Fishman's Pulmonary Diseases and Disorders - PART 17

PART

XVII Acute Respiratory Failure

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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SECTION TWENTY-TWO

Lung Failure

143 CHAPTER

Respiratory Failure: An Overview Michael A. Grippi

I. CLASSIFICATION OF RESPIRATORY FAILURE II. PATHOPHYSIOLOGY Hypoxemic Respiratory Failure Hypercapnic Respiratory Failure Ventilatory Supply vs. Demand III. CATEGORIES OF RESPIRATORY FAILURE Abnormalities of the Central Nervous System Abnormalities of the Peripheral Nervous System or Chest Wall Abnormalities of the Airways Abnormalities of the Alveoli IV. APPROACH TO THE PATIENT V. PRINCIPLES OF MANAGEMENT Triage Decisions Airway Management

Respiratory failure is a condition in which the respiratory system fails in one or both of its gas-exchanging functions— i.e., oxygenation of, and carbon dioxide elimination from, mixed venous (pulmonary arterial) blood. Hence, respiratory failure is a syndrome rather than a disease. Many diseases result in respiratory failure, as discussed elsewhere in this text.

Correction of Hypoxemia and Hypercapnia Search for an Underlying Cause VI. MONITORING PATIENTS WITH ACUTE RESPIRATORY FAILURE VII. COMPLICATIONS OF ACUTE RESPIRATORY FAILURE Pulmonary Cardiovascular Gastrointestinal Infectious Renal Nutritional VIII. PROGNOSIS Morbidity and Mortality in Acute Hypoxemic Respiratory Failure Morbidity and Mortality in Acute Hypercapnic Respiratory Failure

Respiratory failure may be acute or chronic. The clinical presentations of patients with acute and chronic respiratory failure usually are quite different. While acute respiratory failure is characterized by life-threatening derangements in arterial blood gases and acid-base status, the manifestations of chronic respiratory failure are more indolent and may be clinically inapparent.

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Acute Respiratory Failure

Although the causes of respiratory failure are diverse, common underlying pathophysiological mechanisms and management strategies merit a general discussion. This chapter begins with a focus on the definition of respiratory failure and underscores distinctions between acute and chronic varieties. Hypoxemic and hypercapnic respiratory failure are described, and the pathophysiological underpinnings of each type are reviewed. The concepts of ventilatory supply and demand are considered before an overview of the many categories of disease that result in respiratory failure. Finally, an approach to clinical evaluation and management is outlined, followed by a summary of complications and comments on prognosis.

CLASSIFICATION OF RESPIRATORY FAILURE As noted previously, respiratory failure is characterized by inadequate blood oxygenation or carbon dioxide removal.

“Adequacy” is defined by tissue requirements for oxygen uptake and carbon dioxide elimination. In the absence of bedside techniques for direct measurement of these metabolic parameters, clinicians must rely on arterial blood gas values.

Respiratory failure may be classified as hypercapnic or hypoxemic (Fig. 143-1). Hypercapnic respiratory failure is defined as an arterial Pco2 (Paco2 ) greater than 45 mmHg. Hypoxemic respiratory failure is defined as an arterial Po2 (Pao2 ) less than 55 mmHg when the fraction of oxygen in inspired air (Fio2 ) is 0.60 or greater. In many cases, hypercapnic and hypoxemic respiratory failure coexist. Disorders that initially cause hypoxemia may be complicated by respiratory pump failure (see below) and hypercapnia. Conversely, diseases that produce respiratory pump failure are frequently complicated by hypoxemia due to secondary pulmonary parenchymal

Table 143-1 Distinctions between Acute and Chronic Respiratory Failure Category

Characteristic

Hypercapnic respiratory failure Acute Chronic

PaCO2 >45 mmHg

Hypoxemic respiratory failure Acute Chronic

PaO2 <55 mmHg when FIO2 ≥0.60 Develops in min to h Develops over several days or longer

Develops in min to h Develops over several days or longer

processes (e.g., pneumonia or atelectasis) or vascular disorders (e.g., pulmonary embolism).

Distinctions between acute and chronic respiratory failure are summarized in Table 143-1. In general, acute hypercapnic respiratory failure is defined as a Paco2 greater than 45 mmHg with accompanying acidemia (pH less than 7.30).

The physiological effect of a sudden increment in Paco2 depends on the prevailing level of serum bicarbonate anion. In patients with chronic hypercapnic respiratory failure—e.g., due to chronic obstructive pulmonary disease (COPD)—a long-standing increase in Paco2 results in renal “compensation” and an increased serum bicarbonate concentration.

A superimposed acute increase in Paco2 has a less dramatic effect than does a comparable increase in a patient with a normal bicarbonate level.

Figure 143-1 Classification of respiratory failure. Although depicted as distinct entities, hypercapnic and hypoxemic respiratory failure frequently coexist. Either may be acute or chronic.

2511 Chapter 143

Distinction between acute and chronic hypoxemic respiratory failure may not be readily made on the basis of arterial blood gas values. The presence of markers of chronic hypoxemia (e.g., polycythemia or cor pulmonale) provides clues to a long-standing disorder, whereas abrupt changes in mental status suggest an acute event.

It is important to bear in mind that even though the definition of hypoxemic respiratory failure rests on measurement of Pao2 , the major threat of arterial hypoxemia is inadequate tissue oxygenation, reflected in tissue oxygen delivery.

Tissue oxygen delivery is determined by the product of cardiac output and blood oxygen content (see Chapter 13); the latter, in turn, depends on hemoglobin concentration and oxygen saturation. Therefore, factors that lower cardiac output or hemoglobin concentration, or inhibit dissociation of oxygen from hemoglobin at the tissue level, may promote tissue hypoxia without technically producing respiratory failure.

PATHOPHYSIOLOGY Respiratory failure can arise from an abnormality in any of the “effector” components of the respiratory system—central nervous system, peripheral nervous system, respiratory muscles and chest wall, airways, or alveoli (Fig. 143-2). A defect in any of the first four components, which constitute the “respiratory pump,” may cause coexistent hypercapnia and hypoxemia; at least initially, disorders of the alveoli are more apt to result in hypoxemia.

Hypoxemic Respiratory Failure As described in Chapters 10, 11, and 12, four pathophysiological mechanisms account for the hypoxemia seen in a wide variety of diseases: alveolar hypoventilation, ventilationperfusion mismatch, shunt, and diffusion limitation. Alveolar hypoventilation occurs in neuromuscular disorders that

Respiratory Failure: An Overview

affect the respiratory system. In the absence of underlying pulmonary disease, the hypoxemia accompanying alveolar hypoventilation is characterized by a normal alveolar-arterial oxygen gradient, as defined by Eq. (1): Pao2 − Pao2 = [Pio2 − Paco2 /R] − Pao2

(1)

where Pao2 = alveolar Po2 Pao2 = arterial Po2 Pio2 = inspired Po2 Paco2 = arterial Pco2 R = respiratory exchange ratio In contradistinction, disorders in which any of the other three mechanisms are operative are characterized by widening of the alveolar-arterial oxygen gradient, which is normally less than 20 mmHg. With ventilation-perfusion mismatching, areas of low ventilation relative to perfusion contribute to the hypoxemia. Similarly, with shunt, either intrapulmonary or intracardiac, deoxygenated mixed venous blood bypasses ventilated alveoli, resulting in “venous admixture.” Finally, diseases that increase the diffusion pathway for oxygen from the alveolar space to pulmonary capillary impair oxygen transport across the alveolar-capillary membrane.

Although changes in minute and alveolar ventilation can change Paco2 considerably, this is not so for Pao2 . Increases in minute ventilation and, secondarily, in alveolar ventilation, modestly increase Pao2 . Indeed, at a Pao2 above 55 to 60 mmHg, the effect of increasing ventilation on oxygen content is minimal, since the oxyhemoglobin dissociation curve is flat in this range.

Hypercapnic Respiratory Failure At a constant rate of CO2 production (V˙ co2 ), Paco2 is determined by the level of alveolar ventilation. The relationship

Figure 143-2 Functional components of the respiratory system and its controller. Abnormalities in any of the effector components can result in respiratory failure. The central and peripheral nervous systems, respiratory muscles and chest wall, and airways constitute the ‘‘respiratory pump” (shaded boxes). Hypercapnia is the hallmark of respiratory pump failure, while hypoxemia constitutes the primary disturbance in alveolar disorders producing respiratory failure. (From Lanken PN: Respiratory failure: An overview, in Carlson RW, Geheb MA (eds), Principles and Practice of Medical Intensive Care. Philadelphia, WB Saunders, 1993, pp 754–763.)

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Acute Respiratory Failure

between alveolar ventilation, rate of CO2 production, and Paco2 is described by Eq. (2): ˙ = K · V˙ co2 /Paco2 Va

(2)

where ˙ = minute alveolar ventilation Va K = a constant V˙ co2 = rate of CO2 production ˙ which, ˙ 2 is constant, Paco2 is determined by Va, When Vco in turn, is dictated by two factors: minute ventilation (V˙ e ) and the relationship between V˙ e and V˙ a . The latter is determined by the proportion of V˙ e that constitutes dead space ventilation—i.e., the dead space to tidal volume ratio (Vd /Vt ): V˙ e = K · (V˙ o2 · RQ)/(Paco2 /[1 − Vd /Vt ])

(3)

where V˙ o2 = rate of O2 consumption RQ = respiratory quotient (the respiratory exchange ratio in the steady state) Vd = dead space volume Vt = tidal volume Inspection of Eq. (3) indicates that disorders reducing V˙ e or increasing the proportion of dead space ventilation may result in hypercapnia.

Ventilatory Supply vs. Demand A useful theoretical construct for understanding the pathophysiological basis for hypercapnic respiratory failure is the relationship between ventilatory supply and ventilatory demand (Fig. 143-3).

Ventilatory supply is the maximal spontaneous ventilation that can be maintained without development of respiratory muscle fatigue; ventilatory supply is also known as maximal sustainable ventilation (MSV).

Ventilatory demand is the spontaneous minute ventilation, which, when maintained constant, results in a stable Paco2 (assuming a fixed rate of CO2 production).

Normally, ventilatory supply greatly exceeds ventilatory demand. Hence, major changes in minute ventilatory requirements (e.g., during exercise) may occur without hypercapnia.

In lung disease, significant abnormalities may be present before ventilatory demand encroaches on MSV. Consequently, hypercapnia is a late finding. When ventilatory demand exceeds MSV, Paco2 increases.

As a general rule, MSV is approximated as one-half the maximal voluntary ventilation, or MVV (see Chapter 34). A 70-kg adult has an MVV of about 160 L/min, an MSV of 80 L/min, and, under basal conditions, a V˙ e of approximately 6 to 7 L/min (90 ml/kg/min). Normally, therefore, there is a 10- to 15-fold difference between resting V˙ e and MSV. In disease states, the V˙ e requirement may approach a markedly

Figure 143-3 Relationship between ventilatory supply (maximal sustainable ventilation) and ventilatory demand (overall level of ventilation specified by the central nervous system controller).

Relative size of the arrows indicates levels of supply and demand in each of the three circumstances illustrated. A. Normal. Ventilatory supply greatly exceeds ventilatory demand.

Physiological ‘‘reserve” is maintained. B .Ventilatory supply is decreased and ventilatory demand increased (e.g., acute asthma attack). ‘‘Borderline” respiratory failure exists. C . Ventilatory demand exceeds ventilatory supply (e.g., sepsis in a patient with chronic obstructive pulmonary disease). Respiratory muscle fatigue develops, and hypercapnic respiratory failure ensues. See text for details. (From Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 267–280.)

reduced MSV. Further reductions in MSV result in ventilatory demand exceeding supply, and hypercapnia occurs.

