 42:153–162, 1986. Trinkle JK, Furman RW, Hinshaw MA, et al.: Pulmonary contusion—pathogenesis and effect of various resuscitative measures. Ann Thorac Surg 54:177–183, 1992. Trinkle JK, Richardson JD, Franz JL, et al.: Management of flail chest without mechanical ventilation. Ann Thorac Surg 19:355–363, 1975.

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Wagner RB, Jamieson PM: Pulmonary contusion— evaluation and classification by computed tomography. Surg Clin North Am 69:31, 1989. Wagner RB, Slivko B, Jamieson PM, et al.: Effect of lung contusion on pulmonary hemodynamics. Ann Thorac Surg 52:51–58, 1991. Ziegler DW, Agarwal NN: The morbidity and mortality of rib fractures. J Trauma 37:975–979, 1994. Zinck SE, Primack SL: Radiographic and CT findings in blunt chest trauma. J Thorac Imaging 15:87–96, 2000.

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101 Lung Transplantation John C. Wain

I. HISTORY II. RECIPIENT SELECTION General Considerations Specific Disease States III. TRANSPLANT PROCEDURE SELECTION IV. DONOR SELECTION V. LUNG PRESERVATION VI. TECHNIQUES OF LUNG TRANSPLANTATION Anesthetic Management Single-Lung Transplantation Double-Lung Transplantation Heart--Lung Transplantation

Lung transplantation has been used as a successful therapeutic intervention for a variety of end-stage pulmonary parenchymal and vascular diseases over the past 25 years. Advances in recipient and donor selection, surgical technique, and postoperative management have improved early survival. The criteria for the use of either isolated lung transplantation or heart– lung transplantation continue to be defined, with the role for heart–lung transplantation lessening over the past decade. A relative shortage of donor organs has been the major constraint on wider application of this treatment. In addition, chronic rejection in the pulmonary allograft, manifested as obliterative bronchiolitis, remains a major obstacle to longterm patient survival.

HISTORY Pioneering efforts in experimental lung transplantation were undertaken in the 1940s and 1950s. Demikhov performed

This chapter has been slightly modified from the version that appeared in the third edition of Fishman’s Pulmonary Diseases and Disorders.

VII. POSTOPERATIVE MANAGEMENT Ventilation Fluid Management Antimicrobial Therapy Nutrition Immunosuppression Rejection Complications VIII. RESULTS Survival Functional Results Retransplantation IX. SUMMARY

a variety of experiments involving transplantation of pulmonary lobes and heterotopic heart–lung transplantation in dogs. These experiments demonstrated the technical feasibility of such procedures. In addition, the heart and the lung in heart–lung grafts pursued different functional courses, foreshadowing the differing rates of rejection of the heart and lungs that were seen in combined heart–lung transplants performed clinically more than three decades later. Metras reported the results of left-lung transplantation in the dog and presciently emphasized technical factors that are now used clinically for isolated lung transplantation. Subsequent experimental studies showed that the transplanted lung could provide ventilation for the recipient. Clinical lung transplantation was undertaken first by Hardy in 1963. The procedure consisted of a left single-lung transplant performed for a carcinoma of the left lung that involved the hilum. The patient survived for 18 days, dying of renal failure and malnutrition. This effort demonstrated that a transplanted lung could function for the short term in a patient and stimulated further clinical and experimental efforts. Between 1963 and 1978, however, at least 38 attempts were made at isolated lung transplantation, and only one patient survived to hospital discharge. This particular patient

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had undergone a right single-lung transplant for silicosis; he developed a bronchial anastomotic stricture and succumbed to sepsis and chronic rejection 8 months after transplantation. The remaining patients in this 15-year experience all died postoperatively. The major cause of mortality beyond the first postoperative week in these patients was bronchial dehiscence. In addition, most of the patients were greatly debilitated at the time of the procedure, frequently ventilator dependent or in a state of multisystem and multiorgan failure, hindering their ability to survive. It was appreciated that in many of these patients, the available immunosuppressive regimens, which relied on high-dose corticosteroids (2 mg/kg of prednisone per day), significantly compromised postoperative healing of the bronchus and further potentiated the adverse effects of preexisting conditions. The problem of bronchial healing was related to the relative ischemia of the donor bronchus, which followed revascularization of the lung graft without reestablishment of bronchial circulation. One technical approach to this problem was the development of a procedure for combined heart–lung transplantation, allowing for maintenance of collateral bronchial circulation from the coronary circulation and mediastinal tissues. Although the operation was performed primarily for patients with end-stage cardiac failure due to pulmonary hypertension, the initial report of successful heart–lung transplantation demonstrated the feasibility of this approach in obtaining healing of the airway and confirmed the ability of the transplanted lung to provide longterm respiratory function. Subsequently, heart–lung transplantation has been performed for numerous pulmonary parenchymal diseases, including emphysema and bilateral septic lung disease, such as cystic fibrosis. An alternative technique for improving bronchial healing was to optimize the bronchial–pulmonary collateral circulation by limiting the length of the donor bronchus and to revascularize the bronchial circulation extrinsically by wrapping the anastomosis with omentum. In addition to these technical measures, the avoidance of high-dose steroid immunosuppressive regimens, made possible by the use of cyclosporine and the application of growth factors, was shown to improve bronchial anastomotic healing. These advances, combined with the selection of well-conditioned recipients with pulmonary fibrosis, whose pathophysiology favored perfusion and ventilation of the allograft, culminated in the clinical success of isolated single-lung transplantation. Further efforts were made to perfect a technique for isolated doublelung transplantation to expand this approach to patients with bilateral septic lung disease. The initial clinical success of an en bloc double-lung transplant procedure was tempered by a significant incidence of bronchial anastomotic complications. However, further modification of the technique, by either direct bronchial revascularization or bilateral sequential single-lung transplantation, has provided satisfactory results. It has since been shown that despite initial concerns about the physiology of allograft ventilation, isolated singlelung transplantation is also appropriate for patients with endstage chronic obstructive pulmonary disease (COPD). Iso-

lated single- and double-lung transplantation has also been successfully applied to patients with primary pulmonary hypertension or Eisenmenger’s syndrome (with correction of the congenital shunt), for whom combined heart–lung transplantation was initially devised. As the utility of isolated lung transplantation for these pulmonary diseases has been demonstrated, the need for heart–lung transplantation has diminished.

RECIPIENT SELECTION General Considerations The evaluation of a potential candidate for lung transplantation should include a complete assessment of cardiopulmonary function and the patient’s general health in addition to a thorough evaluation of psychosocial status. A battery of screening tests are required, as well as evaluation by members of the transplant team, including pulmonologists, cardiologists, thoracic surgeons, psychiatrists, and social workers (Table 101-1). Contingent on the patient’s status, this evaluation can be completed in many instances on an outpatient basis. A coordinated review of the results of these studies by the multidisciplinary transplant team serves to assure that the best candidates are accepted as potential transplant recipients. Indications Lung transplantation is a treatment of last resort. Potential recipients should be patients with an end-stage pulmonary parenchymal or vascular disease who have a limited life expectancy and for whom no effective alternative therapy is available. The life expectancy of potential recipients is related to both the underlying disease process and the degree of reduction in activities of daily living resulting from the disease, with significant secondary alterations in the patient’s psychosocial status. The variable rates of progression of the diseases for which lung transplantation is performed and the variety of supportive therapies available dictate that many specific criteria are related to a specific disease state. Careful consideration is required before patients with preexisting osteoporosis are accepted for transplantation. In addition, chronic steroid immunosuppressive therapy causes bone loss in all patients and exacerbates the complications of prior osteoporosis. Immunologic study of potential transplant candidates includes assessment of ABO status and cross-matching for transfusion. All patients are currently matched to donors by ABO status, most commonly with ABO-identical donors; virtually all patients require some transfusion in the perioperative period. MHC status is also assessed preoperatively, primarily for use in studies of postoperative outcome, such as the effect of HLA–DR mismatching or donor–recipient microchimerism on chronic rejection. Screening for sensitization to HLA antigens is also done at some centers. Pregnancy, blood transfusion, or prior transplantation can lead to HLA sensitization. Before transplantation, potential

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Table 101-1 Recipient Evaluation for Lung Transplantation Hematology Complete blood count with differential, platelet count, PT, PTT, ESR Chemistry Na, K, Cl, CO2 , BUN, Cr, glucose, osmolality, uric acid, Ca, P, Mg, total protein, albumin, globulin, amylase, bilirubin (direct, indirect), alkaline phosphatase, SGOT, LDH, CPK, triglycerides, cholesterol, HDL/LDL Renal function Urinalysis, 24 h for calcium and creatinine Endocrine TSH, LH, FSH, vitamin D, testosterone (males), estradiol (females) Infectious disease Sputum (Gram’s stain, C+S, fungal smear and culture, AFB smear and culture), CMV, hepatitis B (antigen/antibody), hepatitis C, herpes, varicella, EBV, HIV, rapidplasma reagin, toxoplasma PPD, mumps, Candida skin tests Immunology ABO blood type and cross match, MHC typing, HLA sensitization (PRA screen) Radiology Chest radiograph (AP, lateral), high-resolution chest CT scan, quantitative V/Q scan, quantitative bone density, abdominal ultrasonography, sinus CT∗ Cardiology ECG, echocardiogram with pulse Doppler imaging, right heart catheterization, left heart catheterization† Pulmonary Pulmonary function tests (spirometry, lung volumes, DLCO), Baird level II exercise test‡ ∗ Septic

lung disease. >50 years of age, coronary artery disease or LVEF <45%. ‡ Excluding patients with pulmonary hypertension.

† If

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recipients who show a response of more than 15 percent to the panel of antigens require a direct lymphocytotoxic crossmatch with any potential donor before transplantation. Contraindications Absolute contraindications to lung transplantation include bone marrow failure and hepatic cirrhosis, the latter to be distinguished from reversible hepatic dysfunction due to right heart failure, which resolves following lung transplantation (Table 101-2). In exceptional circumstances, combined liver and lung transplantation may be contemplated, although the risks of such a procedure are likely to be prohibitive. An active malignancy precluding long-term survival, which in the case of most solid tumors implies a disease-free survival beyond 5 years, is also an absolute contraindication. Because of the current limited supply of donor lungs, other significant lifelimiting disorders also stand as a proscription against lung transplantation (Table 101-3). A host of additional factors may be considered relative contraindications to lung transplantation. The age of the recipient may be a significant factor in view of the limited number of donor organs and the presumed subclinical organ dysfunction associated with the aging process that increases the potential for postoperative complications. As the latter factor is variable, a “physiological age” rather than a strict chronologic criterion is appropriate. The type of transplant procedure also influences the significance of age as a contraindication. (Isolated single-lung transplantation is more suitable for older patients because of its lower risk.) Other contraindications are evidence of psychosocial instability that would preclude compliance with the necessary posttransplant regimens and active use of tobacco products during the wait for transplantation. Obesity or cachexia can increase the risk for perioperative morbidity. The same is true of the continued need for high doses of steroid therapy (e.g., more than 20 mg of prednisone per day). Respiratory failure requiring mechanical ventilation before transplantation also increases the likelihood of complications. Most centers will not consider a new patient for evaluation who is completely ventilator dependent or has acutely deteriorated and become ventilator dependent. However, patients who have a chronic need for partial ventilatory assistance or those who have been accepted as transplant candidates and require assisted ventilation because of progression of their native disease may still be considered potential recipients for a limited time. Prolonged mechanical ventilation results in colonization of the lower respiratory tract with significant microbiologic pathogens and a degree of deconditioning and protein wasting that significantly increases the perioperative risk of transplantation. Chronic renal disease may affect eligibility for lung transplantation. All immunosuppressive regimens have some element of renal insufficiency as a complication of therapy, as do many of the antimicrobial regimens required for the management of these patients. As with irreversible hepatic dysfunction, combined renal and lung transplantation may

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Table 101-2 Absolute Contraindications for Lung Transplantation • Malignancy in the last 2 years, with the exception of cutaneous squamous and basal cell tumors. In general, a 5-year disease-free interval is prudent. The role of lung transplantation for localized bronchioalveolar cell carcinoma remains controversial. • Untreatable advanced dysfunction of another major organ system (e.g., heart, liver, or kidney). Coronary artery disease not amenable to percutaneous intervention or bypass grafting, or associated with significant impairment of left ventricular function, is an absolute contraindication to lung transplantation, but heart-lung transplantation could be considered in highly selected cases. • Non-curable chronic extrapulmonary infection including chronic active viral hepatitis B, hepatitis C, and human immunodeficiency virus. • Significant chest wall/spinal deformity. • Documented nonadherence or inability to follow through with medical therapy or office follow-up, or both. • Untreatable psychiatric or psychologic condition associated with the inability to cooperate or comply with medical therapy. • Absence of a consistent or reliable social support system. • Substance addiction (e.g., alcohol, tobacco, or narcotics) that is either active or within the last 6 months.

Relative Contraindications for Lung Transplantation • Age older than 65 years. Older patients have less optimal survival, likely due to comorbidities, and therefore, recipient age should be a factor in candidate selection. Although there cannot be endorsement of an upper age limit as an absolute contraindication (recognizing that advancing age alone in an otherwise acceptable candidate with few comorbidities does not necessarily compromise successful transplant outcomes), the presence of several relative contraindications can combine to increase the risks of transplantation above a safe threshold. • Critical or unstable clinical condition (e.g., shock, mechanical ventilation or extra-corporeal membrane oxygenation). • Severely limited functional status with poor rehabilitation potential. • Colonization with highly resistant or highly virulent bacteria, fungi, or mycobacteria. • Severe obesity defined as a body mass index (BMI) exceeding 30 kg/m2 . Severe or symptomatic osteoporosis. • Mechanical ventilation. Carefully selected candidates on mechanical ventilation without other acute or chronic organ dysfunction, who are able to actively participate in a meaningful rehabilitation program, may be successfully transplanted. • Other medical conditions that have not resulted in end-stage organ damage, such as diabetes mellitus, systemic hypertension, peptic ulcer disease, or gastroesophageal reflux should be optimally treated before transplantation. Patients with coronary artery disease may undergo percutaneous intervention before transplantation or coronary artery bypass grafting concurrent with the procedure.

source: Orens JB, Estenne M, Arcasoy S, et al.: International guidelines for the selection of lung transplant candidates: J Heart Lung Transplant 25:745–755, 2006.

be considered, but the potential risks of the procedure, particularly in the context of the shortage of donor lungs, require careful consideration. In most patients, severe preexisting renal insufficiency is a contraindication for lung transplantation. Severe peripheral vascular disease may be a limiting factor in selecting candidates because of the occasional need for cardiopulmonary support in the perioperative period by either partial cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) via the femoral or subclavian routes. Peripheral vascular disease is also frequently associated with significant coronary or aortic disease, which may greatly increase the morbidity and mortality of the lung transplant procedure. Finally, transplantation in patients with gangrenous changes in the extremities due to peripheral vascular disease is contraindicated because of the potential for

systemic spread of the infectious process during immunosuppression. Infectious diseases have a profound effect on the morbidity and mortality of lung transplantation. Colonization of the respiratory tract with potential pathogens in patients with end-stage pulmonary disease requires careful assessment of anatomic changes in the airways and determination of antimicrobial susceptibility. Significant anatomic abnormalities that preclude mechanical drainage of secretions in either the upper or lower respiratory tract should be dealt with preoperatively (e.g., drainage of chronic sinusitis in patients with cystic fibrosis) or at the time of the transplantation (e.g., removal of the lung containing a focal area of bronchiectasis). Most bacterial flora in transplant candidates have a pattern of antibiotic sensitivity that can be identified preoperatively to define a perioperative antibiotic regimen. For example, lung transplant

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Table 101-3 Contraindications to Lung Transplantation Absolute contraindications Bone marrow failure Hepatic cirrhosis Active malignancy precluding long-term survival Other life-limiting condition Relative Contraindications Physiological age >65 for single-lung transplantation >60 for bilateral-lung transplantation >55 for heart–lung transplantation Psychosocial instability Tobacco use within 6 months Weight outside acceptable range (obesity or cachexia) Prednisone use >20 mg/day or 40 mg q.o.d. Mechanical ventilation Intrinsic renal disease Significant peripheral vascular disease Symptomatic osteoporosis Severe chest wall deformity Sputum with panresistant bacteria or Aspergillus Active hepatitis B or C infection

patients harboring gram-negative bacilli preoperatively were found to be at risk for post–lung transplant pneumonia, demonstrating the importance of preoperative identification and a plan for eradication of potential pathogens. However, Pseudomonas cepaciae, a pathogen found in approximately 15 percent of patients with cystic fibrosis, is often highly resistant to antimicrobials and is a relative contraindication to transplantation unless a suitable pattern of antibiotic sensitivity can be identified before transplantation. Aspergillus fumigatus and other Aspergillus species are also common pathogens in the sputum of patients with septic lung disease or COPD. Interestingly, the presence of organisms in donor lungs is not a predictor of post–lung transplant pneumonia. Viral diseases in a potential lung transplant recipient can also have a significant impact on the outcome of transplantation. Active hepatitis B or C in the lung transplant candidate increases both early and late mortality because of the effect of hepatic dysfunction on perioperative complications and the accelerated progression of these diseases in patients requiring chronic immunosuppression. Cytomegalovirus (CMV), a DNA-type virus that is incorporated into the host genome, can cause both systemic illness and pneumonitis in immunosuppressed patients. Therefore, the serologic CMV status of the recipient is an important determination to make before transplantation. Duncan and Dummer found that CMV infection developed in 54% (32/59) of patients who underwent heart-lung (n = 52), double lung (n = 7), and single lung (n = 2) transplantation and survived for more than 30 days, and that CMV infection was more

Lung Transplantation

common in patients who had been CMV seropositive preoperataively (95%) than those who had been seronegative preoperatively (38%). While some centers prefer to match donor and recipient CMV status as a strategy for minimizing perioperative complications, the use of preemptive prophylactic ganciclovir therapy has been shown to eliminate CMV disease in transplant patients. However, some strains of CMV are resistant to ganciclovir, and because the occurrence of CMV disease is a significant risk factor for morbidity and mortality, ongoing surveillance for CMV based on antigenemia assays and transbronchial lung biopsy is required.

Posttransplant Therapy Although most post–lung transplant infections are caused by bacteria, the highest mortality is associated with fungal infections, pointing to the critical nature of appropriate perioperative and postoperative antibiotic regimens. Postoperatively, patients require an aggressive rehabilitation program to complete their immediate recovery and achieve maximum functional capacity. Severe preexisting osteoporosis or severe chest wall deformity may complicate these efforts, owing to difficulties with bone fractures, pain management, and ambulatory status. Close attention to bone density and calcium homeostasis is required postoperatively in all lung transplant patients on chronic steroid therapy. Most of them benefit from calcium supplementation and/or alendronate to offset the steroid effect. As physical rehabilitation is an important component of posttransplant therapy, it is important that all potential recipients be able to participate in such a rehabilitation program. Although most patients with parenchymal diseases also engage in a preoperative rehabilitation program, patients with pulmonary vascular disease cannot do so because of the considerable risks of such preoperative therapy. For these patients, participation in rehabilitation programs is generally deferred until after the transplant procedure. However, an appropriate psychological and emotional context can be promoted by regular preoperative participation in a patient support group (Table 101-4).

Table 101-4 General Indications for Lung Transplantation End-stage pulmonary parenchymal and/or vascular disease Projected life expectancy <2 years NYHA class III or IV functional level Rehabilitation potential Disease-specific mortality exceeding transplant-specific mortality over 1–2 years

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Table 101-5 Disease-Specific Considerations for Lung Transplantation Chronic Obstructive Pulmonary Disease (COPD) Guidelines for referral BODE index exceeding 5. Guidelines for transplantation Patients with a BODE Index of 7 to 10 of at least 1 of the following: History of hospitalization for exacerbation associated with acute hypercapnia (PCO2 exceeding 50 mmHg). Pulmonary hypertension or cor pulmonale, or both, despite oxygen therapy. FEV1 of less than 20% and either DLCO of less than 20% or homogenous distribution of emphysema.

Cystic Fibrosis/Bronchiectasis Guidelines for referral FEV1 below 30% predicted or a rapid decline in FEV1 â&#x20AC;&#x201D;in particular in young female patients. Exacerbation of pulmonary disease requiring ICU stay. Increasing frequency of exacerbations requiring antibiotic therapy. Refractory and/or recurrent pneumothorax. Recurrent hemoptysis not controlled by embolization. Guideline for transplantation Oxygen-dependent respiratory failure. Hypercapnia. Pulmonary hypertension.

Pulmonary Arterial Hypertension

Sarcoidosis

Guideline for referral NYHA functional class III or IV, Irrespective of ongoing therapy. Rapidly progressive disease. Guideline for transplantation Persistent NYHA class III or IV on maximal medical therapy. Low (<350 meter) or declining 6-MWT. Falling therapy with intravenous epoprostenol, or equivalent. Cardiac index of less than 2 liters/min/m2 . Right atrial pressure exceeding 15 mmHg.

Guideline for referral NYHA functional class III or IV. Guideline for transplantation Impairment of exercise tolerance (NYHA functional class III or IV) and any of the following: Hypoxemia at rest. Pulmonary hypertension. Elevated right atrial pressure exceeding 15 mmHg.

Idiopathic Pulmonary Fibrosis/ Nonspecific Interstitial Pneumonia (NSIP) Guideline for referral Histologic or radiographic evidence of UIP Irrespective of vital capacity. Histologic evidence of fibrotic NSIP. Guideline for transplantation Histologic or radiographic evidence of UIP and any of the following: A DLCO of less than 39% predicted. A 10% or greater decrement in FVC during 6 months of follow-up. A decrease in pulse oximetry below 88% during a 6-MWT. Honeycombing on HRCT (fibrosis score of > 2). Histologic evidence of NSIP and any of the following: A DLCO of less than 35% predicted. A 10% or greater decrement in FVC or 15% decrease in DLCO during 6 months of follow-up. Lymphangioleiomyomatosis (LAM)/ Pulmonary Langerhans Cell Histiocytosis (Eosinophilic Granuloma) Guideline for referral NYHA functional class III or IV. Guideline for transplantation Severe impairment in lung function and exercise capacity (e.g., VO2 max < 50% predicted). Hypoxemia at rest.

source: Orens JB, Estenne M, Arcasoy S, et al.: International guidelines for the selection of lung transplant candidates: J Heart Lung Transplant. 25:745â&#x20AC;&#x201C;755, 2006.

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Specific Disease States The rate of progression of the specific diseases is an important factor in the timing of the evaluation and selection of potential transplant recipients (Table 101-5). The most common indication for lung transplantation is obstructive lung disease, with COPD accounting for 38 percent of all lung transplants and emphysema due to α1 -antitrypsin deficiency accounting for 8 percent of all lung transplants. Patients with these diseases, who demonstrate chronic airway obstruction on pulmonary function tests, tend to remain relatively stable for long periods. Although lung transplantation provides marked symptomatic and functional palliation for these patients, it remains to be proved that lung transplantation improves survival. The FEV1 after administration of a bronchodilator is an excellent predictor of the severity of the disease and is useful, along with assessment of resting PaO2 and PaCO2 , in estimating survival before transplantation. The recently devised BODE index that incorporates multiple factors (B, body mass index; O, obstruction as indicated by the FEV1 as percent predicted; D, degree of dyspnea; and E, exercise capacity) appears to be more accurate in predicting survival in individuals with COPD than the FEV1 only. Accordingly, calculation of the BODE index is now included in the international guidelines for referral and transplantation for COPD (Tables 101-6 and 101-7). Death during the wait for transplantation is rare in these patients, occurring in less than 5 percent of cases. This may be due in part to two factors: their participation in a graduated rehabilitation program while they await transplantation, which may maintain or even increase the patients’ functional capacity, and the institution of oxygen therapy, which improves survival in patients with obstructive lung disease. Supplemental oxygen should be started early and continued throughout the pretransplantation period, along with serial assessments of oxygen consumption based on estimates obtained from the 6-min walk test. Restrictive lung diseases are the indication for lung transplantation in 22 percent of patients who undergo lung transplantation. The most common cause is idiopathic pulmonary fibrosis (IPF), which accounts for 19 percent of lung transplant patients, whereas a variety of interstitial lung diseases with mixed physiological characteristics account for the remainder (Table 101-6). The end-stage fibrotic lung is characterized by severe destruction of gas exchange units, distortion and dilatation of the airways with development of cystic lesions, and replacement of the lung with nondistensible fibrous tissues. The work of breathing in these patients may be increased five times above normal because of the increased elastic load. The vital capacity in patients with pulmonary fibrosis is severely reduced, as is the functional residual capacity (FRC), which is a better indicator of disease severity than total lung capacity. Dead-space ventilation is increased, and may actually increase further during exercise. A marked reduction in diffusing capacity is always present, commonly with some degree of alveolar hyperventilation; as the disease becomes increasingly severe, hypercapnia occurs during exercise and

Lung Transplantation

Table 101-6 Disease-Specific Indications for Lung Transplantation Obstructive lung disease—a BODE index of 7–10 Chronic obstructive pulmonary disease α1 -Antitrypsin deficiency Restrictive lung disease Idiopathic pulmonary fibrosis—FVC <50% predicted, PaO2 < 50 mmHg, PaCO2 > 45 mmHg Pulmonary artery hypertension No response to steroid therapy Interstitial lung disease Sarcoidosis Desquamative interstitial pneumonitis Lymphangioleiomyomatosis Chemotherapy- or radiation therapy–related fibrosis Collagen vascular disorders with primarily pulmonary involvement Eosinophilic granuloma or histiocytosis X Alveolar microlithiasis Septic lung disease Cystic fibrosis—FEV1 < 30% predicted, FVC ≤ 40% predicted, PaO2 < 60 mmHg, room air Bilateral bronchiectasis Hypogammaglobulinemia Postinfectious (childhood measles, pertussis, postpneumonia, or tuberculosis) Immotile cilia syndrome—Kartagener’s syndrome Allergic bronchopulmonary aspergillosis Pulmonary vascular disease Primary pulmonary hypertension—symptomatic disease Eisenmenger’s syndrome

later at rest. Extensive intrapulmonary shunting of blood flow is seen, resulting in hypoxemia and, in later stages, pulmonary hypertension. Progression of the disease may be variable, but patients often deteriorate precipitously and severely, developing progressive hypoxemia and pulmonary hypertension. As a result, the mortality of these patients while they await transplantation is more than 20 percent. Criteria for considering IPF patients for of transplantation include severe dyspnea, forced vital capacity (FVC) less than 50 percent of predicted, resting arterial hypoxemia or hypercarbia, and pulmonary hypertension. However, a downhill clinical course despite adequate medical therapy is the best individual indication for transplantation. Because airway obstruction is frequently a component of the lung disease in some patients with interstitial lung disease, an FEV1 of less than 30 percent of predicted may be an additional useful criterion. Two other factors in patients with

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Table 101-7 The BODE Index for COPD Points on BODE Index∗ Variable

FEV1 (%) of predicted)†

≥65

50–64

36–49

≤35

Distance walked in 6 min (m)

≥350

250–349

150–249

≤149

MMRC dyspnea scale‡

0–1

Body-mass index$

>21

≤21

∗ The cutoff values for the assignment of points are shown for each variable. The total possible values range from 0 to 10. FEV

1 denotes forced expiratory volume in one second. † The FEV categories are based on stages identified by the American Thoracic Society. 1 ‡ Scores on the modified Medical Research Council (MMRC) dyspnea scale can range from 0 to 4, with a score of 4 indicating that the patient is too breathless to leave the house or becomes breathless when dressing or undressing. $ The values for body-mass index were 0 or 1 because of the inflection point in the inverse relation between survival and body-mass index at a value of 21. source: Celli BR, Cote CG, Marin JM, et al: The Body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease.

interstitial lung disease are also important: many of these diseases are systemic, and the effects of the disease on extrapulmonary organs may result in a sufficient number of relative contraindications to exclude the patient from consideration for transplantation; and a number of these diseases, including sarcoidosis and lymphangiomyomatosis, have been shown to recur in the lung graft, underscoring the need for particularly cautious screening of such patients as potential candidates for transplantation. Septic lung disease, including cystic fibrosis and other types of bronchiectasis, accounts for approximately 20 percent of patients undergoing lung transplantation. Candidates with focal or unilateral disease can often be managed with medical treatment or surgical resection of the affected area. In most patients, however, the disease is bilateral or systemic, and the natural history is one of recurrent infection and progressive pulmonary failure. It is important to attempt to establish a cause of the bronchiectasis before transplant evaluation, because of the impact of systemic diseases on management before and after transplantation (Table 101-6). Cystic fibrosis can be diagnosed with a sweat test or from genotyping. Serum immunoglobulin levels should be measured and a careful assessment for evidence for a systemic illness—such as rheumatoid arthritis, ulcerative colitis, or immotile cilia syndrome— should be undertaken. Primary infectious causes, such as tuberculosis and allergic bronchopulmonary aspergillosis, should be identified and treated appropriately before transplantation. Finally, any suggestion of aspiration as a primary or secondary factor demands further investigation, including a barium swallow to rule out gastroesophageal reflux. Many of these patients demonstrate significant shortterm improvements in response to aggressive medical therapy,

which includes postural drainage, intravenous and inhaled antibiotics, and nutritional supplementation. Once medical therapy has been optimized, however, a pattern of more frequent hospitalizations for “clean-outs,” continued weight loss, and progressive functional impairment is indicative of a patient who has a limited life span and should be given priority for transplantation. Cystic fibrosis patients with an FEV1 under 30 percent of the predicted value, a PaO2 under 55 mmHg, or a PaCO2 greater than 50 mmHg have a 2-year mortality of 50 percent; the FEV1 appears to be the most sensitive predictive factor. Any patient with septic lung disease who manifests these criteria should be further evaluated as a potential transplant recipient. While the patient is awaiting transplantation, close medical follow-up is required, and all of the patient’s therapeutic regimen (e.g., postural drainage, DNAse therapy) should be continued. Serial study of sputum microbiology is important for assessing changes in flora. Aerosolized broad-spectrum antibiotic therapy (e.g., colistin 150 mg via nebulizer twice a day) reduces the bacterial load while minimizing the potential for renal toxicity; in some cases, it may transiently improve functional capacity. In the event of progressive hemoptysis, bronchial artery embolization can provide adequate short-term control of the bleeding without significantly compromising technical aspects of the transplant procedure. Finally, institution of nasal ventilation in the patient who is approaching respiratory failure has been shown to prolong viability without adversely affecting the outcome of transplantation. Application of these measures generally ensures that fewer than 20 percent of cystic fibrosis patients will die while awaiting lung transplantation. However, because of the shortage of donor organs and the variability in the progression of the disease, donation of a lung

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from a dying related donor may warrant consideration for some patients. Initial results of this approach, using bilateral isolated lobar transplants from two donors, have been encouraging for patients with cystic fibrosis, without entailing donor mortality or significant morbidity. Pulmonary vascular disease, either primary pulmonary hypertension (PPH) or secondary pulmonary hypertension due to Eisenmenger’s syndrome, accounts for 4 to 5 percent of patients requiring isolated lung transplantation and approximately 25 percent of patients requiring heart–lung transplantation. The criteria for identifying patients who may require transplantation relate to the risks of death due to the underlying disease. On the basis of data from the National Heart, Lung, and Blood Institute registry, it is apparent that a NYHA class III or IV functional status, an elevated central venous pressure, a decreased cardiac index, and an elevated mean pulmonary artery pressure correlate with a poor prognosis. Episodes of near-syncope, syncope, or near-death, which tend to occur later in the course of the disease, are also associated with mortality. It should be noted, however, that alleviation of symptoms or physiological abnormalities by medical therapy using high-dose calcium channel blockers or prostacyclin infusions in PPH patients may significantly modify the natural history of the disease. Therefore, symptomatic patients with PPH who do not respond to medical therapy are the ones best considered for transplantation. Although identical data concerning the natural history of patients with Eisenmenger’s syndrome are not available, similar clinical criteria and evidence of a declining functional status associated with progressive right heart failure are indications for transplantation in these patients. The decision about whether a patient should undergo isolated lung transplantation or heart–lung transplantation may be difficult. However, with the relative shortage of suitable heart–lung donor blocs, and a mortality of 20 to 25 percent among patients with significant pulmonary hypertension who are awaiting lung transplantation, an increasing number of patients with pulmonary vascular disease have undergone isolated lung transplantation. The results with isolated lung transplantation are similar to those with heart– lung transplantation for pulmonary vascular disease provided that there is no significant left ventricular dysfunction [i.e., absence of cardiomyopathy, left ventricular ejection fraction (LVEF) at least 45 percent], that right ventricular diastolic function is maintained (i.e., right ventricular end-diastolic (RVEDP) of 15 mmHg or under), and that there are no incorrectable structural abnormalities. Of interest, the presence of severe right ventricular systolic dysfunction [i.e., right ventricular ejection fraction pressure (RVEF) of 20 percent or less] does not appear to affect the results of isolated lung transplantation, and the severe tricuspid regurgitation and pulmonary valvular regurgitation that are present in virtually all patients preoperatively resolve almost immediately after isolated lung transplantation. Patients with Eisenmenger’s syndrome who have a shunt defect that can be corrected at the time of transplantation are also candidates for isolated lung transplantation. Heart–lung transplantation is primarily lim-

Lung Transplantation

ited to patients with either significant biventricular dysfunction (e.g., severe valvular cardiomyopathy) or incorrectable congenital heart defects.