Factors that Reduce Ventilatory Supply or Increase Ventilatory Demand Disruption of any component of the efferent arm of the respiratory control system may diminish ventilatory supply (Table 143-2). While a variety of diseases produce specific abnormalities along the efferent pathway (e.g., phrenic nerve and respiratory muscle disorders), some result in respiratory

2513 Chapter 143

Respiratory Failure: An Overview

Table 143-2 Factors That Diminish Ventilatory Supply Factor Decreased respiratory muscle strength Muscle fatigue Disuse atrophy

Examples

Recovery from acute respiratory failure, high respiratory rates, increased inspiratory time Prolonged mechanical ventilation, following phrenic nerve injury

Malnutrition

Protein-calorie starvation

Electrolyte abnormalities Arterial blood gas abnormalities Fatty infiltration of diaphragm Unfavorable alteration in diaphragm length–tension relationship

Low serum phosphate or potassium concentrations Low pH, low PaO2 high PaCO2 Obesity Flattened domes of diaphragm caused by hyperinflation

Increased muscle energy requirement or decreased substrate supply High elastic work of breathing High resistive work of breathing Reduced diaphragm perfusion Decreased motor neuron function Decreased phrenic nerve output Decreased neuromuscular transmission Abnormal respiratory mechanics Airflow limitation Loss of lung volume Other restrictive defects

Low lung or chest wall compliance, high respiratory rate Airway obstruction Shock, anemia

Polyneuropathy, Guillain-Barr´e syndrome, phrenic nerve transection or injury, poliomyelitis Myasthenia gravis, use of paralyzing agents

Bronchospasm, upper-airway obstruction, excessive airway secretions After lung resection, large pleural effusion Pain-limited inspiration; tense abdominal distention due to ileus, peritoneal dialysis fluid, or ascites

muscle fatigue—the biochemical, cellular, and molecular mechanisms of which remain poorly understood.

As described previously, ventilatory demand can be assessed according to Eq. (3): V˙ e = K · (V˙ o2 · RQ)/(Paco2 /[1 − Vd /Vt ])

(3)

Any factor that affects terms on the right-hand side of the equation may result in ventilatory demand exceeding supply.

Selected clinical examples are given in Table 143-3.

CATEGORIES OF RESPIRATORY FAILURE Although many different diseases cause respiratory failure, they may be grouped conveniently according to primary abnormalities in the individual effector components of the respiratory system.

Abnormalities of the Central Nervous System A variety of pharmacologic, structural, and metabolic disorders of the central nervous system (CNS) are characterized by suppression of the neural drive to breathe. The resultant hypoventilation and hypercapnia may be acute or chronic.

An overdose of a narcotic or other drug with sedative properties is a common cause of respiratory failure. While the most striking clinical picture occurs with an acute overdose, long-standing use of some agents (e.g., methadone) may result in chronic hypercapnia.

“Structural” CNS abnormalities producing hypercapnic respiratory failure include meningoencephalitis, localized tumors or vascular abnormalities of the medulla, and strokes affecting medullary control centers. Usually, respiratory failure is observed in the context of other neurological findings.

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Table 143-3 Factors That Increase Ventilatory Demand Factor

Clinical Examples

Increased Vd /Vt

Acute asthma, emphysema, late phase of acute respiratory distress syndrome, pulmonary emboli

Increased VO2

Fever, sepsis, trauma, shivering, increased work of breathing, massive obesity

Increased RQ

Excessive carbohydrate feeding

Decreased PaCO2

Hypoxemia, metabolic acidosis, anxiety, sepsis, renal failure, hepatic failure

Source: Data from Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiolosy. Philadelphia, JB Lippincott, 1995, pp. 267–280.

A variety of metabolic derangements may produce hypercapnia through depression of respiratory control centers.

Examples include severe myxedema, hepatic failure, and advanced uremia. In addition, elevation of Pco2 in the CNS results in neural depression, further enhancing CO2 retention. A common clinical setting in which elevation of Paco2 is observed is chronic metabolic alkalosis (e.g., due to diuretic use), as detailed in Chapter 14.

Finally, obesity-hypoventilation syndrome is characterized by hypercapnia due to hypoventilation on a central basis.

The underlying mechanisms have not yet been elucidated.

Abnormalities of the Peripheral Nervous System or Chest Wall A wide variety of disorders of the peripheral nerves, neuromuscular junction, and chest wall may be associated with hypercapnic and hypoxemic respiratory failure. While the hallmark is an inability to maintain a level of V˙ e appropriate for the rate of CO2 production, many of these disorders are complicated by impaired expiratory muscle strength, atelectasis, and aspiration. Through mechanisms outlined previously, hypoxemia develops in conjunction with the hypercapnia.

Among the most common neuromuscular causes of hypercapnic respiratory failure are Guillain-Barr´e syndrome, myasthenia gravis, polymyositis, the muscular dystrophies, and a large number of metabolic muscle disorders. In addition, acute poliomyelitis and traumatic spinal cord injury are associated with hypercapnia. Development of respiratory muscle fatigue during prolonged weaning from mechanical ventilation may cause recurrent hypercapnia in the critical care setting.

Pharmacologic causes of hypercapnia in the intensive care unit are frequently encountered. Use of depolarizing and nondepolarizing paralyzing agents, particularly in conjunction with systemic corticosteroids (e.g., in management of status asthmaticus), cholinergic crisis during therapy of myasthenia gravis, and administration of aminoglycosides to patients with myasthenia are examples.

Primary disorders of the chest wall constitute another important category of neuromuscular respiratory failure. The prototype is severe kyphoscoliosis. Additional examples include flail chest (see Chapter 100), extensive thoracoplasty, morbid obesity, and massive abdominal distention due to ascites or distended loops of bowel.

In each of these disorders, a common pathophysiological sequence develops. Because of inadequate activation of inspiratory muscles or limited thoracic excursion, tidal volume falls. While an increase in respiratory rate compensates initially for the fall in V˙ e (and in V˙ a ), V˙ e eventually declines. In addition, the sigh mechanism is impaired, which, in conjunction with the low tidal volume, results in atelectasis and reduced lung compliance. Reduced lung compliance produces a further fall in tidal volume and an increase in the elastic work of breathing (see Chapter 9). Hence, ventilatory supply becomes limited, while ventilatory demand increases due to a rise in Vd /Vt (as a result of atelectasis and other factors noted below). An imbalance between ventilatory supply and demand arises, and hypercapnia ensues.

Furthermore, an impaired gag reflex in the setting of bulbar weakness, coupled with impaired cough due to respiratory muscle involvement, may result in aspiration pneumonia and secondary hypoxemia.

In addition to the pathophysiology described, structural abnormalities of the thoracic cage (e.g., severe kyphoscoliosis) are characterized by an increase in the elastic component of the work of breathing. This results in a ˙ 2 and a higher proportion of total O2 consumphigher Vo tion by the respiratory muscles (normally, less than 5 percent of V˙ o2 ).

Abnormalities of the Airways Obstructive diseases of the airways—either upper or lower— are common causes of acute and chronic hypercapnia. Examples in the upper airways include acute epiglottitis, aspirated foreign body, tracheal tumor, and narrowing of the trachea or glottis by fibrotic tissue. Disorders of the lower airways include COPD, asthma, and advanced cystic fibrosis.

The underlying mechanisms are multifaceted and variable.

However, several common pathophysiological pathways are operative.

Airway narrowing results in a greater transthoracic pressure gradient requirement for inspiratory airflow. The resistive component of the work of breathing is increased, ˙ 2 . In adand the increase is associated with an elevation in Vo dition, tidal volume falls and dead space ventilation increases.

Respiratory muscle fatigue may develop; the consequences of a shallow breathing pattern ensue.

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Finally, in some disorders (e.g., acute asthma or an exacerbation of COPD), air trapping and lung hyperinflation occur, resulting in diaphragm flattening and worsening diaphragm mechanics (see Chapters 9, 41 and 42). The overall effect is a growing imbalance between ventilatory supply and demand.

Abnormalities of the Alveoli Although diseases characterized by diffuse alveolar filling frequently result in hypoxemic respiratory failure, hypercapnia may complicate the picture. Common clinical examples in this category include cardiogenic and noncardiogenic pulmonary edema, diffuse pneumonia, extensive pulmonary hemorrhage, aspiration of stomach contents, and neardrowning.

Diffuse alveolar filling creates a large right-to-left shunt as pulmonary blood flows through nonventilated or poorly ventilated regions of the lung. In addition, coexisting interstitial edema may impair diffusion across the alveolar-capillary membrane, further impairing oxygenation of mixed venous blood.

In extensive, acute pulmonary disease characterized by alveolar filling, ventilatory demand is high because of hypoxemia and increases in Vd /Vt , the elastic work of breathing (due to reduced lung compliance), the resistive work of breathing (due to airway narrowing and increased airway reactivity), and the neural drive to breathe (mediated by pulmonary parenchymal vagal fibers). In conjunction with heightened ventilatory demand, ventilatory supply is reduced because of alveolar flooding, reduced lung elasticity, respiratory muscle fatigue, and, possibly, reduced blood supply to the diaphragm secondary to shock. Once again, the imbalance between ventilatory supply and demand results in hypercapnia.

APPROACH TO THE PATIENT The diagnosis of acute or chronic respiratory failure begins with clinical suspicion of its presence. Confirmation of the diagnosis is based on arterial blood gas analysis (Table 143-1).

Evaluation for an underlying cause must be initiated early, frequently in the presence of concurrent treatment for acute respiratory failure. While the diagnosis of chronic respiratory failure is usually easily established with clinical findings of chronic hypoxemia (with or without findings of hypercapnia), the diagnosis of acute respiratory failure requires more careful analysis.

Signs and symptoms in acute respiratory failure reflect the underlying disease process and associated hypoxemia or acidemia due to hypercapnia. Localized pulmonary findings reflecting the acute causes of hypoxemia (e.g., pneumonia, pulmonary edema, asthma, or COPD) may be readily apparent. Alternatively, the predominant findings may be systemic (e.g., hypotension due to sepsis). The principal manifestations may even be remote from the thorax—e.g., abdominal

Respiratory Failure: An Overview

pain in acute pancreatitis or leg pain due to a long bone fracture—each associated with acute (adult) respiratory distress syndrome (ARDS) (see Chapter 145). Frequently, neurological or cardiovascular symptoms and signs predominate.

Neurological manifestations include restlessness, anxiety, confusion, seizures, or coma. Asterixis may be seen with severe hypercapnia. Common cardiovascular findings include tachycardia and a variety of arrhythmias. Finally, there may be few or no findings other than a complaint of dyspnea, as in some patients with hypoxemia due to pulmonary embolism.

Once respiratory failure is suspected on clinical grounds, arterial blood gas analysis is performed to confirm the diagnosis, to assist in the distinction between acute and chronic forms, to assess the magnitude and metabolic impact, and to help guide management (Table 143-4).

PRINCIPLES OF MANAGEMENT The principles of management of patients in acute respiratory failure include those that are cause-specific and those that are more general. Triage of the patient to the proper clinical setting, airway maintenance, correction of hypoxemia and hypercapnia, and management of the underlying cause are of paramount importance.

Triage Decisions The first step in management is to determine the appropriate setting for care—admission to a standard inpatient facility or to an intensive or intermediate care unit. Factors that constitute the basis for this decision include the acuity of the respiratory failure; the degree of hypoxemia, hypercapnia, and acidemia; the presence of co-morbid conditions (e.g., cardiac disease or renal insufficiency); and the clinical direction that the patient takes over the first few minutes or hours of observation. At one end of the spectrum is the patient with fulminant hypoxemic respiratory failure, metabolic acidosis, and imminent cardiovascular collapse, who needs emergent intubation, mechanical ventilation, and admission to a critical care unit. At the other end of the spectrum is the patient with COPD and chronic, compensated hypercapnic respiratory failure, who requires observation in an intermediate care unit. Notably, in recent years, a number of studies have indicated that use of noninvasive mechanical ventilation may obviate the need for endotracheal intubation in selected patients with hypercapnic or acute, hypoxemic respiratory failure (other than ARDS-related). Although studies also point to the potential role of noninvasive mechanical ventilation in recurrent respiratory failure following extubation, a multicenter, randomized trial found no reduction in mortality or in the need for reintubation with its use.

Airway Management Assurance of an adequate airway is key in the patient with acute respiratory distress. Whether emergency intubation is

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Table 143-4 Changes in Arterial Blood Gases, Pao2 –Pao2 , and Ventilation in Acute Respiratory Failure Failed Respiratory System Component

pH

Paco2

Pao2

PAo2 –Pao2

V˙ E

V˙ A

Central nervous system

↓

↑

↓∗

NL or ↑†

↓

↓

Peripheral nervous system or chest bellows

↓

↑

↓∗

NL or ↑†

↓

↓

Early phase (before respiratory failure)

↑

↓

NL

↑

↑

↑

“Crossover point”

NL

NL

NL or ↓

↑

↑

NL

With development of respiratory muscle fatigue

↓

↑

↓

↑

↓‡

↓

↓

NL or ↑§

↓

↑

↑

↓

Baseline

NL to ↓

↑

↓

↑

NL or ↑

↓

Flare

↓

↑↑

↓↓

↑

NL, ↑ or ↓‡

↓

Before respiratory muscle fatigue develops

↑

↓

↓↓

↑↑

↑

↑

After respiratory muscle fatigue develops

↓

↑

↓↓

↑↑

↓

↓

Airways In acute asthma

In COPD Non–CO2 retainer CO2 retainer

Alveoli

∗ Pa

o2 may decrease when pneumonia or atelectasis occurs as a complication. o2 –Pao2 ) widens when pneumonia or atelectasis occurs as a complication. ‡V ˙ E declines when frank respiratory muscle failure occurs. § Pa co2 may increase during an exacerbation.

Note: ↑ = increased; ↑↑= very increased; ↓= decreased; ↓↓= very decreased; NL = in normal range.

Source: Data from Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiolosy. Philadelphia, JB Lippincott, 1995, pp. 267–280. † ( Pa

required depends on the clinical circumstances described previously. For patients with chronic respiratory insufficiency, the need for intubation depends on critical arterial blood gas values and the patient’s early acute course. When progressive hypoxemia or hypercapnia is observed over the first few minutes or hours of care, intubation and mechanical ventilation are warranted.

Correction of Hypoxemia and Hypercapnia Once the airway is secured, the clinician must turn attention to the treatment of hypoxemia—the most life-threatening

aspect of acute respiratory insufficiency. The goal is to assure adequate oxygen delivery to tissues, generally achieved with a Pao2 of about 60 mmHg (assuming an adequate hematocrit and cardiac output). In patients who have coronary or cerebrovascular disease, a slightly higher level of arterial oxygenation may be desirable in order to provide a “buffer” for any sudden, unpredictable changes in gas exchange.

The means by which supplemental oxygen is administered is determined by the clinical circumstances. While some patients may simply require nasal prongs or a face mask to achieve an adequate Pao2 , others are best treated with controlled-flow oxygen delivered via a Venturi mask—e.g.,

2517 Chapter 143

the patient with COPD and chronic hypercapnia (see Chapters 42 and 149). Generally, if an acceptable level of oxygenation, as judged by arterial blood gases, cannot be attained using a face mask, or if administration of supplemental O2 causes hypercapnia to worsen significantly (e.g., in some patients with COPD), either noninvasive mechanical ventilation or endotracheal intubation and mechanical ventilation will be required.

While correcting hypoxemia, the clinician must also address any coexisting hypercapnia and respiratory acidosis.

Once again, the immediacy of correction depends on the magnitude of the acidosis and its attendant effects (e.g., elevation of serum potassium). A partly compensated respiratory acidosis in a patient with COPD usually constitutes a less urgent clinical circumstance than does profound respiratory acidosis in a patient with a drug overdose.

Search for an Underlying Cause Finally, as therapy is initiated to correct the hypoxemia, hypercapnia, and acidosis of respiratory failure, a search for the cause of the problem and its management must be undertaken. In some cases, the cause and management are straightforward (e.g., administration of a narcotic antagonist to the patient with a narcotic overdose). In others, a more protracted course may be in store (e.g., long-term ventilator management of fulminant ARDS due to sepsis).

In both brief and prolonged cases of respiratory failure, attention to details of management is important in order to minimize the risks of complications of therapy, as discussed below.

MONITORING PATIENTS WITH ACUTE RESPIRATORY FAILURE Repeated assessment of the patient with incipient or resolving respiratory failure, as well as the patient with frank hypoxemic or hypercapnic failure, is critical in formulating decisions about therapy. Monitoring methods range from routine bedside observations to use of invasive techniques.

For many patients with acute respiratory failure, simple observation of respiratory rate, tidal volume, use of accessory muscles, and presence of paradoxical breathing movements provides evidence of worsening respiratory failure and the need for mechanical ventilation. The patient with asthma or an acute exacerbation of COPD will frequently manifest rapid, shallow breathing and paradoxical thoracoabdominal breathing movements as respiratory mechanics deteriorate.

Once placed on mechanical ventilation, the patient must be monitored carefully for ventilator-associated complications (see below). In addition, placement of indwelling arterial and venous catheters, patient immobilization, and use of a broad range of pharmacologic agents present additional potential threats to the acutely ill patient.

Respiratory Failure: An Overview

While many monitoring techniques are routine and may be universally applicable to patients in a critical care setting (e.g., pulse oximetry), others may be of particular importance in selected clinical circumstances. For example, routine assessment of static respiratory system compliance in a mechanically ventilated patient with ARDS or pulmonary fibrosis may provide an early warning of barotrauma. In the patient with status asthmaticus requiring mechanical ventilation, development of hypotension due to intrinsic positive end-expiratory pressure (PEEP) or “auto-PEEP,” as discussed in Chapters 152 and 153, may signal the need to alter ventilator settings or implement sedation or pharmacologic paralysis.

COMPLICATIONS OF ACUTE RESPIRATORY FAILURE The respiratory patient in a critical care unit must navigate not only the obstacles presented by the underlying pulmonary process, but also the hazards associated with use of mechanical devices and pharmacologic agents. Complications of acute respiratory failure may be broadly categorized as pulmonary, cardiovascular, gastrointestinal, renal, infectious, nutritional, and other (Table 143-5). For details in each of these areas, the reader is referred to other chapters in this text.

Pulmonary Common pulmonary complications of acute respiratory failure include pneumonia (discussed in detail elsewhere), pulmonary emboli, pulmonary barotrauma, pulmonary fibrosis, and complications directly related to use of mechanical devices.

Pulmonary emboli have been reported in up to onefourth of patients with respiratory failure in intensive care units. The diagnosis is difficult in this setting, since patients typically have diffuse underlying lung disease, abnormal gas exchange, and many coexisting potential causes for the clinical, radiographic, and physiological consequences of pulmonary emboli.

Pulmonary barotrauma, identified as the presence of extra-alveolar air in structures that do not normally contain air, may occur in patients receiving mechanical ventilation for a variety of indications. It is particularly common in patients with ARDS. Manifestations of barotrauma include pulmonary interstitial emphysema, pneumothorax, pneumomediastinum, pneumoperitoneum, subcutaneous emphysema, tension lung cysts, and subpleural air cysts.

Pulmonary fibrosis may follow acute lung injury associated with ARDS. In addition, use of high inspired concentrations of oxygen may enhance development of fibrosis in the presence of acute lung injury.

Based on recent studies, a strategy of “low stretch” ventilation has emerged for managing patients with acute lung injury or ARDS and is aimed at minimizing the risks of ventilator-induced pulmonary damage, as discussed in

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Table 143-5 Complications of Acute Respiratory Failure Pulmonary Pulmonary emboli Pulmonary barotrauma (interstitial emphysema, pneumothorax, subcutaneous emphysema, pneumoperitoneum, tension lung cyst, subpleural air cyst) Pulmonary fibrosis Related to Use of Mechanical Devices Complications of mechanical ventilation (infection, arterial desaturation, hypotension, barotrauma, others) Complications of insertion and maintenance of pulmonary artery catheter (pneumothorax, air embolism, arrhythmias, infection, thrombosis, pulmonary artery rupture) Complications of tracheal intubation Related to prolonged intubation attempt (hypoxemic brain injury, cardiac arrest, seizures, others) Related to right main bronchus intubation (hypoventilation, pneumothorax, atelectasis) Self- or inadvertent extubation Endotracheal tube dislodgment Endotracheal tube cuff leak Injury to pharynx, larynx, trachea Complications of tracheotomy (pneumothorax, bleeding, tube dislodgment, tracheoinnominate fistula, tracheoesophageal fistula, tracheal stenosis) Gastrointestinal Hemorrhage (including â&#x20AC;&#x153;stressâ&#x20AC;? ulceration) Ileus Diarrhea Cardiovascular Hypotension Arrhythmias Decreased cardiac output Myocardial infarction Pulmonary hypertension Renal Acute renal failure Fluid retention Infectious Nosocomial pneumonia Bacteremia Sepsis Paranasal sinusitis Nutritional Complications of underlying malnutrition (decreased respiratory muscle strength, immune suppression, others) Complications of enteral feeding (pneumothorax, pleural effusion, sinusitis, aspiration, diarrhea) Complications of parenteral feeding (pneumothorax, sepsis, hyperglycemia, hyperosmolar coma, hypophosphatemia, liver function test abnormalities) Complications of refeeding (hypercapnia) Other Psychiatric (anxiety, depression, confusion, sleep dysfunction, psychosis) Hematological (anemia, thrombocytopenia)

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Chapters 144 and 145. In addition, new approaches to the use of intravenous sedation, namely, daily interruption of the infusion, has been shown to reduce both the duration of mechanical ventilation and length of stay in the intensive care unit.

Common device-related complications include those due to pulmonary artery flotation catheters, endotracheal intubation, and tracheotomy.

Cardiovascular Common cardiovascular complications in patients with acute respiratory failure include hypotension, reduced cardiac output, arrhythmias, pericarditis, and acute myocardial infarction. These complications may be related to the underlying disease process, mechanical ventilation, or use of pulmonary artery flotation catheters.

Gastrointestinal A variety of gastrointestinal complications of acute respiratory failure, particularly during mechanical ventilation, have been well described. The major ones include hemorrhage, gastric distention, ileus, diarrhea, and pneumoperitoneum. â&#x20AC;&#x153;Stressâ&#x20AC;? ulceration is extremely common in patients with acute respiratory failure. Associated risk factors include trauma, shock due to a variety of causes, sepsis, renal failure, and liver disease.

Infectious Nosocomial infections are a frequent complication of acute respiratory failure. Principal among these are pneumonia, sepsis, and urinary tract infections. Each typically occurs with the use of mechanical devices, including endotracheal and tracheotomy tubes, indwelling central venous and pulmonary artery catheters, and urinary bladder catheters.

The incidence of nosocomial pneumonia in the critically ill may be as high as 70 percent for patients in intensive care units, particularly in those with ARDS. The need for prolonged mechanical ventilation is a harbinger for development of nosocomial pneumonia. Not unexpectedly, nosocomial pneumonia occurring in the medical intensive care unit is associated with a significantly increased length of stay and higher mortality. Guidelines have been developed for treatment of patients with ventilator-associated pneumonia.

Renal Acute renal failure and abnormalities in electrolyte and water homeostasis are not uncommon in critically ill patients with acute respiratory failure; the former is observed in approximately 10 to 20 percent of patients in intensive care units.

Development of acute renal failure in a patient with acute respiratory failure carries a poor prognosis and a high mortality. The causes of acute renal failure are numerous and

Respiratory Failure: An Overview

include prerenal azotemia and acute tubular necrosis due to hypotension or use of nephrotoxic drugs.

Nutritional Nutritional complications of acute respiratory failure include the effects of malnutrition on respiratory performance and complications related to the administration of enteral or parenteral nutrition. Complications of enteral nutritional support relate to initial insertion of the catheter (e.g., tracheal or pleural space penetration, pneumomediastinum, pneumothorax, and pleural effusion) and its maintenance (e.g., paranasal sinusitis and aspiration). In addition, vomiting, abdominal distention, and diarrhea are common. Complications of parenteral nutrition are mechanical (e.g., pneumothorax during catheter insertion), infectious (e.g., catheter-related sepsis), or metabolic (e.g., metabolic acidosis, hyperglycemia and hyperosmolar coma, and hypophosphatemia). Hypercapnia, induced by enteral as well as parenteral nutrition, can complicate management of patients who have limited ventilatory reserve.

PROGNOSIS Interpretation of studies addressing the prognosis of patients with acute respiratory failure is subject to a number of constraints, including marked clinical variability in the patients studied, predominance of studies from intensive care units in large university teaching hospitals, and variability in treatment methods employed over the time span of studies performed. In addition, many studies report only hospital mortality, not long-term survival or quality of life.

Finally, findings from large-population studies are difficult to extrapolate to prediction of outcome in a single patient.

Nonetheless, several generalizations can be made regarding the prognosis of patients hospitalized with acute respiratory failure.

Morbidity and Mortality in Acute Hypoxemic Respiratory Failure As expected, mortality in hypoxemic respiratory failure depends on the underlying cause. A number of studies have addressed outcome in patients with ARDS. Mortality in ARDS appears to have improved in recent years, with overall survival now at about 60 percent. Patients who develop sepsis after trauma have a lower mortality than do patients with sepsis that complicates medical disorders.

Not surprisingly, younger patients (those under the age of 70 years) have better survival rates than do older patients.

Notably, patients with preexisting lung disease, higher Fio2 or PEEP requirements, or a lower Pao2 may not necessarily have a poorer chance of survival.