TRANSPLANT PROCEDURE SELECTION Except for patients with bilateral septic lung disease or severe pulmonary arterial hypertension, single-lung transplantation (SLT) is optimal for the majority of end-stage pulmonary diseases that require transplantation. SLT is associated with a shorter wait for donor lungs before transplantation and a lower morbidity and mortality rate after transplantation than other lung transplant procedures performed for the same recipient diagnoses. The surgical mortality for SLT ranges from 3 to 10 percent, relating to the specific transplant indication, the presence or absence of pulmonary hypertension, and the intraoperative need for cardiopulmonary bypass. Double-lung transplantation (DLT) is the procedure of choice for patients with bilateral septic lung disease, such as cystic fibrosis, or for patients with pulmonary arterial pressures that are at near-systemic levels from either primary or secondary causes. Some centers also favor the use of DLT for patients with emphysema who are less than 50 years of age. Typically, however, surgical mortality is higher for DLT than for SLT, ranging from 10 to 15 percent. Surgical mortality is probably higher because of the number of patients with septic lung disease treated by DLT—patients who are at greater risk for complications. Notably, at most large centers, perioperative morbidity from other than infectious complications, including acute graft failure and bronchial dehiscence, is similar for SLT and DLT. For patients with pulmonary vascular disease, DLT is favored over SLT for patients with the higher levels of pulmonary artery (PA) pressures (e.g., systolic PA at least 90 mmHg or mean PA at least 65 mmHg) and more advanced right ventricular dysfunction (e.g., RVEF 20 percent or less). Combined heart–lung transplantation (HLT) has been used successfully for virtually all end-stage pulmonary diseases that require transplantation. However, with the perfection of the techniques of SLT and DLT and in light of the significant limitations in supply of donor organs, the use of HLT has focused on patients with significant refractory right ventricular diastolic dysfunction (e.g., RVEDP more than 15 mmHg), significant intrinsic left ventricular dysfunction, or Eisenmenger’s syndrome and irreparable shunt defects. The surgical mortality for HLT at large centers is about 15 percent; typically, it is higher than the surgical mortality for SLT or DLT for similar disease states (Table 101-8).

DONOR SELECTION The most significant factor limiting wider application of lung transplantation is the supply of donor organs. Unlike other

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Table 101-8 Indications for Specific Lung Transplant Procedures Single-lung transplantation (SLT) Obstructive lung disease Restrictive lung disease Unilateral septic lung disease Primary pulmonary hypertension Eisenmenger’s syndrome with a correctable shunt defect Double-lung transplantation (DLT) Obstructive lung disease (patient <50 years old) Bilateral septic lung disease Primary pulmonary hypertension Eisenmenger’s syndrome with a correctable shunt defect Combined heart–lung transplantation (HLT) Refractory right ventricular end-diastolic dysfunction (RVEDP <15 mmHg) Significant intrinsic left ventricular dysfunction (LVEF <45%) Significant coronary artery disease, not amenable to nonsurgical interventions Eisenmenger’s syndrome with an irreparable shunt defect

solid organs used for transplantation, the lung is exposed, before brain death, to environmental contamination, including both microbiologic pathogens and toxic substances, which may significantly impair its functional capabilities. The microbiologic aspects of this exposure are accentuated by the endotracheal intubation that is a necessary aspect of donor management. In addition, aspiration of oropharyngeal or gastric contents is a common occurrence during the events preceding brain death. Nearly half of all comatose patients develop pneumonia within 1 week of intubation, probably owing to a combination of these factors. Brain death itself may also lead to neurogenic pulmonary edema. In cases of trauma that lead to brain death, significant injury to the thorax may occur, or the volume replacement required for the resuscitation of these patients may limit the suitability of the lungs for subsequent transplantation. As a result, only about 25 percent of cadaveric organ donors are potential lung donors. Criteria for lung donation are meant to identify donors with evidence of good gas exchange in the absence of infection of the airways or parenchyma (Table 101-9). A donor age of less than 60 years and a history of smoking for less than 20 to 30 pack-years are important. Both increasing age and prolonged tobacco use are known to correlate directly with anatomic alterations in the pulmonary parenchyma—which, despite preservation of gas exchange function in the donor, may result in impaired graft function in the recipient. Chest

radiograph should reveal a normal lung on the side of the proposed lung donation. Unilateral pneumonia or parenchymal trauma does not preclude use of the contralateral lung for transplantation in most circumstances. No major thoracic surgery should have been performed on the side of proposed donation, not only because of potential technical limitations but also because such a history usually suggests either a major anatomic abnormality (e.g., prior lobectomy) or pathology (e.g., malignant neoplasm), which would preclude donation. Finally, the size of the donor lungs, based on direct measurement or correlated to body surface area as estimated by donor height, is a useful parameter for one to use when selecting lungs for a particular recipient. Generally, the donor lungs should be within 25 to 30 percent of the predicted size of the recipient’s lungs. Since most recipients have significant abnormalities in lung volume, the predicted size of an ideal recipient lung, estimated from the recipient’s body surface area, should be used for comparison. A donor lung larger than these measurements can be volume reduced at the time of transplantation, whereas a donor lung smaller than these measurements usually should be avoided. Adequate gas exchange has been defined as a PaO2 greater than 300 mmHg on mechanical ventilation, with an FiO2 of 1.0 and positive end-expiratory pressure (PEEP) at least 5 cm H2 O. Minute ventilation should be adjusted to achieve normocarbia, with a tidal volume of 10 to 15 ml/kg and an appropriate respiratory rate. If a unilateral pulmonary process is present, however, a lower PaO2 may be acceptable because of the possibility of mixing of venous blood from the two lungs at the level of the left atrium. In this circumstance, intraoperative evaluation of unilateral gas exchange by sampling from the ipsilateral pulmonary vein for determination

Table 101-9 Characteristics of a Suitable Lung Donor Age <60 years Cigarette smoking <30 pack-years No significant prior thoracic surgery on the side of the donor lung Normal chest radiograph of the donor lung Adequate gas exchange of the donor lung PaO2 > 300 mmHg on FIO2 1.0, PEEP ≥5 cm PvO2 > 450 mmHg on FIO2 1.0, PEEP ≥5 cm Bronchoscopic evaluation demonstrating absence of mucosal inflammation No significant pulmonary trauma or anatomic abnormalities

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of PO2 can be used to determine that the prospective donor lung is satisfactory. All lung donors have some evidence of colonization of the lower respiratory tract by potential pathogens owing to the requisite endotracheal intubation, which bypasses the defense mechanisms of the upper airway. A distal tracheitis is uniformly present after 72 h of intubation. Therefore, a sputum Gram’s stain revealing polymorphonuclear leukocytes or multiple bacterial forms does not necessarily imply invasive infection. For this reason, bronchoscopy is a critical step in the evaluation of any potential lung donor. Bronchoscopy allows inspection of the large airways for the presence of aspirated debris as well as assessment of the character of the secretions and status of the bronchial mucosa. A finding of diffuse bronchial mucosal inflammation is significant, even if only a limited amount of aspirated debris or secretions are present. However, purulent secretions without significant mucosal inflammation in the presence of a clear chest radiograph and preserved gas exchange generally indicate a suitable lung for donation. A potassium hydroxide smear for fungal organisms is also a part of the routine evaluation of the lung donor, although as with the Gram’s stain, the mere presence of fungal organisms does not preclude lung donation. In most cases, the presence of potential pathogens in the donor sputum by either Gram’s stain or fungal smear requires preemptive modification of the recipient’s antimicrobial regimen if such lungs are used for transplantation. At some centers, this treatment is begun by the administration of intravenous or aerosolized antimicrobial therapy to the donor before extraction of the lungs. The donor evaluation is completed by intraoperative inspection of the pleural space and lung. Occasionally, unsuspected parenchymal trauma is evident in the form of a bloody pleural effusion or pulmonary contusion. The donor lung also should be studied for evidence of unsuspected bullous disease or mass lesions. Excisional biopsy and intraoperative pathologic evaluation of any parenchymal mass lesion should be carried out. Finally, the anesthesiologist should be directed to maintain adequate tidal volumes and PEEP during intraoperative ventilation to preserve optimal function of the donor lung before its removal. The appropriateness of a potential lung donor always should be interpreted in the context of the recipient’s disease and clinical status. Older patients, patients with diseases such as COPD (in whom lung transplantation may be largely palliative), and patients with a sudden clinical deterioration, such as those who have recently been placed on mechanical ventilation, may all benefit from transplantation with a lung that does not fulfill all the criteria of an optimal donor lung. Most frequently, the criteria relating to cigarette smoking and PaO2 are breeched in these circumstances. The results have generally been satisfactory in such recipients, suggesting that the use of these “compromised” lung donors may partly address the problem of donor organ shortage. It has also been shown that the effect of the functional status of the donor lung is most significant in the first 24 h after transplantation, and that subsequent graft function depends primarily on factors related

Lung Transplantation

to the recipient. However, the potential effects of using compromised lung on long-term issues, such as the incidence of rejection, is not known. In addition, these studies have underscored that patients with pulmonary hypertension, who are the most difficult to manage postoperatively, are best served by transplantation with noncompromised lungs from optimal donors.

LUNG PRESERVATION The ideal method of pulmonary preservation has not yet been identified. With current techniques, however, satisfactory graft function can be obtained after ischemic intervals as long as 6 to 8 h. As with other vascularized solid organs used for transplantation, the lung consists of a heterogeneous population of cells, of which the vascular endothelial cell appears to be the most sensitive to ischemia. Ischemic injury to the pulmonary vascular endothelium increases its permeability and results in pulmonary edema, the common end point for assessment of injury in models of pulmonary preservation techniques. Hypothermia is the major method used clinically to limit ischemic injury to these cells. The lung also has some unique biologic and physical characteristics that distinguish it from other solid organ transplants: Although it has an absolute requirement for aerobic metabolism, the lung is capable of using ambient oxygen for the metabolism of glucose, even during the ischemic state. In addition, the effective size of the pulmonary vascular bed and thermal conductivity of the lung can be manipulated by the state of lung inflation. Current clinical methods of lung preservation make use of these characteristics to optimize graft function following an ischemic interval. Two techniques are currently being used for lung preservation, core cooling and hypothermic flush perfusion. Extracorporeal core cooling (ECC) is a technique that has been used primarily for procurement of heart–lung donor blocs, commonly in conjunction with multiorgan procurement at abdominal sites. ECC consists of systemic heparinization of the donor and institution of full CPB by means of a transpericardial approach. The donor is cooled to 15◦ C (rectal temperature). Ventricular fibrillation typically develops during this maneuver, and the heart is decompressed through the left ventricle. CPB is then discontinued, and the heart–lung bloc is harvested and transported in a cold ischemic state with the lungs inflated. No flush solutions are used, although the lungs are essentially being flushed by cooled autologous blood during the time of CPB. Safe ischemic times of 6 h or more have been reported with adequate pulmonary function. It is of interest that while oxygenation in lungs preserved by ECC appears to be somewhat less optimal than in those preserved by hypothermic flush techniques, the pulmonary vascular resistance upon reperfusion of the lungs following ECC is generally lower than that seen upon reperfusion of lungs obtained by flush techniques.

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Hypothermic flush perfusion is the method most commonly used for pulmonary preservation in clinical practice. This technique consists of flushing the pulmonary vasculature with a cold solution after systemic heparinization of the donor, followed by extraction and transport of the lungs inflated with 100 percent oxygen. A low-potassium dextran solution is used. The state of inflation of the lungs is important in obtaining optimal perfusion of the pulmonary vasculature by the flush solution, for the effects both of rapid cooling and of direct cellular preservation by the solution itself. Intraoperatively, maintaining a tidal volume similar to that used during the initial donor assessment is important. The addition of PEEP during the procurement procedure maintains FRC and the desired state of inflation of the donor lungs. PEEP also increases the intra-alveolar release of surfactant, minimizing pulmonary compliance abnormalities after implantation of the donor lungs. Ventilation is continued throughout the period of lung perfusion to maintain the effective size of the pulmonary vascular bed. Maintenance of an FiO2 of 1.0 during the procurement is also useful, particularly at the time of lung extraction, to provide an oxygen-rich ambient environment for metabolic activity of the lung during the ischemic interval. The lungs are extracted and transported in a state of inflation that approximates end-tidal inspiration. Some consideration should be given to the fact that the donor lungs may be transported by aircraft, in which a fall in atmospheric pressure may result in further inflation of the lungs. Overinflation of the donor lungs is to be avoided, as this leads to increased capillary permeability and postimplantation pulmonary edema. The administration of prostanoids, either prostaglandin E1 (PgE1 ) or prostacyclin, into the pulmonary circulation before flush perfusion has been shown to improve lung preservation. The mechanism of action of prostanoids includes dilation of the pulmonary vasculature, allowing for better distribution of the flush solution, and decreased leukocyte adhesiveness, which can abrogate the initial events of reperfusion injury. Most commonly in North America, PgE1 is used as a bolus (500 µg) into the pulmonary circulation, with or without the addition of similar amounts of PgE1 directly to the flush solution. The use of prostanoids in combination with intracellular flush solutions has been shown to provide pulmonary preservation equivalent, if not superior, to that with the use of extracellular-type flush solutions alone. Most flush solutions are administered at a temperature of 4◦ C, while topical cooling is carried out by filling of the pleural cavity with iced crystalloid solution. After extraction, the lungs are immersed in crystalloid and packed in ice, resulting in a transport temperature of 1 to 4◦ C. Some studies have shown that lung preservation is superior when a more moderate hypothermia with a temperature of 10◦ C is used. However, because of the concerns regarding the deleterious effects of flush and storage temperatures greater than 10◦ C, and the difficulties in maintaining this temperature during the procurement procedure, clinical flush per-

fusion continues to be performed at the lower temperature ranges. Experimental work has identified numerous adjuncts to the techniques currently used for pulmonary preservation that have the potential for prolonging ischemic intervals. A significant part of the lung injury seen after ischemia has been shown to be due to the phenomenon of reperfusion, which is initiated by leukocyte adhesion to endothelial cells and the production of oxygen-derived free radicals and peroxides. Measures that diminish this response, in addition to the use of prostanoids, include donor leukocyte depletion, the administration of antibodies to block adhesion molecules, the use of inhaled nitric oxide, and the inclusion of oxygen radical scavengers, such as superoxide dismutase or catalase, to the flush solution. In addition, methods of increasing the resistance of cells to ischemic injury, such as the induction of heat shock proteins, have been shown to be beneficial in other organs and may be of some use in lung preservation. Evidence of the effect of these manipulations on tolerable ischemic intervals in clinical lung transplantation awaits additional study.