Approximately two-thirds of patients who survive an episode of ARDS will manifest some impairment of

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pulmonary function one or more years after recovery. The abnormalities include both obstructive and restrictive defects, as well as a reduction in diffusing capacity. The pulmonary function findings do not appear to correlate with whether low or high tidal volumes were used during mechanical ventilation. Pulmonary function abnormalities that persist beyond one year after recovery are unlikely to resolve thereafter. Furthermore, despite recovery of pulmonary function, many survivors of ARDS have persistent functional disabilities one year after discharge, largely due to muscle wasting and weakness.

Approximately three-fourths of survivors of ARDS have neurocognitive findings at hospital discharge; in about onehalf, the findings persist at 2 years postdischarge. Indeed, reduced quality of life and persistent neurocognitive defects represent long-term morbidities of survival in ARDS.

Morbidity and Mortality in Acute Hypercapnic Respiratory Failure In general, several parameters presage a higher mortality in patients admitted with hypercapnic respiratory failure: (1) the patient’s “physiological reserve,” as determined by concurrent cardiopulmonary, renal, hepatic, or neurological disease and the patient’s age; (2) the underlying cause of the acute deterioration; (3) the severity of the respiratory failure, as defined by arterial pH and Pco2 ; and (4) development of complications after onset of acute respiratory failure—e.g., sepsis, pneumonia, renal failure, or gastrointestinal bleeding.

Cachexia and home confinement before hospitalization may also presage a poorer outcome. These harbingers appear to hold true regardless of whether the patient requires mechanical ventilation.

For patients with COPD and acute respiratory failure, overall mortality has declined from approximately 26 percent to 10 percent according to more recent studies. Not unexpectedly, older patients who are significantly more acidemic, hypotensive, or uremic appear to have a higher mortality. The magnitude of the hypoxemia or hypercapnia at the time of presentation may not reliably foretell mortality.

SUGGESTED READING The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000.

Bernard, GR: Acute Respiratory Distress Syndrome: A historical perspective. Am J Respir Crit Care Med 172:798–806, 2005.

Cunnion KM, Weber DJ, Broadhead WE, et al: Risk factors for nosocomial pneumonia: Comparing adult criticalcare populations. Am J Respir Crit Care Med 153:158–162, 1996.

Curtis JR, Hudson LD: Emergent assessment and management of acute respiratory failure in COPD. Clin Chest Med 15:481–500, 1994.

Ely EW, Wheeler AP, Thompson BT, et al: Recovery rate and prognosis in older persons who develop acute lung injury and the acute respiratory distress syndrome. Ann Intern Med 136:25–36, 2002.

Esteban A, Frutos-Vivar F, Ferguson ND, et al: Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 350:2452–2460, 2004.

Gammon RB, Shin MS, Groves RH Jr, et al: Clinical risk factors for pulmonary barotrauma: A multivariate analysis. Am J Respir Crit Care Med 152:1235–1240, 1995.

Ghio AJ, Elliott CG, Crapo RO, et al: Impairment after adult respiratory distress syndrome: An evaluation based on American Thoracic Society Recommendations. Am Rev Respir Dis 139:1158– 1162, 1989.

Grippi MA: Distribution of ventilation, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 41–53.

Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683–693, 2003.

Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 171:340–347, 2005.

Kress JP, Pohlman AS, O’Connor MF, Hall JB: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471–1477, 2000.

Lanken PN: Pathophysiology of respiratory failure, in Grippi MA (ed), Pulmonary Pathophysiology. Philadelphia, JB Lippincott, 1995, pp 267–280.

Lanken PN: Respiratory failure: An overview. In Carlson RW, Geheb MA (eds), Principles and Practice of Medical Intensive Care. Philadelphia, WB Saunders, 1993, pp 754–763.

Marini JJ, Gattinoni L: Ventilatory management of acute respiratory distress syndrome: A consensus of two. Crit Care Med 32:250–255, 2004.

Matthay MA: The adult respiratory distress syndrome: Definition and prognosis. Clin Chest Med 11:575–580, 1990.

Milberg JA, Davis DR, Steinberg KP, et al: Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 273:306–309, 1995.

The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327–336, 2004.

Orme, J Jr, Romney JS, Hopkins, RO, et al: Pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 167:690–694, 2003.

Pepe PE, Marini JJ: Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction.

Am Rev Respir Dis 126:166–170, 1982.

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Piantadosi CA, Schwartz DA: The acute respiratory distress syndrome. Ann Intern Med 141:460–470, 2004.

Pingleton SK: Complications of acute respiratory failure. Am Rev Respir Dis 137:1463–1493, 1988.

Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685– 1693, 2005.

Statement of the American Thoracic Society and the Infectious Disease Society of America: Guidelines for the

Respiratory Failure: An Overview

management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005.

Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1995, 2001.

Unterborn JN, Hill NS: Options for mechanical ventilation in neuromuscular diseases. Clin Chest Med 15:765–781, 1994.

Weiss SM, Hudson LD: Outcome from respiratory failure.

Crit Care Clin 10:197–215, 1994.

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144 Acute Respiratory Distress Syndrome: Pathogenesis Michael A. Matthay

Role of Inflammation Role of Direct Toxicity Biologic Markers

I. PATHOPHYSIOLOGY OF PULMONARY EDEMA IN ACUTE LUNG INJURY Vascular Fluid and Protein Exchange Increased Permeability Pulmonary Edema Lung Physiology

III. VENTILATOR-ASSOCIATED LUNG INJURY Animal Studies Clinical Studies

II. MECHANISMS OF ACUTE LUNG INJURY Path ological Findings Mediators Role of Infection

IV. RESOLUTION OF LUNG INJURY V. CONCLUSIONS

This chapter focuses on the pathogenesis of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS).

Chapter 145 discusses clinical features and clinical management.

PATHOPHYSIOLOGY OF PULMONARY EDEMA IN ACUTE LUNG INJURY Pulmonary edema occurs when fluid is filtered into the lungs faster than it can be removed. Accumulation of fluid may have major consequences on lung function because efficient gas exchange cannot occur in fluid-filled alveoli. Lung structure relevant to edema formation and the forces governing fluid and protein movement in the lungs has been the subject of classic and more recent reviews and chapters, as noted in the “Suggested Reading” included at the end of this discussion.

Vascular Fluid and Protein Exchange The essential factors that govern fluid exchange in the lungs are expressed in the Starling equation for the microvascular barrier: Jv = LpS[(Pc − Pi) − σd(πc − πi)]

(1)

where Jv = the net fluid-filtration rate (volume flow) across the microvascular barrier Lp = the hydraulic conductivity (“permeability”) of the microvascular barrier to fluid filtration (a measure of how easy it is for water to cross the barrier) S = the surface area of the barrier Pc = the pulmonary capillary (microvascular) hydrostatic pressure Pi = the interstitial (“perimicrovascular”) hydrostatic pressure πc = the capillary (microvascular) plasma colloid osmotic (or oncotic) pressure πi = the interstitial (perimicrovascular) fluid osmotic pressure σd = the average osmotic reflection coefficient of the barrier (a measure of the effectiveness of the barrier in hindering the passage of solutes from one side of the barrier to the other) The Starling equation predicts the development of two different kinds of pulmonary edema. Increased pressure pulmonary edema occurs when the balance of the driving forces increases,

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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forcing fluid across the barrier at a rate that can no longer be accommodated by lymphatic drainage. Increased permeability pulmonary edema occurs in the presence of ALI that damages the normal barriers to fluid filtration and allows increased flux of liquid and protein into the extravascular compartments of the lungs.

Thus, pulmonary edema results from increases in either hydrostatic driving pressures (increased pressure edema) or barrier conductance (increased permeability edema), or both. What distinguishes the two types is barrier permeability, which is normal in increased pressure edema, but abnormal in increased permeability edema. Fluid flow into the lungs is driven across the barrier in both types of edema by the balance of pressures. ALI or ARDS results primarily from an increase in lung vascular permeability, although some cases may be made worse by the presence of elevated lung vascular hydrostatic pressures.

into the interstitial and alveolar spaces. The ability of the lymphatics to pump the excess filtrate away is increased when the lungs are injured. Maximal lung lymph flow increases more when the microvascular wall has been injured than when hydrostatic pressure alone is increased, but even this augmented lymphatic-pumping capability is taxed at lower driving pressures. If the epithelial barrier is injured, edema may accumulate readily in alveoli, because most of the resistance to fluid and protein flow into the alveoli is in the epithelial barrier.

Increased permeability edema is often rapid in onset and progression because injured barriers offer much less resistance to flow and because hydrostatic driving pressure is unopposed by increases in osmotic pressure difference. Clinically, many patients with increased permeability edema have a low intravascular hydrostatic pressure, commonly measured as a low or normal pulmonary capillary wedge pressure. In some cases, this reflects the low intravascular pressures associated with the underlying disease process, such as sepsis.

Increased Permeability Pulmonary Edema Increased permeability pulmonary edema is caused by an increase in liquid and protein conductance across the barriers in the lungs. The essential feature is that the integrity of the barrier to fluid and protein flow into the lung interstitium and the alveoli is altered. Increased permeability edema is sometimes called noncardiogenic pulmonary edema, and the resulting clinical syndromes in humans are commonly lumped together as acute lung injury or the acute respiratory distress syndrome.

Accumulation of fluid and protein increases when the lung endothelial and epithelial barriers are injured. If the rate of fluid accumulation exceeds the rate at which it can be removed, increased permeability edema occurs. Because the barriers limiting fluid and protein flow into the lungs do not function normally when the lungs are injured, the lungs are not protected against edema by the usual safety factors. Although increases in fluid and protein filtration across the lung endothelium can be removed by lymphatics and drained away from the alveolar walls as in increased pressure edema, much more fluid and protein are filtered at any given sum of driving pressures because the barriers to their flow are much less restrictive than normal. Edema formation in injured lungs is very sensitive to hydrostatic driving pressures. Driving pressures are often increased when the lungs are injured because of the vasoconstrictive effects of inflammatory mediators such as thromboxanes, which may shift the main site of resistance to postcapillary venules, thus increasing hydrostatic pressure at the microvascular fluid exchange sites, or because of effects on the heart as well as on the circulation. For example, elevated left atrial pressure, pulmonary venoconstriction, or an increase in cardiac output in sepsis can increase hydrostatic pressure at the microvascular fluid exchange sites.

Because the barriers are leaky, the protective osmotic pressure differences across them are lost; driving pressure is unopposed by osmotic pressure, and even normal hydrostatic pressure results in significant fluid and protein extravasation

Lung Physiology The effects of increased permeability edema on lung mechanics and gas exchange depend, in part, on the magnitude of edema accumulation. As with increased pressure edema, the major effects on pulmonary mechanics occur with alveolar flooding. In experimental lung injury, functional residual capacity is decreased as a consequence of alveolar flooding; the loss of units which can be ventilated accounts for most of the decrease in static lung compliance. Computed tomography has provided new insights into structure-function relationship in human ALI. In the early stage of lung injury, when alveolar edema predominates, the lungs are characterized by a more homogeneous alteration of vascular permeability, and edema can accumulate evenly in all lung regions with a nongravitational distribution.

Measurements of pulmonary mechanics in mechanically ventilated patients with ALIs show a decrease in static lung compliance as a consequence of the loss of ventilated lung units. In addition, airflow resistance is increased as a result of decreased lung volume. Bronchospasm may add to the increase in airflow resistance and may be partially reversed in some patients by administration of inhaled bronchodilators. Chest wall compliance is reduced, probably because of alterations in the intrinsic mechanical properties of the chest wall by abdominal distention, chest wall edema, and pleural effusion. Some investigators have reported differing respiratory mechanics and response to positive end-expiratory pressure (PEEP) during mechanical ventilation in patients with ARDS originating from pulmonary disease (e.g., pneumonia, which causes consolidation) versus ARDS due to extrapulmonary disease (which causes edema and subsequent alveolar collapse).

Although the effects of surface forces on decreased lung compliance in ALI were once believed to be small, results of experiments in isolated rabbit lungs indicate that increased permeability edema may produce more severe mechanical

2525 Chapter 144

changes than equivalent degrees of increased pressure edema.

In contrast, experiments in awake sheep have demonstrated that similar degrees of pulmonary edema, regardless of mechanism, cause similar changes in compliance and gas exchange.

Other studies indicate that dynamic and static lung compliances are decreased early in evolving lung injury.

Surfactant is strongly thromboplastic, and coagulation may compound surfactant depletion when plasma proteins enter the airspaces. The injured lung may release substances that can interfere with the normal, low surface tension in the alveoli. In addition, activated neutrophils may impair surfactant function in vitro and degrade major surfactant apoproteins through a combination of proteolysis and oxidantradicalâ&#x20AC;&#x201C;mediated mechanisms. In studies using bronchoalveolar lavage, human lung surfactant obtained from patients at risk for ALI and from those with established ALIs has been reported to be abnormal in chemical composition and functional activity. Abnormalities may also be caused by interactions between surfactant and edema proteins, since plasma proteins (especially fibrin monomers, but also fibrinogen and albumin) interfere with surfactant function. Proteinaceous edema fluid has been associated with surfactant inhibition in several experimental models.

Gas exchange is severely compromised in increased permeability edema because of both intrapulmonary shunting of blood and ventilation-perfusion inequalities. New evidence indicates that patients with early ALI have a marked increase in pulmonary dead space fraction. This finding indicates that many ventilated lung units are not well perfused, although intrapulmonary shunting may also contribute to the elevated dead space. Not surprisingly, minute ventilation is typically twice normal (approximately 12 L/min) at the onset of ARDS.

Acute Respiratory Distress Syndrome: Pathogenesis

This section focuses on the characteristic pulmonary pathological findings in patients with ALI and ARDS and the mechanisms responsible for ALI.

The injured alveolar epithelium is swollen, disorganized, discontinuous, and, frequently, detached from basement membranes, which may be otherwise intact. The alveolar surface may be covered by hyaline membranes. Type I cells are more severely damaged than type II cells. The thin cytoplasmic extensions of cells far from the nucleus, which cover the thin side of the alveolar-capillary barrier, may be most severely affected. The interstitium is widened by edema (especially in peribronchovascular cuffs) and may be filled with leukocytes, platelets, red blood cells, fibrin, and debris (especially near the alveolar walls). The microvascular endothelium is relatively preserved; it usually shows little other than irregular, focal thickening due to cytoplasmic swelling or vacuoles and greater numbers of luminal leukocytes.

After about 5 to 10 days, the exudative phase is followed by a proliferative phase. The relative contributions of the original insult, repair processes, and effects of therapies on this and subsequent phases are not well known. Some abnormalities occurring after the initial exudative phase appear to be related to effects of traditional modes of mechanical ventilation that used tidal volumes between 12 and 15 ml/kg predicted body weight.

Reabsorption of some of the edema fluid characterizes the proliferative phase. Fibrin may be prominent in alveoli and interstitium, and infiltration with inflammatory cells and fibroblasts, which may have been activated very early in the course of lung injury, may be seen. The alveolar epithelium is often cuboidal and made up largely of proliferating type II cells. The air-blood barrier may be thickened by interstitial and epithelial enlargement. The pulmonary vascular bed may be partially or completely disrupted, and structural alterations may reduce its surface area.

Approximately 2 weeks after the initial insult, a final stage may be observed in which fibrotic changes of the alveolar ducts, alveoli, and interstitium predominate. Alveoli may be obliterated, alveolar walls coalesced, and functional lung units lost. The lungs may be emphysema-like, with extensive bullous changes. Notably, even severe changes at any stage may be reversible during a slow recovery back toward normal lung function.

Pathological Findings

Mediators

Based on several studies that included a preponderance of postmortem pathology, the light and electron microscopic appearances of human and animal lung tissue in ALI have been described. Exudative, proliferative, and fibrotic changes usually appear in sequence.

The earliest changes are marked by widespread alveolar and interstitial edema and hemorrhage. Hyaline membranes, composed of precipitated plasma proteins, fibrin, and necrotic debris are frequently found (Fig. 144-1). The alveolar epithelium may be more extensively damaged than is the vascular endothelium, even if the underlying insult is bloodborne. Widespread, local areas of destruction of type I alveolar epithelial cells alternate with normal-appearing alveoli.

The most common clinical disorders associated with the development of ALI are pneumonia, sepsis, gastric aspiration, and major trauma. Other, less common causes include transfusion-associated lung injury, drug overdose, severe acute pancreatitis, and near drowning. The initiating insult to the lungs occurs either via the airways or the bloodstream.

The exact mechanisms by which the lungs are injured have been the subject of intense investigation in humans, animals, and cellular systems. Human studies have provided descriptive data about the events that occur in the airspaces before and after the onset of lung injury. Studies using bronchoalveolar lavage or collection of pulmonary edema fluid

MECHANISMS OF ACUTE LUNG INJURY

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B

A

C

Figure 144-1 A. A low-power light micrograph of lung biopsy specimen collected 2 days after onset of ALI/ARDS secondary to gram-negative sepsis demonstrates key features of diffuse alveolar damage, including hyaline membranes, inflammation, intra-alveolar red blood cells and neutrophils, and thickening of the alveolar-capillary membrane. B . High-power view of a different field illustrates dense hyaline membrane and diffuse alveolar inflammation.

Polymorphonuclear leukocytes are imbedded in the proteinaceous hyaline membrane structure (black arrows). The white arrow points to the edge of an adjacent alveolus, which contains myeloid leukocytes. (Histological sections in A and B courtesy of Dr. K. Jones, University of California, San Francisco). C. Electron micrograph from a classic analysis of ALI/ARDS showing injury to capillary endothelium and alveolar epithelium. LC = leukocyte within the capillary lumen; EC = erythrocytes; EN = blebbing of the capillary endothelium; BM = exposed basement membrane where the epithelium has been denuded; C = capillary; A = alveolar space. (From The ARDS Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.

N Engl J Med 342:1301â&#x20AC;&#x201C;1308, 2000, with permission.)

in patients following the onset of ALI have demonstrated a major acute inflammatory response beginning prior to clinical recognition of ALI. The response peaks during the first 1 to 3 days of clinically defined ALI and resolves slowly over 7 to 14 days in patients who remain intubated. These studies have shown the complexity of the evolving inflammatory responses, characterized by accumulation of acute response cytokines and their naturally occurring inhibitors, oxidants, proteinases and antiproteinases, lipid mediators, growth factors, and the collagen precursors involved in the repair process.

Hypotheses regarding the mechanisms of lung injury have been tested in animal models and in vitro studies, and several reviews have summarized the findings. The existing

animal models do not completely reproduce all of the aspects of ALI in humans, in part because human ALI evolves over a longer period of time than can be studied in the laboratory.

In addition, the lungs of humans are exposed not only to the initial injurious insult, but also to the therapies that are used to treat ALI, such as mechanical ventilation. Experiments using isolated cells have been helpful in testing specific concepts, but the complexity and redundancy of intact biologic systems is not reproduced in simplified experimental systems. By design, most experimental work limits study to one causative agent, thereby reducing actual clinical complexity to the simplicity of a single experimental pathway. Increased permeability edema in humans is likely to be caused by interactions among a number of different pathways acting in parallel or series.

2527 Chapter 144

Studies in isolated organs and small animals in which hemodynamic variables are not measured can be difficult to evaluate. Indices of lung injury, usually measured by the appearance of markers in lungs, lavage fluid, or perfusate, are not determined solely by the barrier function of the microvasculature. Indeed, when vascular endothelium is injured, fluid and protein movement from the vascular space into the lungs is sensitive to hydrostatic driving pressures and filtration surface area. Hence, the effects of experimental interventions may be caused by changes in these parameters and not by changes in microvascular barrier function.

The effects of microvascular driving pressures and surface area can be difficult to evaluate, even in large, instrumented animals. In sheep and goats, interpretation of lung lymph fluid and protein flow changes are further complicated by contributions of extrapulmonary lymphatics, physical forces acting on lymphatics, and possible intranodal modification of lymph. Data from experimental animal models suggest that at least two broad categories of mechanisms of ALI are operative: (1) those that are indirect (i.e., require the participation of intermediary mechanisms, e.g., host defenses); and (2) those that are direct (i.e., do not require intermediary mechanisms; injury probably occurs as a result of contact between an offending substance and lung tissue).

These categories overlap, since once the lungs are injured, inflammatory responses occur, which may compound the primary mechanism of injury. Three major hypotheses regarding the mechanism of ALI are discussed below. Although discussed separately, they are interrelated.

Role of Infection ALI develops in 20 to 45 percent of patients with severe sepsis.

Increased microvascular permeability to albumin has been shown to accompany human sepsis, and infection and the sepsis syndrome are major causes of ALI in humans. Patients who develop shock in response to known or suspected infection have a particularly high incidence of ALI, and the mortality of patients with ALI associated with infection (i.e., sepsis syndrome) is increased. ALI also appears to predispose the lungs to infection, and delayed infection is an important cause of morbidity in patients who survive the initial lung insult.

The mechanism by which infection and sepsis syndrome injure the lungs is not certain. The lung injury is likely related to factors other than direct damage by bacteria or other microorganisms, since the prognosis appears unrelated to documented bacteremia or pneumonia. In experimental animals, intravenous infusions of live Pseudomonas aeruginosa or endotoxins from Escherichia coli or surgically induced peritonitis result in increased permeability pulmonary edema. Instillation of endotoxin into the airways of sheep also leads to lung inflammation with variable degrees of lung injury. P. aeruginosa produces lung injury in pigs, and E. coli endotoxin administration injures the lungs of baboons and dogs; neutrophilic alveolitis is observed in rats and mice. ALI caused by endotoxin in sheep is thought to be an inflamma-

Acute Respiratory Distress Syndrome: Pathogenesis

tory response mediated, at least in part, by neutrophils and tumor necrosis factor (TNF). Endotoxin may also affect the clotting system and metabolic functions of the lungs, as well as predispose the lungs to development of pulmonary infections by increasing adherence of bacteria to injured endothelium.

Exoproducts of bacteria, such as elastase and Pseudomonas exoenzyme U, also have been shown to injure the lungs.

In addition to a direct role in the pathogenesis of lung injury, bacterial products may also have an indirect role by sensitizing the lungs to the effects of mechanical stretch.

Gram-negative lipopolysaccharide causes an acute inflammatory response in the lungs of humans. Bacterial endotoxin enhances the responses of human alveolar macrophages to positive pressure ventilation; pretreatment of rats with intravenous endotoxin enhances cytokine production in the lungs during mechanical ventilation ex vivo. Furthermore, mechanical ventilation using moderate or large tidal volumes increases the sensitivity of lung macrophages to endotoxin in vitro and the expression of the endotoxin recognition molecule, CD14, on lung cells in vivo. Endotoxin recognition pathways are increased in the lungs of patients with ARDS, and the biologic effects of endotoxin are amplified in the lungs of patients with lung injury. The synergism between bacterial products and mechanical stretch suggests that interrupting these pathways might limit some forms of ALI in humans.

Increased permeability edema is associated with impaired antibacterial defenses. In animal models, bacterial infections worsen ALI. The cause of impaired bacterial defenses in acute ALI is not known. Bactericidal properties of the alveolar lining material might be altered in injured or flooded lungs, and alterations in surfactant concentration and function may be important. Although neutrophils may be present in large numbers in the bronchoalveolar lavage fluid of patients with ALI, evidence indicates that the function of the neutrophils is compromised.

Role of Inflammation Substantial evidence implicates host defenses and inflammatory responses in the underlying mechanism of many ALIs. Neutrophils are a vital component of host defenses, and patients with severe neutropenia are at increased risk of bacterial and fungal infections. On the other hand, neutrophils release toxic oxygen radicals, proteases, and other biologically active mediators that initiate inflammation. Other important cells in pathogenesis include alveolar and pulmonary intravascular macrophages, and eosinophils.

Normally, the pulmonary circulation contains a very large pool of marginated neutrophils that change shape in order to squeeze through the lung capillaries. When neutrophils are activated, they stiffen and become less distensible. These neutrophils are retained for longer periods of time in the pulmonary microcirculation. Endothelial activation leads to increased expression of leukocyte adhesion molecules, providing a second mechanism to slow the transit of neutrophils. Trapped neutrophils respond to chemotactic

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gradients generated by chemokines produced by alveolar macrophages and mesenchymal cells and migrate into the airspaces. Activated neutrophils generate and release toxic substances (e.g., oxygen metabolites and granular constituents, such as proteases, and cationic lysosomal enzymes) that disrupt the function of the microvascular and epithelial barriers. Normally, these barriers limit liquid and protein flow out of the vascular space and into the alveolar spaces, mitigating development of permeability edema.

Inflammatory responses also have the potential to induce lung cell injury by activating cell death pathways, leading to apoptosis. Bacterial products, such as Pseudomonas Exoenzyme U and mechanical stretch, may lead to direct cellular necrosis. Apoptosis is mediated by a family of death receptors, including TNF and Fas receptors. The Fas ligand (FasL) is a 45 kD peptide that is shed from the cell surface by the action of metalloproteinases. Biologically active soluble FasL (sFasL) accumulates in the lungs of patients with ARDS, inducing apoptotic death of human lung epithelial cells in vitro. Human sFasL induces epithelial cell death in the lungs of rabbits; a monoclonal antibody that activates membrane Fas causes alveolar wall apoptosis and fibrosis in the lungs of mice.