TECHNIQUES OF LUNG TRANSPLANTATION Anesthetic Management Proper perioperative management of the recipient is crucial to obtain the best outcome following lung transplantation. Close cooperation and understanding between the anesthesiology and surgical teams are essential. An appreciation of the unique aspects of the physiology of the various types of lung transplant recipient is also important. Patients with COPD have reduced expiratory flow rates, air trapping, and increased lung volumes. In advanced states, chronic pulmonary artery hypertension develops and leads to cor pulmonale in 10 to 40 percent of patients. These patients are usually oxygen dependent, dyspneic, orthopneic, and quite anxious. Following endotracheal intubation, extreme care should be taken to allow adequate expiratory time for emptying of the lungs, avoiding the cardiovascular instability caused by “pulmonary tamponade” due to progressive air trapping in the lungs and reduction of ventricular filling. Tension pneumothorax due to rupture of bullae can also occur but is relatively uncommon. Patients with restrictive lung disease have progressive fibrosis of the lung tissue, with secondary hypoxemia and progressive pulmonary hypertension. Patients with these diseases have an increased work of breathing and are oxygen dependent and extremely dyspneic before transplantation. Many of these patients have evidence of cor pulmonale at the time of transplantation and can not tolerate occlusion of the pulmonary artery during implantation of the donor lung without the support of cardiopulmonary bypass. Careful and repeated assessment of filling pressures and cardiac output is required to allow prompt interventions in such patients. Patients with septic lung disease demonstrate primarily the abnormalities in pulmonary function seen in patients with

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obstructive airway disease. However, these recipients have excessive copious purulent secretions, which can exacerbate air trapping and also contribute to marked V/Q abnormalities— particularly during single-lung ventilation. Careful management of double-lumen endotracheal tubes to avoid contamination of the contralateral lung graft and attention to bronchopulmonary hygiene to avoid obstruction of the lumens of these tubes are needed in these patients. Finally, recipients with pulmonary vascular disease who present for transplantation have marginally compensated cor pulmonale and are extremely dyspneic and anxious. Patients with PPH become oxygen dependent late in the course of their disease, although oxygen is commonly administered to these patients to lessen the hypoxic contribution to their pulmonary hypertension. For this reason, oxygen therapy should be continued throughout the time of preoperative preparation and line placement to avoid abrupt right heart dysfunction. Because these patients have normal pulmonary mechanics, they generally tolerate mechanical ventilation well. Patients with Eisenmenger’s syndrome are well adapted to chronic hypoxemia. In these patients, supplemental oxygen does not reverse the hypoxemia and may even worsen arterial hypoxemia by eliciting systemic vasodilatation and increasing right-to-left shunting. All lung transplant procedures should be performed with CPB available on standby. However, CPB is best avoided in cases of septic lung disease or when there are known extensive intrapleural adhesions, to avoid excessive bleeding complications. No specific preoperative factors can be used to predict the need for CPB—with the exception of either PPH or Eisenmenger’s syndrome, for which CPB is requisite for the procedure. For other lung transplant recipients, assessment of the need for CPB is best made intraoperatively by trial clamping of the pulmonary artery, followed by assessment of hemodynamic parameters, oximetry, and if available, ventricular function testing by transesophageal echocardiography. Progressive deterioration in these parameters requires unclamping of the pulmonary artery and an attempt to optimize factors such as preload, inotropic support, PaO2 , PaCO2 , and pulmonary vascular resistance. If repeat trial clamping of the pulmonary artery is still not tolerated, plans for CPB are made. Typically, cannulation after systemic heparinization is via the femoral vessels for SLT and via a transpericardial approach for patients undergoing DLT or HLT.

Single-Lung Transplantation The approach to SLT requires an initial decision regarding the side of implantation. Most commonly, the native lung with the least pulmonary function based on preoperative V/Q scans is excised. In some patients, however, specific technical factors, such as a prior pleurodesis, may override this factor. When the function of the two lungs is equal or when the need for CPB is anticipated, the right side is preferred because of the greater ease of surgical exposure and the institution of CPB via the ascending aorta and right atrium. A right-sided approach also facilitates exposure for closure of intracardiac

Lung Transplantation

defects in patients with Eisenmenger’s syndrome. Despite the potential differences in size of the right and left hemithorax, there does not appear to be any long-term difference in outcome following right or left SLT. Most often, exposure for SLT is via a generous posterolateral thoracotomy through the fifth intercostal space or the bed of the excised fifth rib. When elective CPB via the right hemithorax is planned, the use of a fourth interspace may facilitate placement of the cannulae. The ipsilateral groin is included in the surgical field in the event that cannulation of the femoral vessels is required for partial CPB. Although the use of femoral sites for cannulation requires repair of the vessels after removal of the cannulae, it does provide a site for additional venous drainage with use of intrathoracic cannulation sites. Femoral cannulation sites also provide access for conversion to ECMO support if acute graft failure occurs immediately after implantation. Occasionally, when the repair of an associated intracardiac defect requires an anterior approach, a median sternotomy may be used for right SLT in patients with Eisenmenger’s syndrome. The donor lung is prepared for implantation and then wrapped in sponges soaked with cold crystalloid solution and placed into the hemithorax. The bronchial anastomosis is performed first. Although a variety of techniques have been described, the essential points are to minimize the length of both the donor and recipient bronchi to preserve collateral blood supply and achieve some degree of anastomotic overlap. The smaller bronchus, most commonly the donor bronchus, is telescoped into the larger bronchus with either a technique of interrupted sutures or a combination of running sutures on the membranous wall and interrupted sutures on the anterior wall in a figure-eight or horizontal mattress fashion. Polyfilament absorbable suture (e.g., 4-0 polyglactin) or monofilament suture, either absorbable (e.g., polydioxanone) or nonabsorbable (e.g., polypropylene), may be used. The anastomosis is then covered by either local peribronchial tissue or local pedicled flaps of thymic tissue or pericardial fat (Fig. 101-1). The order of the vascular anatomoses can vary even though the pulmonary artery anastomosis is frequently the more technically difficult to perform. A continuous 5-0 polypropylene suture is used for each anastomosis, leaving the ends untied for de-airing upon reperfusion of the lung. For the pulmonary artery anastomosis, the length of the donor and recipient vessels requires careful assessment to avoid kinking. For the left atrial anastomosis, the confluence of the recipient pulmonary veins is incised to create a left atrial cuff. Occasionally, dissection in the interatrial groove is required to allow more proximal placement of the vascular clamp on the recipient left atrium (Fig. 101-2). After completion of these anastomoses, the lung is gently reinflated. Perfusion of the lung graft is then reestablished, initially in an antegrade fashion, evacuating air via the left atrial suture line. The atrial clamp is removed, with the atrial suture line under a fluid level to prevent entrainment of air into the left heart. Ventilation of the donor lung is resumed, and after a few minutes to allow the vascular suture lines to adapt to the distention caused by

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Figure 101-1 Bronchial anastomosis for lung transplantation. A technique of approximation using stay sutures at the junction of the cartilaginous and membranous walls is shown. A running suture is used for the membranous wall (1), followed by an interrupted suture technique of horizontal mattress sutures on the cartilaginous wall to achieve telescoping of the donor into the recipient bronchus (2). Significant anastomotic overlap is achieved with this technique (3), with additional anastomotic coverage obtained by approximation of peribronchial and mediastinal tissues about the site (4). (From Pearson FG: Thoracic Surgery. New York, Churchill Livingstone, 1995, with permission.)

increased flow, these suture lines are secured. Hemostasis is then obtained, two chest tubes are placed, and the chest is closed in a standard fashion. Following reintubation with a single-lumen tube, flexible bronchoscopy is completed to inspect the bronchial anastomosis and clear the airway of blood or residual secretions.

Double-Lung Transplantation The most frequently performed DLT procedure is that of bilateral sequential SLT. This procedure has a significantly lower incidence of bronchial complications than the en bloc DLT procedure, and is technically less difficult to perform than en bloc DLT with simultaneous bronchial artery revascularization. The exposure for bilateral sequential lung transplantation is via bilateral anterolateral thoracotomies through the fourth or fifth intercostal space, connected by a transverse sternotomyâ&#x20AC;&#x201D;the so-called clam shell incision (Fig. 101-3). The incision provides adequate exposure for mobilization of intrapleural adhesions, even after previous pulmonary resec-

tions or pleurodesis, and also provides excellent access for institution of CPB and correction of intracardiac defects. In most patients, the entire incision is made at the beginning of the procedure, and both lungs are completely mobilized. For patients with emphysema who undergo DLT, however, the contralateral hemithorax may be left closed until after the first lung graft is implanted; this sequence minimizes the tendency to overinflation of the native lung that may occur during the initial implantation procedure. The mobilization and pneumonectomy of the native lung and the implantation of the lung graft are conducted in the same manner as described for SLT. Thymic and anterior mediastinal tissue on a superiorly based vascular pedicle may be mobilized for coverage of the bronchial anastamoses. Living related lung transplantation is most commonly performed as a bilateral sequential transplant procedure using the clam shell incision. Cardiopulmonary bypass is instituted electively after the recipient native lungs are mobilized. Each of the donor lobes is implanted at the recipient hilum. Typically, there is little discrepancy in size between the lobar bronchus and pulmonary vein of the donor (usually an adult) and the main bronchus and left atrium of the typical pediatric recipient. The order of the anastomoses (bronchus first) and the technique are the same as for cadaveric SLT and DLT. Overinflation of the lobar graft is more likely than with a cadaveric allograft and may contribute to postoperative pulmonary edema. A marked size discrepancy between the lobar allograft and the recipient hemithorax is uncommon; if present, the descrepancy should be treated conservatively (e.g., by avoiding chest tube suction rather than by aggressive surgical measures such as thoracoplasty). In all cases, sufficient remodeling of the thorax or hyperinflation of the lobar grafts will occur to obliterate any residual pleural space.

Heart--Lung Transplantation Either a standard median sternotomy or a clam shell incision may be used for HLT. The latter provides better access for mobilization of intrapleural incisions and is particularly useful for recipients with septic lung disease or prior pulmonary procedures. Following institution of CPB, the lungs are removed by an extrapericardial approach using successive stapling of the bronchovascular structures at the pulmonary hila. The donor right atrium is incised from the inferior vena cava to the right atrial appendage. Inspection is made for the presence of an atrial septal defect and adequate closure of the superior vena cava. The donor bloc is positioned by passing the lungs into the pleural spaces via the retrophrenic pedicles. If a tracheal anastomosis is used, the posterior pericardium is incised between the ascending aorta and superior vena cava to expose the distal trachea and, after the donor and recipient tracheas have been trimmed, a distal tracheal anastomosis is performed. Some centers prefer bilateral bronchial anastomoses at the mediastinal pleural reflection, using a telescoping technique as described for SLT. This approach obviates dissection in the posterior mediastinum and may be associated

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Lung Transplantation

Figure 101-2 Implantation of the donor lung at the right hilum. 1. The bronchial anastomosis is performed first, followed by the vascular anastomoses. A clamp is placed on the proximal pulmonary artery, and the anastomosis is performed distal to the first upper-lobe arterial branch in the recipient, which has been ligated. A clamp is placed on the left atrium intrapericardially. 2. After excision of the pulmonary vein stumps, the confluence of the pulmonary veins is incised to create a cuff of left atrium for anastomosis. 3. Atrial anastomosis is performed with a running monofilament suture following approximation with stay sutures superiorly and inferiorly. 4. On completion of the anastomosis, the sutures are left untied until lung reinflation and antegrade reperfusion is completed to evacuate air from the donor vasculature. (From Shields TW: General Thoracic Surgery. Philadelphia, Lea & Febiger, 1994, with permission.)

Figure 101-3 Approach to double-lung transplantation. The clam shell incision is used, consisting of bilateral anterior thoracotomy with transverse sternotomy, defined by the line of the inframammary crease. Entrance into the chest is through either the fourth or fifth intercostal space, followed by placement of bilateral rib retractors. (From Shields TW: General Thoracic Surgery, Philadelphia, Lea & Febiger, 1994, with permission.)

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with fewer anastomotic complications. The right atrial anastomosis is completed, followed by the aortic anastomosis. The aortic cross clamp is removed, and after reinflation of the lungs, the heart is de-aired via the pulmonary artery and left ventricle. After defibrillation, the patient is weaned from CPB.

POSTOPERATIVE MANAGEMENT Ventilation In most cases, ventilatory management folllows standard criteria. The FiO2 is adjusted to maintain a PaO2 greater than 65 mmHg. Standard volume ventilation is used, with a tidal volume of 12 to 15 ml/kg and PEEP of 5 to 7.5 cm H2 O. Significant barotrauma due to increased airway pressures is extremely uncommon after lung transplantation, and higher airway pressures may have a beneficial effect in minimizing postoperative pulmonary edema. Transition from volume ventilation to pressure ventilation before extubation may be useful to decrease the work of breathing and serves to minimize differences in compliance between the native lung and allograft following SLT. Appropriate management of postoperative pain is also helpful in weaning these patients from the ventilator. Extubation is performed when the mental status of the patient is normal and the patient has achieved a reasonable rate of ventilation and spontaneous tidal volume, typically 48 to 72 h after the procedure. Maintaining good bronchopulmonary hygiene, with frequent endotracheal aspiration of secretions and physiotherapy, is important in achieving and maintaining extubation in these patients. Patients with emphysema who undergo SLT are an exception to the above guidelines. These patients require particular attention to airway pressures and to the compliance difference between the allograft and the native lung. Hyperinflation of the native lung may not only result in compromise of cardiac filling but also interferes progressively with ventilation of the allograft. Efforts to control hyperinflation of the native lung include use of slightly lower tidal volumes (9â&#x20AC;&#x201C;12 ml/kg) accompanied by higher respiratory rates to preserve minute ventilation and lower levels of PEEP (1â&#x20AC;&#x201C;3 cm H2 O). Positioning of the patient with the native lung down may further increase the impedance of that hemithorax and limit hyperinflation, although increased blood flow to the native lung induced by this maneuver may require adjustment of ventilatory parameters to maintain normocarbia. In rare circumstances, when significant edema has occurred in the allograft, independent lung ventilation using a double-lumen endotracheal tube may be needed. In patients with significant pulmonary hypertension who undergo lung transplantation, the postoperative pulmonary hemodynamics are unique. In these patients, the right ventricle has been conditioned to generate peak systolic pressures against a markedly elevated pulmonary vascular resistance (PVR). Following lung transplantation, the PVR abruptly decreases to near-normal levels, accompanied by im-

proved ventricular hemodynamics. Minimal catecholamine stimulation occurs when the patient awakes from anesthesia or is weaned from a ventilator, causing the right ventricle to respond by generating peak systolic pressures similar to those that existed preoperatively. The resultant abrupt increase in pulmonary artery pressure, in combination with increased capillary permeability due to ischemia and reperfusion injury and the absence of lymphatic continuity, causes fluid to accumulate rapidly in the donor lung. Typically, this pulmonary edema is very rapid in onset and results in hypoxia that elicits additional increase in pulmonary artery pressure. Preemptive treatment for this condition is necessary and requires maintenance of a high degree of sedation, or even of muscle paralysis, in the first 3 to 5 days after surgery. Following this period, patients can be awakened cautiously and weaned from the ventilator with standard methods while cardiac output, blood gases, and pulmonary artery pressures are closely monitored.

Fluid Management The goal of fluid management after lung transplantation is to minimize the accumulation of edema fluid in the implanted lung while maintaining optimal cardiac function. As previously noted, the effects of ischemia, reperfusion injury, and lymphatic discontinuity all contribute to a tendency to develop pulmonary edema in the lung graft. Pulmonary artery pressures and pulmonary capillary wedge pressures need to be kept as low as possible after surgery without compromising ventricular preload. For most patients, a reduction in PVR almost immediately after lung transplantation results in improved right ventricular and, secondarily, left ventricular performance. However, some inotropic support may be required in patients who have preexisting right ventricular hypertrophy, particularly when pressure overload of the right ventricle occurs during the implantation procedure or following CPB.

Antimicrobial Therapy Bacterial prophylaxis entails the use of vancomycin for prophylaxis against gram-positive organisms in combination with a broad-spectrum antibiotic to provide appropriate coverage for organisms identified preoperatively from the sputum of the recipient. Recipients who have been recently hospitalized, and therefore exposed to respiratory therapy equipment, or those with cystic fibrosis, require specific antibiotic coverage against Pseudomonas species, based on susceptibility data. For cystic fibrosis patients, ongoing surveillance of sputum flora and determination of antibiotic sensitivities are important in the waiting period before transplantation so that an appropriate multidrug antimicrobial regimen can be developed for perioperative use. The addition of antimicrobial inhalation therapy, using either tobramycin or colistin, can have additive effects in the management of Pseudomonas. Postoperative antibacterial coverage should be modified if pathogens not already covered by the recipientspecific regimen are found in the sputum of the donor.

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Routine prophylaxis for fungal organisms is useful when preoperative recipient sputum cultures have demonstrated the presence of Aspergillus species at any time before the transplant procedure, when there has been evidence of heavy overgrowth of yeast (e.g., Candida) in the donor sputum culture, or when cytolytic induction immunosuppression is used. In the case of Aspergillus, prophylactic therapy requires the use of amphotericin B; in the latter instances, fluconazole or low-dose ketoconazole therapy is effective. The occurrence of herpes simplex infection, including mucosal ulceration and pneumonitis, has been eliminated by the routine use of acyclovir prophylaxis after lung transplantation. However, CMV infection remains a significant problem following lung transplantation. The incidence of CMV infection after lung transplantation is related to the preoperative CMV status of both the donor (D) and the recipient (R). A discordant CMV status between donor and recipient may result in either primary infection of the donor lungs by the recipient (in the case of D+/R+) or the more serious circumstance of primary systemic CMV infection (in the case of D+/R+). In either case, the incidence of acute and chronic rejection and mortality are higher than among patients in whom CMV status is concordant. For this reason, many centers prefer to match D and R status. However, the use of ganciclovir prophylaxis has been shown to eliminate the incidence of primary disease and to improve the outcome of CMV-disparate lung transplants. Pneumocystis carinii infection in lung transplant patients has been eliminated by the routine use of trimethoprim-sulfamethoxazole beginning 1 week after surgery.

Nutrition Maintaining optimal nutrition in the postoperative period is a useful adjunct for improving surgical outcome. When prolonged ventilatory support is required, the use of intravenous hyperalimentation or, preferably, enteral alimentation via a nasogastric feeding tube is mandatory. Patients with cystic fibrosis have a malabsorptive syndrome, which requires resumption of preoperative pancreatic enzyme supplementation. These patients have difficulty absorbing medications such as cyclosporineâ&#x20AC;&#x201D;a circumstance that may be improved by the intake bof bile salts (e.g., ursodeoxycholic acid 330 mg with each cyclosporine dose).

Immunosuppression The induction of a state of relatively nonspecific immune suppression by pharmacologic means has been the key to successful clinical lung transplantation. While the ideal method would be to achieve specific, permanent tolerance of the allograft without the need for chronic medication, this is not possible at present. As a result, although the current regimens lead to satisfactory control of most acute rejection processes, the combined side effects of these medications and their incomplete ability to control chronic rejection in the lung account

Lung Transplantation

for the major long-term morbidity and mortality associated with lung transplantation. The immunosuppressive regimens used for lung transplantation are based on the successful protocols that have evolved for renal and heart transplantation. Virtually all centers use a three-drug regimen for immunosuppression (a calcineurin inhibitor, cell-cycle inhibitor, and steroids), with the hope of obtaining additive effects in terms of immune suppression while limiting drug toxicities. Most lung transplant programs use steroids as part of the regimen for the induction of immunosuppression. However, some centers have used cytolytic therapies such as daclizumab, basiliximab (antiCD25), Campath (anti-CD52), OKT3, and anti-thymocyte globulin for this purpose. These therapies are typically initiated within 24 hours of transplantation, and are typically combined with the usual triple-drug regimen of steroids, a calcineurin inhibitor, and a cell-cycle inhibitor. Cyclosporine remains the mainstay of immunosuppression for lung transplantation. Intravenous administration is usually begun before the graft is implanted and continued postoperatively, provided renal function remains satisfactory. Subsequent conversion to oral dosing is completed when gastrointestinal function is normal. Blood levels of cyclosporine correlate with immunosuppressive effects and toxicity. Whole blood levels of 350 to 400 ng/ml or serum levels of 150 to 200 ng/ml are considered therapeutic. Nephrotoxicity, the major side effect of cyclosporine, results from vasoconstriction of the afferent glomerular arteriole. Azathioprine, a purine analog, is converted to several purine metabolites, including 6-mercaptopurine, in red cells and hepatocytes. These purine metabolites have a variety of inhibitory effects on hematologic cell proliferation, with a somewhat greater effect on T cells than B cells. Azathioprine is begun at a dosage of 2 to 2.5 mg/kg per day and adjusted downward to maintain a white blood cell count of more than 4000 cells/ml. The dosage is the same for both the intravenous and oral routes. If necessary, azathioprine may be omitted for several days without significant compromise of its immunosuppressive effect. Corticosteroids have a variety of effects on the immune response, mediated by the interaction of the steroid with a high-affinity cytoplasmic receptor. Steroids affect both inflammation and immunity, and modulate lymphocyte-, mononuclear phagocyteâ&#x20AC;&#x201C;, and antigen-presenting cell functions. Prednisone, prednisolone, and methylprednisolone are all synthetic derivatives of cortisol that are used clinically for transplant patients. Intraoperatively, methylprednisolone is administered before reperfusion of the lung graft. Postoperatively, in the absence of cytolytic induction therapy, moderate-dose corticosteroid therapy is used in combination with cyclosporine and azathioprine for induction immunosuppression. An oral dose of prednisone (0.5 mg/kg per day) is usually begun on postoperative day 5 to 7. Although corticosteroids have profound inhibitory effects on wound healing, their use in this fashion in the immediate postoperative period has not adversely affected the outcomes of lung transplantation.

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Various antilymphocyte antibody preparations, socalled cytolytic therapies, have been used in clinical lung transplantation. Both polyclonal preparations, such as antilymphocyte globulin and antithymocyte globulin (ATG), and a murine monoclonal antibody to the CD3 complex of human lymphocytes (OKT3) have been used. Initially, it was believed that strict avoidance of corticosteroids was needed in the early postoperative period to assure satisfactory healing of the bronchial anastomosis. As a result, cytolytic therapy was thought to be necessary to induce immunosuppression before the initiation of steroid therapy in the second postoperative week. The subsequent demonstration that moderatedose corticosteroid therapy was well tolerated immediately after lung transplantation, as described, as well as concerns regarding the risks of cytolytic therapy, resulted in most centers’ reserving the use of these agents for the treatment of refractory acute rejection. The two most significant concerns regarding the use of cytolytic therapy have been the increased incidence of CMV disease and the incidence of posttransplant lymphoproliferative disorder (PTLD). CMV disease can be effectively eliminated by several strategies, including matching of D/R CMV status and the use of prophylactic ganciclovir. The incidence of PTLD may also be minimized by the use of ganciclovir, which has additional effects against the Epstein-Barr virus (EBV), the likely cause of PTLD in most cases. Tacrolimus (FK-506) is a macrolide compound with a mechanism of action similar to that of cyclosporine through an immunophilin protein called the FK-binding protein (FKBP). Tacrolimus has been used for induction immunosuppression as part of a three-drug regimen with azathioprine and steroids and as a rescue therapy for patients with refractory rejection on a standard three-drug regimen (cyclosporine, azathioprine, and steroids). Toxicity is similar to that of cyclosporine and includes reversible renal dysfunction, hypertension, and neurotoxicity. New-onset diabetes mellitus has also been reported. Hypertrichosis and gingival hyperplasia have not been seen with tacrolimus. In a randomized trial in lung transplant patients of three-drug regimens containing either cyclosporine or tacrolimus, the incidence of postoperative fungal infections was higher in patients receiving tacrolimus. Sirolimus (rapamycin) is an analog of tacrolimus that also binds to MTOR (mammalian target of rapamycin). It inhibits the response of T lymphocytes to IL-2 and other cytokines but does not inhibit IL-2 production. Rapamycin has been shown to reverse ongoing rejection and prolong graft survival in animal models. However, rapamycin has been associated with airway anastamotic dehiscence (a major complication) when used for immunosuppression early posttransplant. Although the drug does not cause nephrotoxicity, a major toxicity is necrotizing vasculitis of the gastrointestinal tract. Concurrent cyclosporine administration increases the potency of rapamycin, suggesting that it may be used in combination with cyclosporine to lower the overall toxicity of a multidrug immunosuppressive regimen. Mycophenolic acid inhibits de novo purine synthesis by inhibiting the con-

version of inosine monophosphate to xanthine monophosphate. Since lymphocytes depend almost exclusively on de novo purine synthesis, mycophenolic acid selectively inhibits their replication, including the formation of cytotoxic lymphocytes and both primary and secondary antibody formation. Mycophenolic acid has been shown to reverse acute rejection that is resistant to both corticosteroids and OKT3. It appears to have primarily gastrointestinal side effects, including nausea, gastritis, and ileus, without significant myelosuppressive toxicity.

Rejection Lung grafts contain a large population of immunocompetent cells, including lymphocytes and macrophages within the parenchyma, hilar and pulmonary lymph nodes, and bronchus-associated lymphoid tissue (BALT). Most of these cells are memory T cells. A prominent interaction occurs between donor and recipient immune cells during the early period after implantation. Analysis of cells obtained by bronchoalveolar lavage (BAL) during the first month after transplant demonstrates donor-specific lymphocyte proliferation, suggesting in vivo mixed lymphocyte reactivity at a time when both donor and recipient immune-competent cells are present. Subsequently, rapid replacement of donor lymphocytes and macrophages occurs. By 90 days after transplantation, most of the intraparenchymal cells are of recipient origin and BALT has been markedly depleted. In view of these rapid and profound changes in immune cell populations, it is not surprising that rejection is common in lung allografts and that, in the case of heart–lung grafts, lung rejection may occur more frequently than, and independent of, rejection of the heart (Table 101-10). A protocol of routine transbronchial biopsy of the lung for identification of histologic evidence of lung rejection is usually recommended for both heart–lung and isolated-lung transplants because of the likelihood of rejection that may occur with minimal clinical symptoms. Typically, surveillance bronchoscopy is performed at 3 weeks, 6 weeks, 3 months, 6 months, 9 months, and 12 months after surgery. Bronchoscopy and biopsy are, of course, also performed for clinical symptoms or for changes in lung spirometry such as a decrease in FEV1 . Acute rejection (AR) is characterized by perivascular and subendothelial mononuclear cellular infiltrates (Fig. 1014). Airway inflammation, a lymphocytic bronchitis or bronchiolitis, may also be seen as a component of AR. Clinically, the patients manifest dyspnea, low-grade fever, hypoxemia, and pulmonary infiltrates on chest radiograph. Flexible bronchoscopy with BAL and transbronchial biopsy are the most useful methods of differentiating AR from infection. BAL is most useful in excluding infection and is not generally helpful in confirming rejection. The transbronchial biopsy is assessed with a standard histologic grading of AR based on the degree of perivascular infiltrate, with an additional category for assessing the degree of airway inflammation (Table 101-10). Although the severity of the perivascular process determines the “grade” of AR, the bronchial inflammation may

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Table 101-10 Working Formulation for Classification and Grading of Pulmonary Allograft Rejection Acute rejection—[with/without (B)] Grade A0, None Grade A1, Minimal Grade A2, Mild Grade A3, Moderate Grade A4, Severe Airway inflammation—lymphocytic bronchitis/ bronchiolitis B0, no airway inflammation B1, minimal airway inflammation B3, moderate airway inflammation B4, severe airway inflammation BX, ungradeable because of sampling problem, infection, tangential cutting, etc. Chronic airway rejection—bronchiolitis obliterans Active Inactive D. Chronic vascular rejection—accelerated graft vascular sclerosis source: Yousem SA, Berry GJ, Cagle PT, et al.: Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 15:1–15, 1996.

be a significant factor in predicting the later development of chronic rejection that involves the airways. Because the incidence of AR in the first 3 weeks after lung transplantation exceeds 90 percent at most centers, antirejection therapy is usually administered empirically for

Figure 101-4 Lung allograft rejection–-acute rejection, grade 2. Acute rejection is characterized by lymphocytic infiltration about pulmonary vessels. Grading of the rejection process is based on the extent of the lymphocytic infiltration into the surrounding lung parenchyma.

Lung Transplantation

transplant recipients with the appropriate clinical syndrome, even in the absence of confirmatory biopsy findings, if no infectious cause is found by BAL. The initial treatment of AR is by the administration of a brief course of high-dose corticosteroids (e.g., methylprednisolone 500 mg intravenously every day for 3 days). Ganciclovir prophylaxis (5 mg/kg twice a day, tapered over 6 weeks) is necessary for all patients with CMVdisparate D/R status when antirejection therapy is initiated. In most patients, symptomatic and radiographic improvement is seen within 48 h. Thereafter, the maintenance dose of steroids is usually increased for several weeks and then slowly reduced to prerejection levels. As a rule, it is not necessary to repeat transbronchial biopsy to confirm resolution of the AR unless symptoms or radiographic abnormalities persist. Occasionally, some patients with persistent findings require a second course of steroids, either as previously administered or as a slightly longer course of oral therapy (e.g., “recycling” beginning with prednisone 200 mg a day and then a dosage reduced by 40 mg a day to return to a maintenance dose 10 mg a day higher than the dose on which rejection occurred). For the rare patient in whom these methods do not bring about resolution of the process, repeat bronchoscopy for BAL and transbronchial biopsy are recommended to confirm the diagnosis. If persistent AR is identified, cytolytic therapy with OKT3 or ATG should be considered. Chronic rejection (CR) in the lung may affect either the pulmonary vasculature or the airway. Occasionally, accelerated sclerosis of the pulmonary arteries and veins may be encountered in lung allografts. These changes are analogous to the CR identified in many isolated cardiac allograft recipients. In fact, when this type of CR is identified in the lungs of HLT recipients, it appears to correlate with similar changes in the coronary arteries of these patients. More typically, CR in the lung is manifested by obstructive changes in the small airways. Clinically, progressive dyspnea occurs, although a gradual decline in FEV1 or in expiratory flow rates often precedes symptoms. Histologically, this process is identified as bronchiolitis obliterans and consists of dense eosinophilic scarring of the membranous and respiratory bronchioles (Fig. 101-5). Further progression of this process leads to worsening dyspnea and bronchiectasis with secondary infection. Although this form of CR is uncommon in the first 3 months after lung transplantation, up to 50 percent of patients develop it within 2 years, and the mortality at 3 years after diagnosis is 40 percent or higher. Risk factors for the development of this process include episodes of severe AR, three or more episodes of mild AR, and, in some centers, the occurrence of CMV disease. Some studies have suggested that the use of OKT3 for induction immunosuppression or the use of tacrolimus as part of a three-drug immunosuppressive regimen has been associated with a lower incidence of CR of the lung involving the airways. The term bronchiolitis obliterans syndrome (BOS) has been used to identify patients with CR of the lung involving the airways. Progressive symptoms and an unexplained fall in expiratory flow rates are the hallmarks of this process. Because of sampling limitations of transbronchial biopsy, some

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Management of progressive BOS in its later stages is mostly palliative. At its most advanced stage, BOS is essentially an acquired form of septic lung disease, and management is similar to that required for other patients with septic lung disease awaiting lung transplantation. Salvage therapies such as total lymphoid irradiation and extracorporeal photopheresis have met with limited success. Retransplantation has been performed for some patients with BOS. The results demonstrate a significantly increased perioperative mortality for such patients. One-year survival is approximately 45 percent, less than half that for primary lung transplantation. Approximately 40 percent of patients surviving retransplantation develop recurrent BOS by 3 years—an incidence similar to that following primary lung transplantation. Figure 101-5 Lung allograft rejection–-obliterative bronchiolitis. Chronic rejection in the lung most commonly involves the small airways, resulting in obliterative bronchiolitis. Dense submucosal scarring occurs and may completely obstruct the lumen of small airways. The process may be categorized as active or inactive, depending on the degree of associated inflammation.

patients with CR may not have histologic proof of bronchiolitis obliterans despite a course of progressive deterioration. Therefore, the diagnosis of BOS is based on symptoms and objective changes in pulmonary function and does not require histologic evidence of bronchioitis obliterans (Table 101-11). The clinical condition of patients with BOS is graded on a scale from 0 to 3. Although some patients with BOS will remain stable within a given grade, most demonstrate evidence of disease progression. Some evidence suggests that augmented immunosuppression may stabilize the BOS process, particularly if initiated early in its evolution. Treatment is usually directed to patients with symptomatic BOS (grades 1–3). Augmented corticosteroid therapy, including the use of inhaled steroids, cytolytic agents, and tacrolimus, has been used for this purpose. Whether one type of therapy offers a specific advantage over another in the treatment of this syndrome is not yet clear.

Table 101-11 Staging Classification of Bronchiolitis Obliterans Syndrome Stage

Severity

FEV1 (%5 baseline)

No symptoms

>80%

Mild

66–80%

Moderate

51–65%

Severe

≤50%

All stages may be subcategorized according to the presence (subcategory a) or absence (subcategory b) of histologic evidence of bronchiolitis obliterans.