Apoptosis and inflammation pathways intersect, as stimulation of membrane Fas induces cytokine production in human macrophages and inflammation in the lungs of rabbits and mice. In addition, lung injury may be able to trigger apoptosis pathways in distant organs, such as the kidney, perhaps by increasing the concentrations of circulating sFasL. Thus, inflammatory responses may trigger cell death pathways, and cell death pathways triggered by sFasL may induce inflammation in the lung alveolar environment. Recent human studies implicate apoptosis in human lung injury.

Role of Direct Toxicity Inflammation is not required for all forms of ALI. ALI or ARDS can develop in neutropenic patients. A clinical trial using granulocyte colony-stimulating factor to increase the number and activation state of circulating neutrophils in patients with severe pneumonia was not associated with an increased incidence of ARDS. Lung injuries that do not require the participation of neutrophils have been described in animal models.

Direct lung injury is also thought to occur in humans.

Putative agents that directly injure the lungs include mechanical forces during mechanical ventilation, toxic and corrosive chemicals and gases (e.g., hydrochloric and other acids, ozone, ammonia, chlorine, phosgene, nitrogen dioxide, the vapors of cadmium and mercury, combustion products, and oxygen, especially at high concentrations), ionizing radiation, aspiration of fresh water (near drowning) or hydrocarbon compounds (e.g., kerosine, gasoline, and dry-cleaning fluid), high temperatures (parenchymal lung burns from fires or explosions), and mechanical injuries (e.g., lung contusion from nonpenetrating chest trauma or blast injury from explosions or lightning). Many of these injuries develop rapidly, support-

ing the idea that injury is caused directly by contact with the respiratory epithelium in the airways and/or alveolar walls.

Inflammatory pathways are likely to be rapidly activated following many types of direct lung injury, as probably occurs following aspiration of gastric secretionsâ&#x20AC;&#x201D;one of the most common clinical causes of ALI. Lung injury occurs rapidly, especially to the epithelium. The injury is probably related, in part, to the low pH of the aspirated stomach contents (aspiration of gastric contents with pH greater than 2.5 is relatively benign; aspiration of gastric contents with pH less than 2.5 causes severe pulmonary injury). Aspirated acid is almost immediately neutralized. However, within hours, proinflammatory mediators are released, the injured lung is infiltrated with neutrophils, fibrin accumulates in the alveolar spaces, and further structural damage is seen on histological examination.

Biologic Markers Considerable interest exists in finding a simple test of blood, urine, or bronchoalveolar lavage fluid that would identify patients at risk for, or in the earliest stages of, ALI, or that might predict clinical outcome.

Although products of complement activation have been proposed as markers, their serum levels correlate poorly with lung injury. Measurement of circulating endotoxin is not appropriately sensitive or specific for the presence or risk of developing lung injury. The same is true for measurements of release or activity of angiotensin-converting enzyme. Von Willebrand factor (VWF) antigen may be useful as a plasma marker of impending ALI in patients with nonpulmonary sepsis. Recent work confirms that VWF levels are elevated in the edema fluid and plasma of patients with ALI and correlate with poor clinical outcomes. While increases in other biochemical and inflammatory markers, including surfactant protein D and interleukin-6, correlate somewhat with lung injury and mortality, no simple biologic marker currently serves in the same diagnostic capacity as do cardiac enzymes in evaluation of suspected acute myocardial infarction.

Because neutrophils are implicated in the mechanism of many lung injuries, their detection in the lungs, assessment of their function, or assay of the toxic metabolites they release might be useful. For example, increased hydrogen peroxide levels have been measured in the breath and urine of patients with ALI, presumably reflecting the presence of oxygen metabolites in the injured lungs. Evidence of increased oxidant activity has been reported in bronchoalveolar lavage fluid in patients with lung injury.

Finally, other mediators of inflammation in ALI have been studied. For example, increased levels of TNF are detected in blood and bronchoalveolar lavage fluid in lung injury, but an association between TNF levels and development of ARDS has not been found. Furthermore, elevated TNF levels are found in patients with severe congestive heart failure. Lipoxygenase products of arachidonic acid metabolism have been detected in pulmonary edema fluid, bronchoalveolar lavage fluid, plasma, and urine, and elastase has been

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Figure 144-2 Multiple cellular responses and mediators contribute to alveolar-capillary membrane injury (righthand side) and the transition from normal alveolar structure and function (left-hand side) in the acute phase of ALI/ARDS. Original investigations of the pathogenesis of ALI/ARDS searched for single mediators that provided final common pathways to inflammation and alveolar edema. Current concepts of pathogenesis involve multiple molecular factors of several classes, a variety of responding cells, and an imbalance between injurious and reparative signals and pathways. See text and Ware & Matthay (2000) and Matthay & Zimmerman (2005). (Reprinted from Matthay MA, Zimmerman GA: Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319â&#x20AC;&#x201C;327, 2005, with permission.)

detected in bronchoalveolar lavage fluid in the setting of lung injury.

ALI follows a wide variety of insults of varying severity. Furthermore, many abnormalities detected in ALI are found in other diverse, severe illnesses that do not involve the lungs. Therefore, the likelihood that any single marker that unequivocally identifies the risk or the presence of ALI will be found seems remote. An investigative focus on particular subgroups of patients with common causes of injury, coupled with study of much larger groups of more definitively diagnosed patients, might prove helpful. An approach that has not received much attention is investigation of the sensitivity and specificity of combinations of biologic markers. The new field of proteomics will expand this type of investigation and, perhaps, identify patterns of protein abnormalities that can be found in plasma, urine, edema fluid, and bronchoalveolar lavage in patients with ARDS.

Figure 144-2 depicts multiple pathways involved in the pathogenesis of ALI and ARDS in the context of normal and injured alveoli. Emphasis is placed on potential pathways for injury across the vascular endothelium and alveolar epithelium.

VENTILATOR-ASSOCIATED LUNG INJURY The most important development of the last 10 years in our understanding of the pathogenesis and treatment of ALI is recognition that the long-standing practice of mechanically ventilating patients with ALI or ARDS using high tidal volumes and airway pressures actually worsens the injury. Animal studies first suggested the potential contributory role of high tidal volumes and elevated airway pressures in the

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pathogenesis of lung injury; subsequently, clinical trials confirmed the findings.

Animal Studies Animal experiments have shown that ventilation using high tidal volumes may increase vascular filtration pressures; produce stress fractures of microvascular endothelium, alveolar epithelium, and basement membranes; and cause lung rupture (so-called ventilation-induced lung injury). The injury appears to be due to increased lung excursions at high volumes (“volutrauma”), rather than the high-airway pressure, per se, since it can be prevented by limiting thoracic motion (e.g., by placing the chest in a cast). The concept of volutrauma was first established in 1974 when investigators found that modestly elevated tidal volumes, especially in the absence of PEEP, caused lung edema in rats. Several years later, additional animal studies further demonstrated the potential injurious role of high tidal volumes and elevated airway pressures, an effect termed ventilator-induced lung injury (VILI).

Subsequent experiments demonstrated that VILI could also induce release of several proinflammatory cytokines, injuring the lung and other organs—a process referred to as “biotrauma.” These animal studies stimulated clinical investigation that revolutionized the care of patients with ALI or ARDS.

Clinical Studies The compelling evidence from animal experiments and small clinical trials prompted clinical studies aimed at testing the potential benefit of lower tidal volumes and reduced airway pressures in management of ALI or ARDS. In a large, multicenter, National Heart Lung and Blood–sponsored trial of 861 patients, mortality was reduced from 40 to 31 percent using a tidal volume of 6 ml/kg/ideal body weight and a limited plateau airway pressure of less than 30 cm H2 O. In this trial, use of small tidal volumes was associated with a lower incidence of nonpulmonary organ failure. The protocol for carrying out the lung protective ventilatory strategy is described in detail in Table 144-1. The results of the trial have transformed the management of patients with ALI or ARDS. A follow-up clinical trial has shown that ventilation using the limited tidal volume and plateau pressure of the original study is associated with an overall reduction of mortality to 26 percent. In the follow-up study, although elevated levels of PEEP did not decrease mortality, the basic lung protective strategy was validated as effective.

The beneficial mechanism underlying the low tidal volume strategy is unclear. An Italian study has shown that use of low tidal volumes in patients with ARDS attenuates the inflammatory response in both lungs and bloodstream, as measured by reductions in neutrophil and cytokine concentrations in bronchoalveolar lavage and cytokines in circulating blood. Other studies have confirmed a number of these findings. In addition, a reduction in alveolar epithelial injury appears likely, based on a decline in plasma surfactant protein

D levels. Additional clinical and experimental studies are underway. A reduction in lung endothelial and epithelial injury, attenuated inflammatory responses, reduced edema formation, and more rapid resolution of lung edema are likely part of the mechanism(s).

RESOLUTION OF ACUTE LUNG INJURY In the last two decades, considerable progress has been made in understanding the mechanisms responsible for resolution of lung edema. More limited progress has been made in understanding the resolution of lung inflammation.

Considerable advances have been made in our understanding of the clearance of fluid and solute from alveoli.

Active sodium and chloride transport across the alveolar and distal airway epithelial barriers into the interstitium drives edema fluid removal from the airspaces. The uninjured alveolar epithelium has a remarkable ability to rapidly clear fluid from the airspaces. Even when mild-to-moderate alveolar injury occurs, salt and water transport capacity is often preserved. In severe injury, when the barrier is disrupted, the capacity to clear edema is lost. The vascular endothelium becomes the limiting barrier between the vascular space and airspace. Clinically, the capacity to remove some alveolar edema fluid (as indicated by increase in edema fluid to plasma protein concentration ratio) in the first 12 hours following ALI is a favorable prognostic finding; the associated mortality rate is only 20 percent. In contrast, an inability to resorb alveolar edema fluid early in the course of injury is associated with a mortality of nearly 80 percent. Thus, the function of the alveolar epithelial barrier early in the course of ALI may be a useful prognostic index, serving as a marker of the severity and extent of injury.

In uninjured, ex vivo human lungs, alveolar fluid clearance is increased by administration of salmeterol. In addition, experimental studies have shown that even in the presence of ALI and alveolar edema, alveolar fluid clearance can be increased pharmacologically (e.g., by catecholamines), thereby representing a potential therapeutic intervention.

Clearance of protein from flooded alveoli is much slower (1 to 2 percent per hour) than clearance of fluid (10 to 20 percent per hour), resulting in an increased concentration of protein in airspaces. If the alveolar edema formed during increased lung vascular permeability clots, its removal from flooded alveoli may be slowed. Clotting may occur because extravasation of plasma into airspaces can lead to clotting system activation by surfactant or macrophage-derived procoagulants.

Most of the interstitial water in pulmonary edema lies in the peribronchovascular loose connective-tissue spaces, rather than in alveolar walls. Because the lymphatic capillaries are arranged to drain only the alveolar wall interstitium, this route for edema removal is not significant for most interstitial edema. A study in goats showed that lung lymph originates mainly from alveolar wall interstitial fluid. The contribution

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Acute Respiratory Distress Syndrome: Pathogenesis

Table 144-1 National Institute of Heart, Lung, and Blood, ARDS Network: Lung Protective Ventilatory Strategy Ventilator mode

Volume assist-control

Tidal volume

≤ 6 ml/kg PBW

Plateau pressure

≤ 30 cmH2 O

Ventilation set rate, pH goal

6–35, adjusted to achieve arterial pH ≥7.30, if possible

Inspiratory flow, I:E

Adjust flow to achieve I:E = 1:1–1:3

Oxygenation goal

55 ≤Pao2 ≤80 mmHg or 88 ≤Spo2 ≤95%

FIO2 /PEEP Combinations Fio2

0.3

0.4

0.4

0.5

0.5

0.6

0.7

0.7

0.7

0.8

0.9

0.9

0.9

1.0

PEEP, cmH2 O

5

5

8

8

10

10

10

12

14

14

14

16

18

18, 22, 24

(Further increases in PEEP to 34 cmH2 O allowed, but not required) Weaning

Attempts to wean by pressure support required when Fio2 /PEEP ≤0.40/8

PBW = predicted body weight Male PBW = 50 + 2.3 [height (inches) − 60] or 50 + 0.91[height (cm) − 152.4] Female PBW = 45.5 + 2.3[height (inches) − 60] or 45.5 + 0.91[height (cm) − 152.4] I:E = ratio of inspiratory to expiratory duration Pao2 = partial pressure of oxygen in arterial blood Spo2 = oxyhemoglobin saturation measured by pulse oximetry Source: Adapted from Acute Respiratory Distress Syndrome Network: Ventilation with low tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000, with permission.

of the lung lymphatic system to clearance of interstitial edema in bronchoalveolar cuffs and interlobular septa is small. The maximum possible contribution by lung lymphatics to clearance of interstitial edema liquid is less than 10 percent, with airway loss of liquid through evaporation occurring at about twice the rate of lymphatic clearance.

In a study of in situ perfused sheep lungs with experimentally induced low- and high-protein pulmonary edema, interstitial liquid was resorbed into the circulation in inverse proportion to its protein concentration. Only a very small fraction of interstitial edema was cleared by the lung lymphatics during recovery from either type of edema.

Some fluid from the loose peribronchovascular interstitium may drain directly into the bloodstream by crossing the walls of blood vessels in the lungs. A study of isolated sheep lungs made edematous by raising vascular pressures

showed that the primary route of edema clearance is by vascular resorption (60 percent of filtered water cleared over 3 hours, including 42 percent by resorption into the bloodstream and 18 percent by lymphatic, pleural, and mediastinal drainage).

Edema may also drain into the pleural space. Pleural effusions are more common in increased pressure pulmonary edema (25 to 50 percent of patients; usually on the right if unilateral). However, they occur in ALI as well (35 percent of patients). As much as 25 to 30 percent of edema fluid may leave the lungs through the pleural space. A significant portion of the interstitial edema probably follows the prevailing pressure gradient in the lungs to drain into the mediastinum, where it may be picked up by the lymphatics.

Short-term alveolar protein clearance appears to proceed primarily by paracellular diffusion. The process depends

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on the size of the proteins. Most proteins are cleared intact, rather than as degraded, smaller fragments. However, a few specific proteins (e.g., vasoactive intestinal peptide and gastrin) are degraded before being cleared.

Receptor-mediated clearance may play a role. An albumin-binding protein (albondin) is expressed on lung microvascular endothelial cells. An antibody to this protein reacts with cellular proteins of alveolar epithelial cells, which also appear to have albondinlike binding sites for albumin.

In addition, a polymeric immunoglobulin receptor has been described. The significance of these receptors in protein clearance is, however, unclear.

Finally, the general consensus is that transcytosis (transport via vesicles) is not a major mechanism for clearing bulk quantities of albumin or other proteins from the alveolar space. Over the long term, phagocytosis and catabolism by macrophages account for most protein clearance from the alveolar spaces. All insoluble, precipitated proteins are removed in this way. Macrophages are also ultimately responsible for removing senescent and dead neutrophils and other debris. The presence of a small, ciliated surface area of the distal airspaces suggests that the mucociliary route accounts for only a minor fraction of alveolar protein clearance. Complete clearance of alveolar protein from pulmonary edema by any route is slow.

Little is known about the mechanisms and signals that regulate endothelial barrier function or how increased endothelial permeability is returned to normal.

CONCLUSIONS Among the major advances in respiratory medicine and physiology over the last three decades has been the acquisition of important new knowledge on the physiology of fluid, solute, and protein transport in healthy and diseased lungs.

Pulmonary edema, defined as the abnormal accumulation of extravascular lung fluid, is a pathological state that occurs when fluid is filtered into the lungs faster than it can be removed.

The many causes of pulmonary edema are grouped into two main pathophysiological categories: (1) increased pressure edema, which results from an increase in hydrostatic or osmotic forces (or both) that act across the barriers that normally restrict movement of fluid and solutes in the lungs; and (2) increased permeability edema, which is seen in ALI in which a breakdown of the normal barrier properties of lung endothelium or epithelium develops. Although these two different types of pulmonary edema share many features, usually they can be distinguished by careful clinical, radiological, and physiological evaluation. They also differ in treatment and prognosis.

Major advances in the treatment of ALI have occurred because of the successful application of lung protective ventilatory strategies early in the course of the illness (Table 144-1).

A low tidal volume (6 ml/kg/ideal body weight), coupled with a plateau pressure limit (less than 30 cm H2 O) has resulted in the first therapy demonstrated to reduce mortality in patients with ALI. Recently, the National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network published the results of the Fluid and Catheter Treatment Trial (FACTT), a large randomized trial comparing a liberal fluid management strategy to a conservative fluid management strategy in patients with ALI. Patients were also randomized to receive either a pulmonary arterial catheter or a central venous catheter for monitoring and fluid management. There were no differences in clinical outcomes between the pulmonary or central venous catheter utilization. In contrast, there was a marked difference in outcome between the liberal and the conservative fluid management arms of the study. Patients in the conservative fluid management arm had 2.5 more ventilator-free days than those in the liberal fluid management arm with concordant improvements in pulmonary physiology. There was also a 2.9 percent reduction in the 60day mortality rate in the conservative fluid management arm compared with the liberal fluid management arm, although this difference did not reach statistical significance.

New insights into the pathogenesis of ALI suggest that other therapies may also prove to be efficacious in reducing mortality in this common form of severe acute respiratory failure. A major development has been the ability to conduct large, prospective, randomized, clinical trials (e.g., those sponsored by the National Heart, Lung, and Blood Institute) to test a variety of therapies important in supportive patient care, including use of mechanical ventilation, intravenous fluids, and a variety of pharmacologic agents. Such trials have led to a better understanding of the pathogenesis of human ALI and have confirmed the importance of ventilator-associated lung injury. In addition, ancillary pathogenetic studies carried out on biologic samples from clinical trials have advanced our understanding of underlying mechanisms. In the future, additional human studies will be needed to explore new therapeutic strategies suggested by basic investigation conducted in animal models of ALI.

SUGGESTED READING Albertine K, Soulier MF, Wang Z, et al: Fas and Fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 161:1783â&#x20AC;&#x201C;1796, 2002.

The ARDS Network: A trial of mechanical ventilation with higher versus lower positive end-expiratory pressures in patients with acute lung injury and acute respiratory distress syndrome. N Engl J Med 351:327â&#x20AC;&#x201C;336, 2004.

The ARDS Network: Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564â&#x20AC;&#x201C; 2575, 2006.

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The ARDS Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000.

Dos Santos CC, Slutsky AS: Invited review: Mechanisms of ventilator-induced lung injury: A perspective. J Appl Physiol 89:1645–1655, 2000.

Dreyfuss D, Saumon G: Ventilator-induced lung injury: Lessons from experimental studies. Am J Respir Crit Care Med 157:294–323, 1998.

Eisner M, Parsons P, Matthay MA, et al and The ARDS Network: Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 58:983– 988, 2003.

Hastings R, Folkesson HG, Matthay MA: Mechanisms of alveolar protein clearance in the intact lung. Am J Physiol Lung Cell Mol Physiol 286:L679–L689, 2004.

Hirsch J, Hansen KC, Burlingame AL, et al: Proteomics: Current techniques and potential applications to lung disease. Am J Physiol Lung Cell Mol Physiol 287:L1–23, 2004.

Imai Y, Parodo J, Kajikawa O, et al: Injurious mechanical ventilation and end-organ epithelial cell apoptosis and organ dysfunction in an experimental model of acute respiratory distress syndrome. JAMA 289:2104–2112, 2003.

Lum H, Malik AB: Regulation of vascular endothelial barrier function. Am J Physiol 267:L223–L241, 1994.

Matthay MA, Folkesson HG, Clerici C: Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 82:569–600, 2002.

Matthay MA, Martin TR: Pulmonary edema and acute lung injury, in Murray JF, Nadel JA (eds), Textbook of Respiratory Medicine, 4th ed, Vol 1. Philadelphia, Elsevier Saunders, 2005, pp 322–329.

Acute Respiratory Distress Syndrome: Pathogenesis

Matthay MA, Zimmerman GA. Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319–327, 2005.

Matute-Bello G, Winn RK, Jonas M, et al: Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: Implications for acute pulmonary inflammation. Am J Pathol 158:153–161, 2001.

Nelson S, Belknap SM, Carlson RW, et al: A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with communityacquired pneumonia. J Infect Dis 178:1075–1080, 1998.

Nuckton TJ, Alonso JA, Kallet RH, et al: Pulmonary deadspace fraction as a risk factor for death in the acute respiratory distress syndrome. N Engl J Med 346:1281–1286, 2002.

Ranieri VM, Suter PM, Tortorella C, et al: Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: A randomized controlled trial. JAMA 282:54–61, 1999.

Robbins I, Newman JH, Brigham KL: Increased-permeability pulmonary edema from sepsis/endotoxin, in Matthay M, Ingbar, DH (eds), Pulmonary Edema. New York, Marcel Dekker, 1998, pp 203–245.

Sakuma T, Folkesson HG, Suzuki S, et al: Beta-adrenergic agonist stimulated alveolar fluid clearance in ex vivo human and rat lungs. Am J Respir Crit Care Med 155:506–512, 1997.

Ware LB, Matthay MA: Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med 163:1376–1383, 2001.

Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342:1334–1349, 2000.

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145 Acute Lung Injury and the Acute Respiratory Distress Syndrome: Clinical Features, Management, and Outcomes Jason D. Christie

Paul N. Lanken

I. DESCRIPTION AND DEFINITIONS Consensus Definitions of ALI and ARDS Limitations of Consensus Definitions II. EPIDEMIOLOGY Incidence and Mortality Rate Factors Influencing Risk of ALI and ARDS Factors Influencing Mortality from ALI and ARDS III. CLINICAL PRESENTATION AND DIAGNOSIS Path ology and Pathophysiology Clinical Presentation Differential Diagnosis Approach to Clinical Diagnosis

DESCRIPTION AND DEFINITIONS In 1967, Ashbaugh and co-authors described a syndrome characterized by the acute onset of dyspnea, severe hypoxemia, diffuse lung infiltrates, and decreased respiratory system compliance in the absence of evidence for congestive heart failure. The syndrome, initially called acute respiratory distress in adults (to contrast it with acute respiratory distress in neonates), is now known as the acute respiratory distress syndrome (ARDS). Following the initial report, other authors utilized various definitions that incorporated elements related to time of onset, presence of hypoxemia and radiographic infiltrates, and absence of overt congestive heart failure.

In 1988, Murray and others introduced the Lung Injury Score (LIS), an assessment tool for ARDS that reflects the extent of radiographic infiltrates, severity of hypoxemia

IV. APPROACH TO TREATMENT Goals of Management Diagnosis and Treatment of Precipitating Causes and Other Comorbidities Management of Respiratory Failure V. CLINICAL COURSE, OUTCOME, AND LONG-TERM SEQUELAE Clinical Course and Duration Trends in Mortality Rates Causes of Death Long-Term Sequelae

and reduced respiratory system compliance, and level of positive end expiratory pressure (PEEP) used in mechanically ventilating affected patients. The LIS incorporates these four parameters that are graded on a scale of 0 to 4: (1) the ratio of PaO2 to FiO2 (PaO2 / FiO2 ); (2) total respiratory compliance; (3) level of PEEP; and (4) extent of radiographic infiltrates (assessed by noting the number of quadrants in the chest radiograph containing infiltrates). The LIS equals the sum of the scores for the four variables divided by four. In clinical studies, a score of 2.5 or more is generally used as a threshold for severe disease.

Consensus Definitions of Acute Lung Injury and Acute Respiratory Distress Syndrome Prior to 1994, published studies used non-uniform definitions of ARDS, prompting an American European Consensus

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 145-1 American European Consensus Conference Criteria for Acute Lung Injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) Clinical Variable

Criteria for Acute Lung Injury

Criteria for Acute Respiratory Distress Syndrome

Onset

Acute

Acute

Hypoxemia

PaO2 /FiO2 ≤ 300mm Hg

PaO2 /FiO2 ≤ 200 mmHg

Chest radiograph

Bilateral infiltrates consistent with pulmonary edema

Bilateral infiltrates consistent with pulmonary edema

Noncardiac cause

No clinical evidence of left atrial hypertension or, if measured, pulmonary artery occlusion pressure ≤ 18mmHg

No clinical evidence of left atrial hypertension or, if measured, pulmonary artery occlusion pressure ≤ 18 mmHg

Source: Bernard GR, Artigas A, Brigham KL, et al: The American-European Consensus Conference of ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818, 1994.

Conference (AECC) to develop standardized definitions for ARDS and acute lung injury (ALI): a broader category that encompasses ARDS. The AECC definitions included the acute onset of illness, bilateral chest radiographic infiltrates consistent with pulmonary edema, poor systemic oxygenation, and absence of evidence for left atrial hypertension (Table 145-1). The syndrome is ALI when the ratio of PaO2 to FiO2 (PaO2 /FiO2 ) is less than or equal to 300 and ARDS when the ratio is less than or equal to 200.