Complications Surgical Complications Major technical complications following lung transplantation have become increasingly rare with improvements in surgical technique and perioperative management. Postoperative hemorrhage requiring reexploration is very uncommon with the use of the clam shell incision to improve operative exposure for patients requiring DLT or HLT and with the routine use of aprotonin infusions during CPB to diminish fibrinolysis. Pulmonary artery obstruction can occur as a result of anastomotic stenosis, kinking, or extrinsic compression. In these patients, persistent pulmonary hypertension and unexplained hypoxemia may be evident. Attention to anatomic factors, such as the length of donor and recipient pulmonary arteries and division of the pericardial attachments surrounding the donor pulmonary artery, as well as awareness of the potential for a flap wrapping the bronchial anastomosis to compress the adjacent anastomosis, helps to avoid these problems. Left atrial anastomotic obstruction can also occur because of faulty anastomotic technique or extrinsic compression by clot, pericardium, or an omental flap. This problem results in more severe abnormalities than pulmonary artery obstruction, including marked pulmonary hypertension and ipsilateral pulmonary edema. Diagnostic methods for these vascular anastomotic complications include routine intraoperative measurement of anastomotic gradients and transesophageal echocardiography, which is particularly helpful in assessing the left atrial anastomosis. Postoperatively, diagnostic measures include contrast angiography and ventilation/perfusion scanning. Reoperation and correction of the anastomosis are indicated if clinical compromise is apparent, which is particularly likely if there is significant left atrial anastomotic obstruction. Some transplanted lungs demonstrate acute graft dysfunction, even without evidence of vascular anastomotic complications (Table 101-12). As many as 20 percent of patients have severe early abnormalities of lung function, with rapidly progressive pulmonary edema, persistent pulmonary hypertension, and a markedly diminished pulmonary compliance that occurs rapidly after graft implantation. This process is to be differentiated from the “reimplantation response” that

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Table 101-12 Recommended Grading System for Primary Graft Dysfunction (PGD)

Grade

Pao2 /Fio2

Radiographic Infiltrates Consistent with Pulmonary Edema

>300

Absent

>300

Present

200â&#x20AC;&#x201C;300

Present

<200

Present

source: Christie JD, Carby M, Bag R, et al: Report of the ISHLT Working Group on Primary Lung Dysfunction, part II: Definition. J Heart Lung Transplant, 24:1454â&#x20AC;&#x201C;1459, 2005.

is seen in almost all patients 36 to 96 h after transplantation and consists of perihilar and peribronchiolar edema without significant abnormalities in gas exchange. In some patients, acute graft dysfunction is due to unsuspected abnormalities in the donor lung, such as aspiration or contusion, whereas in others it may be due to inadequate pulmonary preservation. However, no cause has been identified. Management includes evaluation of the vascular anastomoses, to rule out a potentially correctable technical complication, and maintenance of oxygenation using volume ventilation and PEEP. In most patients, regardless of the supportive measure required, the process resolves over several days. Pleural space complications are not uncommon after lung transplantation, although they are usually of minor significance. Pneumothorax may occur on either the side of a lung graft or on the side of a native lung. Pneumothoraces that arise from the lung graft are of greatest concern because of the possibility that airway dehiscence communicates with the pleural space. Fortunately, this is a rare occurrence. Nonetheless, flexible bronchoscopy is always indicated for diagnostic purposes in patients presenting with this problem. In most patients, placement of a chest tube with reexpansion of the lung limits the process acutely. More commonly, pneumothorax is the result of rupture of a bullous lesion in an emphysematous native lung after SLT. Conservative management with intercostal tube drainage is indicated. Occasionally, pneumothoraces are noted after DLT when a significant size discrepancy exists between the donor lungs and recipient thorax. In these patients, the space resolves spontaneously in a short time and specific interventions are not required. Pleural effusions are common after lung transplantation, particularly when a significant size disparity exists between the donor lungs and the thorax. Continued chest tube drainage following the primary procedure is not indicated as a preventive measure for these effusions and may actually lead to secondary infection and empyema. Management of these effusions is best done conservatively, with

Lung Transplantation

diuretic therapy and dietary salt restriction. Invasive measures, such as thoracentesis and tube drainage, are indicated only for effusions complicated by a delayed pneumothorax, for enlarging effusions, or for large effusions that persist for more than 4 weeks after surgery. Airway complications have been significantly less common in the recent experience with lung transplantation. Bronchial ischemia is the most common cause of postoperative airway complications. The most common methods of lung transplantation do not provide direct revascularization of the bronchial arterial circulation, and the donor bronchus must rely entirely on collateral perfusion from the pulmonary circulation in the initial postimplantation period. Airway ischemia at this time leads to mucosal ulceration followed by progressive mural necrosis. Localized bronchomalacia is frequently present adjacent to this region. A spectrum of abnormalities, ranging from anastomotic dehiscence to submucosal fibrosis, may occur as a result. Most commonly, partial anastomotic dehiscence occurs, followed by formation of granulation tissue and eventually some degree of anastomotic stenosis. The reduced incidence of these complications has been attributed to methods of anastomosis that limit the length of the donor bronchus, minimizing the amount of airway for which collateral perfusion is required. Most anastomotic techniques emphasize trimming the donor bronchus to within two rings of the upper-lobe orifice and the preservation of peribronchial tissues containing the collateral circulation. Telescoping the bronchi and covering the anastomosis with vascularized tissue are also useful adjunctive measures. The use of omentum does not appear to be a critical factor in most cases, although in patients who require prolonged mechanical ventilation because of graft dysfunction or in whom anastomotic dehiscence develops, the presence of an omental wrap helps to minimize the morbidity caused by these complications. The effect of improved methods of lung preservation and of more specific immunosuppression on the decrease in airway complications is difficult to quantitate, but these factors are probably of some importance in the reduced incidence of this problem. The overall incidence of airway complications in all lung transplant patients is 15 to 20 percent. In approximately half of these patients, the diagnosis is made from endoscopic surveillance alone, and healing occurs without further treatment or secondary complication. In the rest, the airway complication requires more specific management and may lead to secondary complications. Of these patients, 70 percent require anastomotic dilatation or stent placement and 20 percent develop a bronchopleural fistula that requires a chest tube and perhaps reoperation. Death due to extensive airway necrosis or secondary infectious complications occurs in 10 percent of patients who develop symptomatic airway complications. Another complication following lung transplantation is myocardial infarction, which is usually due to pressure overload during the implantation procedure and can be prevented in most patients by prompt initiation of CPB. Postoperative

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management of these patients is similar to the routine management of patients with myocardial ischemia; it consists of the judicious use of nitrate therapy, reductions in preload and afterload, and observation for dysrhythmias. Atrial dysrhythmias are also common, as with other types of cardiothoracic surgery, and are managed in a similar fashion. Transplant patients are also prone to significant gastrointestinal complications, whose manifestations may be obscured by the anti-inflammatory effects of immunosuppressive therapy. Hepatobiliary and pancreatic complications are especially common after intrathoracic transplantation, particularly when CPB has been required. Preventive measures include laparoscopic cholecystectomy for patients with symptomatic biliary disease before transplantation. Postoperatively, continued surveillance of pancreatic exocrine function, bilirubin, and liver function tests is indicated to allow prompt diagnosis and intervention for specific abnormalities. In view of the surgical stress and use of corticosteroids in these patients, all patients should receive H2 -blocking agents and antacid therapy postoperatively to prevent upper gastrointestinal hemorrhage. Infectious Complications Lung transplant patients have several unique attributes that account for a rate of infectious complications that is higher than the rate for other transplant recipients. Before implantation, the donor lung may contain significant pathogens, owing to the changes in lung defense mechanisms that follow intubation and brain death. After the transplant, the lung allograft continues to be exposed both to the external environment and sites in the upper respiratory tract, such as the sinuses, that may contain significant pulmonary pathogens. Finally, the lack of a cough reflex and a disturbed pattern of mucociliary clearance in the donor lung after the transplant predispose to pulmonary infection. An aggressive approach to the evaluation of all new pulmonary infiltrates, in either the lung graft or the native lung, is required in these patients. Flexible bronchoscopy with BAL or protected brushing is needed for proper diagnosis of pulmonary infections after lung transplantation. BAL specimens from both lungs should be routinely sent for Gramâ&#x20AC;&#x2122;s stain, fungal smear, and acid-fast bacilli smear as well as for culture of these organisms. In addition, analysis of BAL for P. carinii, Legionella species, and viral assays is required. Bacterial pneumonia is the most commonly acquired infection after lung transplantation. Pneumonia occurs most frequently within 2 months of transplantation and is usually due to gram-negative bacilli. Diagnosis made with bronchoscopy and treatment with antibiotics administered intravenously lead to prompt resolution in most cases. Depending on the organism, aerosolized antimicrobial therapy, in addition to intravenous therapy, may be helpful. Potential native sources of contamination of the respiratory tract should be evaluated, particularly in patients with cystic fibrosis or recurrent pneumonias. Chronic sinusitis is common in cystic fibrosis patients and acts as a source of contamination of the lower respiratory tract. Careful otolaryngologic evaluation

and sinus drainage are indicated in selected patients. Gastroesophageal reflux is common in both cystic fibrosis patients and patients with COPD and can lead to recurrent aspiration pneumonias in dependent regions of the lungs. In most patients, conservative treatment with elevation of the head of the bed and the administration of promotility agents, in addition to the H2 -blocking agents taken by most transplant recipients, control the reflux. In patients who have undergone SLT, the native lung may occasionally be a site of graft contamination or, more commonly, may become the site of pneumonia or a lung abscess. Standard therapy is recommended for such cases, although a localized area of anatomic abnormality in the native lung (e.g., focal bronchiectasis) may require surgical excision if it proves to be the source of recurrent infection. Viral infections can be a major source of morbidity or mortality for lung transplant patients. Previously, herpes simplex virus infection was an occasional cause of tracheobronchitis or pneumonitis following lung transplantation. The use of prophylactic acyclovir or ganciclovir has eliminated these infections. Respiratory syncytial virus (RSV), which can cause pneumonitis and bronchiolitis in immunosuppressed patients, has been more frequently identified in lung transplant patients during the time of peak community infection (from November to March). Treatment of RSV requires the use of aerosolized ribavirin and RSV hyperimmune globulin. Although successful treatment of the acute disease has been reported, a major issue remains regarding the potential for later development of obliterative bronchiolitis following RSV infection. Cytomegalovirus, a member of the human herpesvirus family, is the second most frequent cause of infection in the lung transplant patient and the most important opportunistic infection that occurs in these patients. Following infection with CMV, the virus remains in a latent state in the body; evidence of the infection can be identified from a positive serologic assay. Approximately 80 percent of adults are seropositive for CMV. Immunosuppression can cause reactivation of the latent virus and shedding of CMV into both the urine and sputum. Viremia may also be detected in more advanced cases of reactivation disease. CMV infection of a lung transplant recipient can occur either from reactivation of latent virus or direct transmission to the patient. Direct transmission, which occurs by the transfusion of blood products obtained from seropositive donors into seronegative recipients, has been essentially eliminated by administration of blood products only from seronegative donors to seronegative recipients. The incidence of CMV infection in the lung transplant recipient is related to the serologic status of both donor and recipient. Recipients who are seronegative for CMV and receive seronegative lungs should never develop CMV infection, provided they are protected from transmission of the virus by transfusion. CMV should never be found in their sputum. Alternatively, recipients who are seropositive for CMV and receive lungs from seropositive donors rarely develop CMV infection because of their preoperative immunity. However, these patients shed CMV in their sputum when the latent virus is reactivated by immunosuppression. When a seropositive

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CMV pneumonitis or primary infection with viremia. Other centers, however, have demonstrated the efficacy of a prophylactic regimen of ganciclovir (5 mg/kg intravenously twice a day, tapered over 6 weeks) in minimizing the incidence of CMV disease, even when donor–recipient CMV mismatching occurs. In these preemptive regimens, ganciclovir is used for all patients who are at risk for CMV disease during the induction of immunosuppression and whenever immunosuppression is augmented to treat acute rejection. This approach has led to an improvement in survival for patients with disparate donor–recipient CMV status. Relapse rates remain high, however, and the best approach to the management of the lung transplant patient with a mismatched donor–recipient CMV status remains to be determined. Figure 101-6 Cytomegalovirus (CMV) pneumonitis. A characteristic cytotrophic change in the pulmonary parenchyma is seen with invasive CMV infection.

recipient receives a lung from a seronegative donor, reactivation of the recipient’s CMV can cause CMV pneumonitis in the lung graft. This is an invasive infection, with evidence of viral-induced cytotrophic changes in the pulmonary parenchyma in addition to the presence of CMV in the sputum (Fig. 101-6). In these cases, CMV pneumonitis is generally well treated with a course of ganciclovir (5 mg/kg intravenously twice a day for 4 weeks). Conversely, when seronegative recipients receive lungs from a seropositive donor, reactivation of the CMV in the donor lung can cause a primary infection of the recipient. Primary CMV infection of an immunosuppressed host, such as the recipient of a lung transplant, is a potentially fatal systemic illness associated with viremia, pneumonitis, hepatitis, encephalitis, retinitis, and enterocolitis. Such patients require both ganciclovir (5 mg/kg intravenously twice a day) and CMV hyperimmune globulin (10 g intravenously every month) for prolonged courses of therapy until the disease is eradicated. Ganciclovir administered prophylactically three times weekly was found to be as effective as daily administration for up to 3 months after lung transplantation in the prevention of CMV infection. Ganciclovir is also effective therapy for CMV in patients with pneumonitis or primary infection, but the occurrence of CMV infection in these patients can lead to significant morbidity. CMV infection seems to elicit acute graft rejection in many instances, requiring a complicated treatment plan to balance the need for augmented immunosuppression against adequate treatment of the infection. Primary CMV infection was associated wth 54 percent mortality, which in turn was associated with a high rate of pulmonary superinfections during the first year after transplantation. In addition, CMV disease in some series appears to be a risk factor for the subsequent development of BOS, the most common cause of late mortality following lung transplantation. Many centers strive to match donor and recipient CMV status to minimize the potential for these problems. When precise donor–recipient matching is performed, the use of ganciclovir is reserved for cases of invasive CMV disease—i.e.,

Neoplastic Complications Immunosuppression increases the risk of development of neoplasms after lung transplantation. The risk applies to a specific group of solid tumors, including squamous cell cancers of the lip and skin, Kaposi’s sarcoma, soft tissue sarcomas, carcinomas of the vulva and perineum, and hepatobiliary tumors. Transplant recipients are not at increased risk for developing the more common cancers encountered in the general population, such as carcinoma of the lung, breast, colon, or prostate, and some of the newer agents, such as mycophenolate mofetil and sirolimus may have antitumor properties, although they have yet to be studied long-term to determine whether they will reduce malignancy-related mortality. The most common malignancy seen after lung transplantation is a type of B-cell lymphoid proliferation known as posttransplant lymphoproliferative disorder (PTLD). PTLD represents a morphologically diverse group of polyclonal lymphoid proliferations. The pathogenesis of PTLD appears to be related to EBV infection of B lymphocytes that are stimulated to proliferate by the recipient’s immunosuppression. Clinically, a distinction can be made between patients presenting with PTLD within 1 year after transplantation and those presenting with PTLD at later times. The early patients tend to have localized disease that responds to a temporary reduction in immunosuppression; their long-term prognosis is excellent. Patients who present after 1 year usually have disseminated disease that does not respond to reduced immunosuppression and requires cytotoxic chemotherapy for treatment. The mortality from lymphoma in these patients is 70 percent. Epstein-Barr virus seronegative patients with high levels of immunosuppression have such a high risk for lymphoproliferative disorder as to preclude transplantation in some cases. Of interest is that the use of ganciclovir for prophylaxis against CMV disease in lung transplant patients may also help to control the incidence of PTLD, since ganciclovir also has significant activity against EBV. Future trials to assess the impact of ganciclovir therapy on the incidence of PTLD are planned. Rituximab and chemotherapy have been shown to be effective in EBV-positive patients with PTLD who fail or do not tolerate reduction in immunosuppression, however, although rituximab is well tolerated, chemotherapy is associated wth marked toxicity.

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RESULTS Survival Mortality following lung transplantation has decreased significantly over the past decade. The cause of this reduction is probably multifactorialâ&#x20AC;&#x201D;i.e., the result of technical improvements in the procedure, of improved recipient selection and preoperative management, and increasing experience in perioperative management of these patients. In most recent series, surgical mortality following lung transplantation has been between 10 and 15 percent. The surgical mortality of DLT ranges from 15 to 20 percent as compared to that of SLT, which is usually 10 percent or less. This difference is attributable, in large part, to the increased likelihood of postoperative infectious complications in patients with septic lung disease who require DLT. Surgical mortality after HLT is usually slightly higher than for patients undergoing DLT, probably owing to the more advanced disease state of patients who require HLT. Most centers have not noted a marked difference in surgical mortality for patients undergoing SLT for different diseases, although preoperative pulmonary hypertension in these patients usually increases the risk of perioperative morbidity. Infection is the major cause of early mortality in lung transplant recipients, accounting for 30 to 45 percent of deaths. The likelihood of pulmonary infection is greatest in the first 100 days after transplantation, before recipient defense mechanisms (e.g., cough) are restored. Risk factors for infection during this period include a positive sputum culture from the donor, a lower PaO2 in the donor lung (under 350 mmHg), a prolonged ischemic time (greater than 6 h), recipient age greater than 40 years, and CMV disease as the result of donorâ&#x20AC;&#x201C;recipient mismatching without ganciclovir prophylaxis. Postoperative graft failure with diffuse alveolar damage may also contribute to early mortality in as many as 15 percent of patients. Improved surgical techniques, preservation solutions, and donor management strategies have reduced the incidence of primary graft dysfunction. Cardiovascular decompensation is the third leading cause of early death. In most cases, this process occurs in the clinical setting of adult respiratory distress syndrome and persistent pulmonary hypertension with secondary cardiac dysfunction. Coronary artery disease or myocardial infarction is uncommon in these patients. Long-term survival data indicate a cumulative survival rate of 70 to 80 percent at 1 year. Survival curves can vary significantly beyond 1 year, depending on the disease for which transplantation was performed. Patients with emphysema and those with pulmonary vascular disease appear to have a survival advantage over patients with restrictive lung disease or septic lung disease, in whom infectious complications or recurrence of native disease in the lung graft is more common. By 3 years, survival ranges from 75 percent in the former group to 55 percent in the latter group. At this interval, BOS begins to have a significant impact on survival as well, leading to an overall survival rate of only 50 percent at 5 years. Causes of death in this period include infection, which

has another peak of increased incidence throughout the second postoperative year, and BOS, which can be identified in half of the patients who survive to 3 years. Malignancy, usually PTLD, is the third most common cause of late mortality following lung transplantation.

Functional Results Most patients surviving lung transplantation experience a highly significant improvement in their functional capability over their preoperative state. Typically, patients can resume an exercise program without oxygen supplementation by 6 weeks after transplantation. However, in some patients who require muscular paralysis for management of postoperative graft failure, a demyelinating process may delay full recovery for 2 to 3 months. Survivors of primary graft dysfunction are frequently left with significant functional deficits. Improvements occur regardless of the native disease that led to transplantation. Unless BOS occurs, functional capacity based on the standards of reproducible exercise testing remains stable for at least 3 years. Controversy exists over the potential benefit of SLT as compared to DLT for younger patients with emphysema. Although the results of spirometry are obviously better in DLT recipients, exercise tolerance is similar initially in the two groups. Whether a significant later advantage exists for DLT recipients that would offset the increased perioperative risk of the procedure remains to be seen. Similarly, functional results following SLT or DLT for pulmonary vascular disease demonstrate little objective difference between the two approaches. However, DLT may provide a slight advantage in patients in whom preoperative pulmonary artery pressures approach systemic levels, because such an approach provides the maximum reduction of pulmonary vascular resistance. In addition, because the allograft receives up to 95 percent of the blood flow in these patients after SLT, the development of BOS, even at grade 1, has profound functional implications. The development of BOS in patients who have undergone DLT for pulmonary vascular disease causes less immediate hemodynamic compromise because the partition of blood flow between the two lungs is similar.

Retransplantation Pulmonary retransplantation has been undertaken with increasing frequency in recent years. Retransplantation is used either as a method to correct an acute complication, such as graft failure or diffuse airway necrosis, or as a treatment for a chronic process in the graft, such as BOS or airway stenosis. At the present time, BOS appears to be the most common indication. A variety of approaches have been used, including redo ipsilateral SLT, contralateral SLT, and DLT following either SLT or DLT. These are technically challenging procedures, with a surgical mortality of nearly 50 percent. Factors contributing to a more favorable outcome include an ambulatory status before retransplantation, the use of ABO-identical grafts, and prior institutional experience with

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retransplantation; notably, retransplantation with a CMVseronegative donor has also been associated with a favorable outcome. The long-term results of retransplantation are much worse than those of initial lung transplantation. Oneyear survival is about 45 percent, and 2-year survival is about 35 percent. BOS occurs with a frequency similar to that seen with primary lung transplantation and can be identified in one-third of patients 2 years after retransplantation.

SUMMARY Significant progress has been made in the development of techniques of lung transplantation for all types of end-stage pulmonary diseases. Isolated lung transplantation has been applied with increasing success to the entire group of patients, including those with pulmonary vascular disease. A shortage of donor organs, however, remains the most significant obstacle to wider use of this method of treatment. Techniques of donor lung preservation and implantation allow ischemic intervals of 6 to 8 h for reasonable postoperative function. Surgical mortality is 10 to 15 percent, slightly lower for SLT and slightly higher for DLT and HLT. Functional results in survivors of the operation are excellent. Infection remains a significant source of morbidity and mortality in both the early and late postoperative periods. However, the most significant impediment to long-term survival is the development of chronic rejection in the lung allograft, manifested as BOS, in half of the patients by 5 years after transplantation. Further measures to prevent or treat this malady are critical to improving long-term survival rates following lung transplantation.

SUGGESTED READING Aboyoun CL, Tamm M, et al.: Diagnostic value of followup transbronchial lung biopsy after lung rejection. Am J Respir Crit Care Med 164:460–463, 2001. Alexander BD, Tapson VF: Infectious complications of lung transplantation. Transpl Infect Dis 3:128–137, 2001. Angel LF, Levine DJ, et al.: Impact of a lung transplantation donor-management protocol on lung donation and recipient outcomes. Am J Respir Crit Care Med 174:710–716, 2006. Arcasoy SM, Fisher F, et al.: Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part V: Predictors and outcomes. J Heart Lung Transplant 24:1483–1488, 2005. Arcasoy SM, Hersh C, et al.: Bronchogenic carcinoma complicating lung transplantation. J Heart Lung Transplant 20:1044–1053, 2001. Arcasoy SM, Kotloff RM: Lung transplantation. N Engl J Med 340:1081–1091, 1999.

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Aris RM, Maia DM, et al.: Post-transplantation lymphoproliferative disorder in the Epstein-Barr virus-naive lung transplant recipient. Am J Respir Crit Care Med 154:1712–1717, 1996. Avlonitis VS, Wigfield CH, et al.: Early hemodynamic injury during donor brain death determines the severity of primary graft dysfunction after lung transplantation. Am J Transplant 7:83–90, 2007. Bando K, Paradis IL, et al.: Analysis of time-dependent risks for infection, rejection, and death after pulmonary transplantation. J Thorac Cardiovasc Surg 109:49–57; discussion 57–59, 1995. Bando K, Paradis IL, et al.: Comparison of outcomes after single and bilateral lung transplantation for obstructive lung disease. J Heart Lung Transplant 14:692–698, 1995. Barr ML, Baker CJ, et al.: Living donor lung transplantation: Selection, technique, and outcome. Transplant Proc 33:3527–3532, 2001. Barr ML, Schenkel FA, et al.: Living donor lobar lung transplantation: Current status and future directions. Transplant Proc 37:3983–3986, 2005. Baz MA, Layish DT, et al.: Diagnostic yield of bronchoscopies after isolated lung transplantation. Chest 110:84–88, 1998. Bergin CJ, Castellino RA, et al.: Acute lung rejection after heart-lung transplantation: Correlation of findings on chest radiographs with lung biopsy results. AJR Am J Roentgenol 155:23–27, 1990. Berry GJ, Brunt EM, et al.: A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 9:593–601, 1990. Bhorade SM, Vigneswaran W, et al.: Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation. J Heart Lung Transplant 19:1199–1204, 2000. Bloom RD, Doyle AM. Kidney disease after heart and lung transplantation. Am J Transplant 6:671–679, 2006. Boehler A, Estenne M. Post-transplant bronchiolitis obliterans. Eur Respir J 22:1007–1018, 2003. Bonde PN, Patel ND, et al.: Impact of donor lung organisms on post-lung transplant pneumonia. J Heart Lung Transplant 25:99–105, 2006. Borel JF, Feurer C, et al.: Biological effects of cyclosporin A: A new antilymphocytic agent. Agents Actions 6:468–475, 1976. Brock MV, Borja MC, et al.: Induction therapy in lung transplantation: A prospective, controlled clinical trial comparing OKT3, anti-thymocyte globulin, and daclizumab. J Heart Lung Transplant 20:1282–1290, 2001. Brugiere O, Thabut G, et al.: Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome. Eur Respir J 25:813–819, 2005. Buell JF, Gross TG, et al.: Malignancy after transplantation. Transplantation 80:S254–264, 2005. Cahalin L, Pappagianopoulos P, et al.: The relationship of the 6-min walk test to maximal oxygen consumption in

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transplant candidates with end-stage lung disease. Chest 108:452–459, 1995. Cahill BC, Somerville KT, et al.: Early experience with sirolimus in lung transplant recipients with chronic allograft rejection. J Heart Lung Transplant 22:169–176, 2003. Cantu E, Parker W, et al.: Pulmonary xenotransplantation: Rapidly progressing into the unknown. Am J Transplant 4:25–35, 2004. Celli BR, Cote CG, et al.: The body-mass index, airflow obstruction, dyspnea, and exercise capacity in chronic obstructive pulmonary disease. N Engl J Med 350:1005–1012, 2004. Chakinala MM, Ritter J, et al.: Reliability for grading acute rejection and airway inflammation after lung transplantation. J Heart Lung Transplant 24:652–657, 2005. Chakinala MM, Trulock EP: Acute allograft rejection after lung transplantation: Diagnosis and therapy. Chest Surg Clin North Am 13:525–542, 2003. Chakinala MM, Walter MJ: Community acquired respiratory viral infections after lung transplantation: Clinical features and long-term consequences. Semin Thorac Cardiovasc Surg 16:342–349, 2004. Chalermskulrat W, Neuringer IP, et al.: Human leukocyte antigen mismatches predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest 123:1825–1831, 2003. Chamberlain D, Maurer J, et al.: Evaluation of transbronchial lung biopsy specimens in the diagnosis of bronchiolitis obliterans after lung transplantation. J Heart Lung Transplant 13:963–971, 1994. Chan KM, Allen SA: Infectious pulmonary complications in lung transplant recipients. Semin Respir Infect 17:291–302, 2002. Chhajed PN, Malouf MA, et al.: Interventional bronchoscopy for the management of airway complications following lung transplantation. Chest 120:1894–1899, 2001. Chhajed PN, Tamm M, et al.: Role of flexible bronchoscopy in lung transplantation. Semin Respir Crit Care Med 25:413– 423, 2004. Christie JD, Carby M, et al.: Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: Definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 24:1454–1459, 2005. Christie JD, Kotloff RM, et al.: Clinical risk factors for primary graft failure following lung transplantation. Chest 124:1232–1241, 2003. Christie JD, Kotloff RM, et al.: The effect of primary graft dysfunction on survival after lung transplantation. Am J Respir Crit Care Med 171:1312–1316, 2005. Cooper JD, Billingham M, et al.: A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 12:713–716, 1993. Cooper JD, Patterson GA, et al.: Results of single and bilateral lung transplantation in 131 consecutive recipients.

Washington University Lung Transplant Group. J Thorac Cardiovasc Surg 107:460–470; discussion 470–471, 1994. Corcoran TE, Smaldone GC, et al.: Preservation of posttransplant lung function with aerosol cyclosporin. Eur Respir J 23:378–383, 2004. D’Armini AM, Roberts CS, et al.: When does the lung die? I. Histochemical evidence of pulmonary viability after death. J Heart Lung Transplant 13:741–747, 1994. Date H, Lynch JP, et al.: The impact of cytolytic therapy on bronchiolitis obliterans syndrome. J Heart Lung Transplant 17:869–875, 1998. Daud SA, Yusen RD, et al.: The impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 175:507–513, 2006. Davis RD Jr, Lau CL, et al.: Improved lung allograft function after fundoplication in patients with gastroesophageal reflux disease undergoing lung transplantation. J Thorac Cardiovasc Surg 125:533–542, 2003. de Bruyn G, Whelan TP, et al.: Invasive pneumococcal infections in adult lung transplant recipients. Am J Transplant 4:1366–1371, 2004. de Perrot M, Liu M, et al.: Ischemia-reperfusion–induced lung injury. Am J Respir Crit Care Med 167:490–511, 2003. Derom F, Barbier F, et al.: Ten-month survival after lung homotransplantation in man. J Thorac Cardiovasc Surg 61:835–846, 1971. Dockrell DH, Strickler JG, et al.: Epstein-Barr virus-induced T cell lymphoma in solid organ transplant recipients. Clin Infect Dis 26:180–182, 1998. Doyle AM, Warburton KM, et al.: 24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12week course. Transplantation 81:1106–1111, 2006. Drew RH, Dodds Ashley E, et al.: Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lungtransplant recipients. Transplantation 77:232–237, 2004. Dummer JS, Lazariashvilli N, et al.: A survey of anti-fungal management in lung transplantation. J Heart Lung Transplant 23:1376–1381, 2004. Duncan AJ, Dummer JS, et al.: Cytomegalovirus infection and survival in lung transplant recipients. J Heart Lung Transplant 10:638–644; discussion 645–646, 1991. Duncan SR, Paradis IL, et al.: Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients. Am Rev Respir Dis 146:1419–1425, 1992. Egan TM: Non-heart-beating donors in thoracic transplantation. J Heart Lung Transplant 23:3–10, 2004. Egan TM, Murray S, et al.: Development of the new lung allocation system in the United States. Am J Transplant 6:1212–1227, 2006. Elstrom RL, Andreadis C, et al.: Treatment of PTLD with rituximab or chemotherapy. Am J Transplant 6:569–576, 2006. End A, Helbich T, et al.: The pulmonary nodule after lung transplantation. Cause and outcome. Chest 107:1317– 1322, 1995.

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Estenne M, Maurer JR, et al.: Bronchiolitis obliterans syndrome 2001: An update of the diagnostic criteria. J Heart Lung Transplant 21:297–310, 2002. Ettinger NA, Bailey TC, et al.: Cytomegalovirus infection and pneumonitis. Impact after isolated lung transplantation. Washington University Lung Transplant Group. Am Rev Respir Dis 147:1017–1023, 1993. Ferrer J, Roldan J, et al.: Acute and chronic pleural complications in lung transplantation. J Heart Lung Transplant 22:1217–1225, 2003. Fischer S, Matte-Martyn A, et al.: Low-potassium dextran preservation solution improves lung function after human lung transplantation. J Thorac Cardiovasc Surg 121:594– 596, 2001. Fisher AJ, Donnelly SC, et al.: Enhanced pulmonary inflammation in organ donors following fatal non-traumatic brain injury. Lancet 353:1412–1413, 1999. Fisher AJ, Donnelly SC, et al.: Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation. Am J Respir Crit Care Med 163:259– 265, 2001. Fisher AJ, Donnelly SC, et al.: Objective assessment of criteria for selection of donor lungs suitable for transplantation. Thorax 59:434–437, 2004. Fremes SE, Patterson GA, et al.: Single lung transplantation and closure of patent ductus arteriosus for Eisenmenger’s syndrome. Toronto Lung Transplant Group. J Thorac Cardiovasc Surg 100:1–5, 1990. Gabbay E, Walters EH, et al.: Post-lung transplant bronchiolitis obliterans syndrome (BOS) is characterized by increased exhaled nitric oxide levels and epithelial inducible nitric oxide synthase. Am J Respir Crit Care Med 162:2182– 2187, 2000. Gamez P, Cordoba M, et al.: Lung transplantation from outof-hospital non–heart-beating lung donors. One-year experience and results. J Heart Lung Transplant 24:1098– 1102, 2005. Garfein ES, Ginsberg ME, et al.: Superiority of end-to-end versus telescoped bronchial anastomosis in single lung transplantation for pulmonary emphysema. J Thorac Cardiovasc Surg 121:149–154, 2001. Garrity ER Jr, Hertz MI, et al.: Suggested guidelines for the use of tacrolimus in lung-transplant recipients. J Heart Lung Transplant 18:175–176, 1999. Garrity ER Jr, Villanueva J, et al.: Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin 2 receptor antibody. Transplantation 71:773–777, 2001. Gerbase MW, de Perrot M, et al.: Selective monoclonal versus polyclonal antibodies for induction of immunosuppression in lung recipients. Clin Pharmacol Ther 72:103, 2002. Gerhardt SG, McDyer JF, et al.: Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 168:121–125, 2003. Gerna G, Lilleri D, et al.: Monitoring of human cytomegalovirus-specific CD4 and CD8 T-cell immunity in patients receiving solid organ transplantation. Am J Transplant 6:2356–2364, 2006.

Lung Transplantation

Gerna G, Vitulo P, et al.: Impact of human metapneumovirus and human cytomegalovirus versus other respiratory viruses on the lower respiratory tract infections of lung transplant recipients. J Med Virol 78:408–416, 2006. Girnita AL, McCurry KR, et al.: HLA-specific antibodies are associated with high-grade and persistent-recurrent lung allograft acute rejection. J Heart Lung Transplant 23:1135– 1141, 2004. Glanville AR, Aboyoun CL, et al.: Cyclosporine C2 target levels and acute cellular rejection after lung transplantation. J Heart Lung Transplant 25:928–934, 2006. Glanville AR, Estenne M: Indications, patient selection and timing of referral for lung transplantation. Eur Respir J 22:845–852, 2003. Gordon SM, Avery RK: Aspergillosis in lung transplantation: Incidence, risk factors, and prophylactic strategies. Transplant Infect Dis 3:161–167, 2001. Green TP, Timmons OD, et al.: The impact of extracorporeal membrane oxygenation on survival in pediatric patients with acute respiratory failure. Pediatric Critical Care Study Group. Crit Care Med 24:323–329, 1996. Groetzner J, Kur F, et al.: Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 23:632–638, 2004. Groetzner J, Wittwer T, et al.: Conversion to sirolimus and mycophenolate can attenuate the progression of bronchiolitis obliterans syndrome and improves renal function after lung transplantation. Transplantation 81:355–360, 2006. Hachem RR, Chakinala MM, et al.: The predictive value of bronchiolitis obliterans syndrome stage 0-p. Am J Respir Crit Care Med 169:468–472, 2004. Hachem RR, Chakinala MM, et al.: A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation. J Heart Lung Transplant 24:1320– 1326, 2005. Hachem RR, Khalifah AP, et al.: The significance of a single episode of minimal acute rejection after lung transplantation. Transplantation 80:1406–1413, 2005. Hachem RR, Yusen RD, et al.: Thrombotic microangiopathy after lung transplantation. Transplantation 81:57–63, 2006. Hadjiliadis D, Duane Davis R, et al.: Gastroesophageal reflux disease in lung transplant recipients. Clin Transplant 17:363–368, 2003. Hadjiliadis D, Howell DN, et al.: Anastomotic infections in lung transplant recipients. Ann Transplant 5:13–19, 2000. Hamawy MM. Molecular actions of calcineurin inhibitors. Drug News Perspect 16:277–282, 2003. Hardin CA, Kittle CF: Experiences with transplantation of the lung. Science 119:97–98, 1954. Hardy JD, Webb WR, et al.: Lung homotransplantation in man. JAMA 186:1065–1074, 1963. Hauke R, Smir B, et al.: Clinical and pathological features of posttransplant lymphoproliferative disorders: Influence on survival and response to treatment. Ann Oncol 12:831– 834, 2001.

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Hertz MI, Jordan C, et al.: Randomized trial of daily versus three-times-weekly prophylactic ganciclovir after lung and heart-lung transplantation. J Heart Lung Transplant 17:913–920, 1998. Higenbottam T, Stewart S, et al.: Transbronchial lung biopsy for the diagnosis of rejection in heart-lung transplant patients. Transplantation 46:532–539, 1988. Hodges TN, Torres FP, et al.: Community acquired respiratory viruses in lung transplant patients: Incidence and outcomes. J Heart Lung Transplant 20:169–170, 2001. Huddleston CB, Bloch JB, et al.: Lung transplantation in children. Ann Surg 236:270–276, 2002. Humar A, Kumar D, et al.: A trial of valganciclovir prophylaxis for cytomegalovirus prevention in lung transplant recipients. Am J Transplant 5:1462–148, 2005. Husain S, Chan KM, et al.: Bacteremia in lung transplant recipients in the current era. Am J Transplant 6:3000–3007, 2006. Husain S, Paterson DL, et al.: Voriconazole prophylaxis in lung transplant recipients. Am J Transplant 6:3008–3016, 2006. Iacono AT, Corcoran TE, et al.: Aerosol cyclosporin therapy in lung transplant recipients with bronchiolitis obliterans. Eur Respir J 23:384–390, 2004. Kahan BD, Rajagopalan PR, et al.: Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group. Transplantation 67:276–284, 1999. Kaiser L, Aubert JD, et al.: Chronic rhinoviral infection in lung transplant recipients. Am J Respir Crit Care Med 174:1392– 1399, 2006. Keenan RJ, Konishi H, et al.: Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 60:580–584; discussion 584–585, 1995. Keshavjee S, Davis RD, et al.: A randomized, placebocontrolled trial of complement inhibition in ischemiareperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg 129:423–438, 2005. Kesten S, Chamberlain D, et al.: Yield of surveillance transbronchial biopsies performed beyond two years after lung transplantation. J Heart Lung Transplant 15:384–388, 1996. Kesten S, Rajagopalan N, et al.: Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation. Transplantation 61:427–430, 1996. Khalifah AP, Hachem RR, et al.: Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death. Am J Respir Crit Care Med 170:181–187, 2004. Khalifah AP, Hachem RR, et al.: Minimal acute rejection after lung transplantation: A risk for bronchiolitis obliterans syndrome. Am J Transplant 5:2022–2030, 2005. King RC, Binns OA, et al.: Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation. Ann Thorac Surg 69:1681–1685, 2000.

Knoop C, Haverich A, et al.: Immunosuppressive therapy after human lung transplantation. Eur Respir J 23:159–171, 2004. Kotloff RM, Ahya VN: Medical complications of lung transplantation. Eur Respir J 23:334–342, 2004. Kovarik JM, Snell GI, et al.: Everolimus in pulmonary transplantation: Pharmacokinetics and exposure-response relationships. J Heart Lung Transplant 25:440–446, 2006. Krenn K, Klepetko W, et al.: Recipient vascular endothelial growth factor serum levels predict primary lung graft dysfunction. Am J Transplant 7:700–706, 2007. Kshettry VR, Kroshus TJ, et al.: Early and late airway complications after lung transplantation: Incidence and management. Ann Thorac Surg 63:1576–1583, 1997. Kumar D, Erdman D, et al.: Clinical impact of communityacquired respiratory viruses on bronchiolitis obliterans after lung transplant. Am J Transplant 5:2031–2036, 2005. Langone AJ, Helderman JH: Disparity between solid-organ supply and demand. N Engl J Med 349:704–706, 2003. Lau CL, Palmer SM, et al.: Influence of panel-reactive antibodies on posttransplant outcomes in lung transplant recipients. Ann Thorac Surg 69:1520–1524, 2000. Ljungman P, Griffiths P, et al.: Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 34:1094–1097, 2002. Malouf MA, Glanville AR: The spectrum of mycobacterial infection after lung transplantation. Am J Respir Crit Care Med 160:1611–1616, 1999. Martinez JA, Paradis IL, et al.: Spirometry values in stable lung transplant recipients. Am J Respir Crit Care Med 155:285– 290, 1997. Mattner F, Fischer S, et al.: Post-operative nosocomial infections after lung and heart transplantation. J Heart Lung Transplant 26:241–249, 2007. Maziak DE, Maurer JR, et al.: Diaphragmatic paralysis: a complication of lung transplantation. Ann Thorac Surg 61:170– 173, 1996. Meade MO, Granton JT, et al.: A randomized trial of inhaled nitric oxide to prevent ischemia-reperfusion injury after lung transplantation. Am J Respir Crit Care Med 167:1483– 1489, 2003. Mehrad B, Paciocco G, et al.: Spectrum of Aspergillus infection in lung transplant recipients: Case series and review of the literature. Chest 119:169–175, 2001. Meier-Kriesche HU, Li S, et al.: Immunosuppression: Evolution in practice and trends, 1994–2004. Am J Transplant 6:1111–1131, 2006. Mughal MM, Gildea TR, et al.: Short-term deployment of selfexpanding metallic stents facilitates healing of bronchial dehiscence. Am J Respir Crit Care Med 172:768–771, 2005. Nathan SD, Barnett SD, et al.: Bronchiolitis obliterans syndrome: utility of the new guidelines in single lung transplant recipients. J Heart Lung Transplant 22:427–432, 2003. Novick RJ: Innovative techniques to enhance lung preservation. J Thorac Cardiovasc Surg 123:3–5, 2002. Novick RJ, Stitt L: Pulmonary retransplantation. Semin Thorac Cardiovasc Surg 10:227–236, 1998.

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Orens JB, Boehler A, et al.: A review of lung transplant donor acceptability criteria. J Heart Lung Transplant 22:1183– 1200, 2003. Orens JB, Estenne M, et al.: International guidelines for the selection of lung transplant candidates: 2006 update: A consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 25:745–755, 2006. Orens JB, Shearon TH, et al.: Thoracic organ transplantation in the United States, 1995–2004. Am J Transplant 6:1188– 1197, 2006. Oto T, Rosenfeldt F, et al.: Extracorporeal membrane oxygenation after lung transplantation: Evolving technique improves outcomes. Ann Thorac Surg 78:1230–1235, 2004. Otulana BA, Higenbottam T, et al.: Lung function associated with histologically diagnosed acute lung rejection and pulmonary infection in heart-lung transplant patients. Am Rev Respir Dis 142:329–332, 1990. Palmer SM, Baz MA, et al.: Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection. Transplantation 71:1772–1776, 2001. Palmer SM, Burch LH, et al.: Innate immunity influences long-term outcomes after human lung transplant. Am J Respir Crit Care Med 171:780–785, 2005. Palmer SM, Miralles AP, et al.: Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: Results of a randomized, prospective study. Chest 116:127– 133, 1999. Palmer SM, Miralles AP, et al.: Gastroesophageal reflux as a reversible cause of allograft dysfunction after lung transplantation. Chest 118:1214–1217, 2000. Pasque MK, Cooper JD, et al.: Improved technique for bilateral lung transplantation: Rationale and initial clinical experience. Ann Thorac Surg 49:785–791, 1990. Patterson GA, Cooper JD, et al.: Technique of successful clinical double-lung transplantation. Ann Thorac Surg 45:626– 633, 1988. Patterson GM, Wilson S, et al.: Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation: a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second. J Heart Lung Transplant 15:175–181, 1996. Perreas KG, McNeil K, et al.: Extended ganciclovir prophylaxis in lung transplantation. J Heart Lung Transplant 24:583– 587, 2005. Pierre AF, Keshavjee S: Lung transplantation: donor and recipient critical care aspects. Curr Opin Crit Care 11:339– 344, 2005. Pochettino A, Kotloff RM, et al.: Bilateral versus single lung transplantation for chronic obstructive pulmonary disease: Intermediate-term results. Ann Thorac Surg 70:1813– 1818; discussion 1818–1819, 2000. Pratschke J, Wilhelm MJ, et al.: Brain death and its influence on donor organ quality and outcome after transplantation. Transplantation 67:343–348, 1999.

Lung Transplantation

Prekker ME, Nath DS, et al.: Validation of the proposed International Society for Heart and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J Heart Lung Transplant 25:371–378, 2006. Reinsma GD, ten Hacken NH, et al.: Limiting factors of exercise performance 1 year after lung transplantation. J Heart Lung Transplant 25:1310–1316, 2006. Reynaud-Gaubert M, Thomas P, et al.: Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Functional and bronchoalveolar lavage cell findings. Am J Respir Crit Care Med 161:1924–1929, 2000. Rocha PN, Rocha AT, et al.: Acute renal failure after lung transplantation: incidence, predictors and impact on perioperative morbidity and mortality. Am J Transplant 5:1469– 1476, 2005. Sager JS, Kotloff RM, et al.: Association of clinical risk factors with functional status following lung transplantation. Am J Transplant 6:2191–2201, 2006. Sakamaki F, Hoffmann H, et al.: Reduced lipid peroxidation and ischemia-reperfusion injury after lung transplantation using low-potassium dextran solution for lung preservation. Am J Respir Crit Care Med 156:1073–1081, 1997. Schroder C, Scholl F, et al.: A modified bronchial anastomosis technique for lung transplantation. Ann Thorac Surg 75:1697–1704, 2003. Schulman LL, Weinberg AD, et al.: Mismatches at the HLADR and HLA-B loci are risk factors for acute rejection after lung transplantation. Am J Respir Crit Care Med 157:1833– 1837, 1998. Schulman LL, Weinberg AD, et al.: Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation. Am J Respir Crit Care Med 163:437–442, 2001. Sekine Y, Waddell TK, et al.: Risk quantification of early outcome after lung transplantation: Donor, recipient, operative, and post-transplant parameters. J Heart Lung Transplant 23:96–104, 2004. Singh N, Limaye AP, et al.: Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: A prospective, multicenter, observational study. Transplantation 81:320–326, 2006. Smith JD, Danskine AJ, et al.: The effect of panel reactive antibodies and the donor specific crossmatch on graft survival after heart and heart-lung transplantation. Transplant Immunol 1:60–65, 1993. Snell GI, Boehler A, et al.: Eleven years on: A clinical update of key areqas of the 1996 lung allograft rejection working formulation. J Heart Lung Transplant 26:423–430, 2007. Snell GI, Valentine VG, et al.: Everolimus versus azathioprine in maintenance lung transplant recipients: An international, randomized, double-blind clinical trial. Am J Transplant 6:169–177, 2006. Speich R, Thurnheer R, et al.: Efficacy and cost effectiveness of oral ganciclovir in the prevention of cytomegalovirus

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disease after lung transplantation. Transplantation 67:315– 320, 1999. Steen S, Sjoberg T, et al.: Transplantation of lungs from a non–heart-beating donor. Lancet 357:825–829, 2001. Studer SM, Orens JB: Cadaveric donor selection and management. Semin Respir Crit Care Med 27:492–500, 2006. Sundaresan S, Semenkovich J, et al.: Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs. J Thorac Cardiovasc Surg 109:1075– 1079; discussion 1079–1080, 1995. Sundaresan S, Trachiotis GD, et al.: Donor lung procurement: Assessment and operative technique. Ann Thorac Surg 56:1409–1413, 1993. Thabut G, Mal H, et al.: Graft ischemic time and outcome of lung transplantation: A multicenter analysis. Am J Respir Crit Care Med 171:786–791, 2005. Thabut G, Vinatier I, et al.: Influence of preservation solution on early graft failure in clinical lung transplantation. Am J Respir Crit Care Med 164:1204–1208, 2001. Theise ND, Haber MM, et al.: Detection of cytomegalovirus in lung allografts. Comparison of histologic and immunohistochemical findings. Am J Clin Pathol 96:762–766, 1991. Thomson AW, Fairchild RL: The last 5 years of basic science investigation in transplant immunology. Am J Transplant 6:1768–1773, 2006. Todd TR, Goldberg M, et al.: Separate extraction of cardiac and pulmonary grafts from a single organ donor. Ann Thorac Surg 46:356–359, 1988. Toronto Lung Transplant Group: Unilateral lung transplantation for pulmonary fibrosis. N Engl J Med 314:1140–1145, 1986. Treede H, Klepetko W, et al.: Tacrolimus versus cyclosporine after lung transplantation: A prospective, open, randomized two-center trial comparing two different immunosuppressive protocols. J Heart Lung Transplant 20:511–517, 2001. Trulock EP, Edwards LB, et al.: Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult lung and heart-lung transplantation report— 2006. J Heart Lung Transplant 25:880–892, 2006. Trulock EP, Ettinger NA, et al.: The role of transbronchial lung biopsy in the treatment of lung transplant recipients. An analysis of 200 consecutive procedures. Chest 102:1049– 1054, 1992. Valentine VG, Robbins RC, et al.: Total lymphoid irradiation for refractory acute rejection in heart-lung and lung allografts. Chest 109:1184–1189, 1996. Van Muylem A, Melot C, et al.: Role of pulmonary function in the detection of allograft dysfunction after heart-lung transplantation. Thorax 52:643–647, 1997.

Vilchez R, McCurry K, et al.: Influenza and parainfluenza respiratory viral infection requiring admission in adult lung transplant recipients. Transplantation 73:1075–1078, 2002. Villanueva J, Bhorade SM, et al.: Extracorporeal photopheresis for the treatment of lung allograft rejection. Ann Transplant 5:44–47, 2000. Vincenti F. What’s in the pipeline? New immunosuppressive drugs in transplantation. Am J Transplant 2:898–903, 2002. Walker RC, Paya CV, et al.: Pretransplantation seronegative Epstein-Barr virus status is the primary risk factor for posttransplantation lymphoproliferative disorder in adult heart, lung, and other solid organ transplantations. J Heart Lung Transplant 14:214–221, 1995. Ware LB, Wang Y, et al.: Assessment of lungs rejected for transplantation and implications for donor selection. Lancet 360:619–620, 2002. Weill D, Lock BJ, et al.: Combination prophylaxis with ganciclovir and cytomegalovirus (CMV) immune globulin after lung transplantation: Effective CMV prevention following daclizumab induction. Am J Transplant 3:492–496, 2003. Whitford HM, Orsida B, et al.: Features of bronchoalveolar lavage (BAL) in lung transplant recipients (LTR) who later develop bronchiolitis obliterans syndrome (BOS). J Heart Lung Transplant 20:176, 2001. Wilkes DS, Egan TM, et al.: Lung transplantation: opportunities for research and clinical advancement. Am J Respir Crit Care Med 172:944–955, 2005. Wood KE, Becker BN, et al.: Care of the potential organ donor. N Engl J Med 351:2730–2739, 2004. Yates B, Murphy DM, et al.: Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 172:772–775, 2005. Young LR, Hadjiliadis D, et al.: Lung transplantation exacerbates gastroesophageal reflux disease. Chest 124:1689– 1693, 2003. Yousem SA, Berry GJ, et al.: Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group. J Heart Lung Transplant 15:1–15, 1996. Zamora MR, Nicolls MR, et al.: Following universal prophylaxis with intravenous ganciclovir and cytomegalovirus immune globulin, valganciclovir is safe and effective for prevention of CMV infection following lung transplantation. Am J Transplant 4:1635–1642, 2004. Zheng L, Walters EH, et al.: Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation. Thorax 55:53–59, 2000.