The AECC coined the term ALI to facilitate diagnosing patients earlier in the course of their ARDS and identify patients who have a milder form of acute hypoxemic respiratory failure than ARDS. The AECC definitions of ALI and ARDS are intentionally broad in order to encompass different types of acute hypoxemic respiratory failure occurring in a wide variety of settings. Most patients with ALI progress to ARDS, prompting some to use the composite abbreviation ALI/ARDS to describe all patients with a PaO2 /FiO2 less than or equal to 300 who meet the other AECC criteria (Table 145-1).

Limitations of Consensus Definitions Despite standardization of definitions of ALI and ARDS, little data are available to support their reliability and validity.

In fact, various components of the definitions remain problematic: (1) The chest radiograph is subject to variability in interpretation; (2) PaO2 /FiO2 may vary according to ventilator parameters, e.g., PEEP, and at extremes of FiO2 ; and (3) accuracy in excluding the presence of heart failure may be influenced by measurement methodology and timing, as discussed below.

Although interpretation of chest radiographs can be inaccurate and variable among observers, formal training can reduce variability.

The PaO2 /FiO2 criterion is influenced by the level of PEEP and other transient factors, including the presence or absence of airway secretions or inadequate sedation. Increasing PEEP generally increases PaO2 at a given FiO2 . The consequent increase in PaO2 /FiO2 may result in a ratio that no longer meets inclusion criteria for ALI. Conversely, without any PEEP, values of PaO2 /FiO2 less than 300 may reflect simple atelectasis rather than ALI or ARDS. Adding PEEP may recruit sufficient atelectatic lung to raise PaO2 /FiO2 greater than 300, thereby excluding such patients from meeting this criterion for ALI. Finally, diagnostic criteria for left atrial hypertension on purely clinical grounds may be inaccurate. Use of a pulmonary artery catheter may also be inconclusive, since the pulmonary artery occlusion pressure (PAOP) in ALI/ARDS may be higher than 18 mm Hg due to intravascular volume loading, particularly in the setting of goal-directed management paradigms for sepsis (see Chapter 146). Conversely, some patients with pulmonary edema due to congestive heart failure and high left atrial pressures have normal pulmonary artery occlusion pressures by the time the catheter is inserted and PAOP is measured.

Several clinical trials have used the aforementioned standardized definitions of ALI and ARDS to specify study inclusion criteria for their study populations. Using the AECC definitions of ALI and ARDS in clinical trials that have shown therapeutic benefit adds important validity to the definitions.

Clinicians can generalize the results of these trials to clinical decisions involving their own patients if they meet the same criteria for ALI or ARDS as used in the clinical trial. Further refinement of the reliability and validity of definitions of ALI and ARDS are important future directions for clinical studies. More reliable definitions will not only improve estimates of the public health impact of these syndromes, but also will decrease misclassification errors that can be especially

2537 Chapter 145

problematic for research aimed at clarifying mechanisms in ALI and ARDS, e.g., genetic epidemiological studies.

EPIDEMIOLOGY Over the last several decades, the epidemiology of ALI and ARDS has become more clearly delineated.

Incidence and Mortality Rate A landmark epidemiologic study of the incidence of ALI and ARDS in the United States between 1999 and 2000—the King County Lung Injury Project (conducted in King County, Washington)—represents the first broad, population-based epidemiological study of ALI and ARDS in the United States using standardized definitions. Study results included an estimated incidence of ALI of 78.9 per 100,000 person-years and an age-adjusted incidence of 86.2 per 100,000 personyears. The incidence of ARDS was estimated as 58.7 per 100,000 person-years with an age-adjusted incidence of 64.0 per 100,000 person-years. The incidence of ALI increased dramatically with age, with an incidence of 306 per 100,000 person-years for ages 75 through 84 years. By extrapolation, an estimated 190,600 cases of ALI and 141,500 cases of ARDS occur each year in the United States (Table 145-2).

Although prior estimates of the incidence of ALI and ARDS had been lower, those studies were limited by incomplete and nonvalidated data, inaccuracies in the definition of the syndromes, and use of administrative coding. Thus, the estimates from King County Lung Injury Project serve as the best indicator of the public health impact of ALI and ARDS in the United States.

During the time of observation in the King County Lung Injury Project study, the mortality from ALI was 38.5 percent and from ARDS was 41.1 percent. These figures translate into an estimated 74,500 annual deaths from ALI in the United States. To put this mortality rate in perspective, more people die annually from ALI than from AIDS, asthma, and breast cancer combined. Other than lung cancer, ALI is responsible for more annual deaths than any cause of cancer, including lymphomas, leukemias, and breast, prostate, colon, ovarian, and pancreatic cancers (Table 145-3). Although the mortality rates from ALI and ARDS may have fallen since the King County Lung Injury Project was conducted in 1999– 2000 (due to usage of low tidal volume ventilation strategies), ALI and ARDS likely still have a major public health impact.

Table 145-3 Estimated Annual Number of Deaths in the US from Selected Causes

Table 145-2

Cause

Estimated Incidence, Hospital Days and Intensive Care Unit (ICU) Days for Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) in the United States (US)

ALI∗

74,500

ARDS

59,000

Variable

ALI

ARDS

Crude incidence, per 100,000 person-years

78.9

58.7

Age-adjusted incidence, per 100,000 Person-years

86.2

64.0

Estimated annual Number of cases in US

190,600

Estimated annual number of hospital days in US

3,622,00

Estimated annual number of days in ICU in US

2,154,000

141,500

2,746,000

1,642,000

From Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005.

ALI and ARDS

Asthma

Number of Deaths

4,621

AIDS

18,017

Breast cancer

40,870

Leukemia

22,570

Lung cancer

163,510

Lymphoma

20,610

Ovarian cancer

16,210

Pancreatic cancer

31,800

Prostate cancer

30,350

∗ Includes

59,000 deaths from ARDS. Source: Data for ALI and ARDS are from Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005; all other are from CDC National Center for Health Statistics (http://www.cdc.gov/nchs/).

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Furthermore, as the population of the United States becomes older, the incidence of ALI and its associated annual death rate can be expected to rise.

Precipitating Causes The severe extensive lung inflammation in ALI and ARDS represents the common final pathogenetic process in response to a large variety of precipitating causes, which result in either direct or indirect (systemic) lung injury. In general, direct causes of ALI include those that originate within the lung, such as aspiration of gastric contents or viral pneumonia. Examples of indirect causes include severe systemic inflammatory response syndrome (SIRS) or severe sepsis, ingested toxins, hypotension, and ischemia-reperfusion injury. Although some causes of ALI may fit into either category (e.g., multilobar pneumonia with septic shock), the classification scheme is useful both for considering the many predisposing causes of ALI and their varying mechanisms of lung injury and for future development of therapies aimed at different categories of ALI. Table 145-4 lists precipitating causes of ALI and ARDS according to this construct.

Factors Influencing Risk of ALI and ARDS Not all patients with an underlying cause (e.g., sepsis) for ALI or ARDS develop the syndrome. In addition to inherent risk differences within at-risk populations, specific clinical variables may be important.

Clinical variables found to be associated with an increased risk of ARDS include chronic alcohol abuse, hypoproteinemia, advanced age, increased severity, and extent of injury or illness as measured by injury severity score (ISS) or APACHE score, hypertransfusion of blood products, and possibly, cigarette smoking. Diabetes mellitus decreases the risk of ALI. Since many of the studies addressing this issue are retrospective or based on a single center’s experience, the consistency and generalizability of identified risk factors have not been confirmed. Nonetheless, the mechanistic underpinnings of these probable associations are the subject of ongoing research.

Factors Influencing Mortality from ALI and ARDS Clinical variables at the onset of ALI and ARDS that are associated with increased mortality include advanced age, lower PaO2 /FiO2 , high plateau pressure (i.e., low respiratory system compliance), greater extent of pulmonary infiltrates, chronic liver disease, nonpulmonary organ dysfunction, increased global severity of illness, hypoproteinemia, and greater length of hospitalization prior to onset of ALI/ARDS. In addition, an increased dead space fraction has been identified as a risk factor for increased mortality, possibly indicating the importance of early loss of the pulmonary vascular bed as a sign of greater disease severity. Although various precipitating causes of ALI and ARDS carry somewhat different prognoses,

Table 145-4 Common Direct and Indirect (Systemic) Precipitating Causes of ALI and ARDS Direct Precipitating Cause

Indirect (Systemic) Precipitating Cause∗

Aspiration of gastric fluids

Acute pancreatitis

Bacterial pneumonia (diffuse), e.g., Legionnaire’s disease

Blood transfusions with transfusion-related acute lung injury (TRALI)

Chest trauma with lung contusion

Post-cardiopulmonary bypass

Near-drowning

Primary graft failure of lung transplantation

Pneumonia due to Pneumocystis carinii

Severe sepsis and septic shock

Toxic inhalations, e.g., smoke inhalation, inhaled crack cocaine

Toxic ingestions, e.g., aspirin, tricyclic antidepressants

Viral pneumonia, e.g., influenza, severe acute respiratory syndrome (SARS)

Trauma with multiple fractures and the fat-emboli syndrome

∗ In

indirect or systemic mechanism of lung injury, the lung injury results from deleterious effects on the alveolar epithelium by inflammatory or other mediators delivered via the pulmonary circulation (see Chapters 144 and 146 Matthay Deutschman for details).

Source: Christie JC, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds): Principles of Critical Care, 3d ed. New York, McGraw-Hill, 2005; p 518, reproduced with permission.

the strategy of low tidal volume ventilation utilized by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI)–sponsored ARDS Clinical Trials Network (ARDSNet) as part of its clinical trials appears to be equally efficacious in all subgroups.

CLINICAL PRESENTATION AND DIAGNOSIS The clinical presentation and diagnosis of ALI/ARDS are fundamentally related to the syndrome’s pathophysiological changes, regardless of the underlying etiology. A brief description of the pathology and pathophysiology is provided before a detailed discussion of clinical aspects of the disorder. The reader is also referred to Chapter 144 for additional details on disease mechanisms.

2539 Chapter 145

Pathology and Pathophysiology

100% O2

A number of inter-related mechanisms contribute to the development and clinical course of ALI and ARDS. Inflammatory cytokines, oxygen radicals, activation of coagulation and complement, platelet and immune cell activation, generation of proteases, and abnormal fluid fluxes resulting in edema fluid generation and defective epithelial alveolar fluid clearance have all been hypothesized to play a role in the early stages. In addition, factors specific to apoptosis, edema fluid resolution, and fibrosis and repair, as well as the response to mechanical ventilation are likely to play a role in the pathophysiology of the later phases of ALI and ARDS. Pathologically and clinically, ALI can be divided into early and late phases of lung injury (Fig. 145-1). In the early phase (first few hours or days), light microscopy shows interstitial and alveolar edema, capillary congestion, and intraalveolar hemorrhage with minimal evidence of cellular injury. Electron microscopy reveals changes of endothelial cell swelling, widening of intercellular junctions, increased numbers of pinocytotic vesicles, and disruption and denudation of the basement membrane. Inflammatory cell infiltration of the lung interstitium may also be seen. Protein-rich pulmonary edema and its clinical effects are most pronounced in the early exudative phase. Hyaline membranes containing condensed fibrin and plasma proteins form over the next several days. Later in the exudative phase, inflammatory cells become more numerous within the lung interstitium, and extensive necrosis of type I alveolar epithelial cells is present.

EXUDATIVE STAGE Edema

FRACTION OF MAXIMUM

1.5

Hyaline Membranes

PROLIFERATIVE STAGE Interstitial Inflammation

Interstitial Fidrosis.

0.5

0

1

ALI and ARDS

2 3 4 5 6 7 8 9 10 11 12 13 14 TIME FOLLOWING INJURY (DAYS)

Figure 145-1 Schematic representation showing time course of evolution of the acute respiratory distress syndrome (ARDS).

The early or exudative phase is characterized by a pulmonary capillary leak with interstitial and alveolar edema and hemorrhage followed by hyaline membrane formation. Within as short a period of time as 7 to 10 days, a proliferative phase may appear with marked interstitial and alveolar inflammation and cellular proliferation, followed by fibrosis and disordered healing (see text for discussion). (Reproduced with permission from Katzenstein AA, Askin FB: Surgical Pathology of Non-Neoplastic Lung Diseases, 2nd ed. Philadelphia, Saunders, 1990.)

PA O2 =650 Pvo2 = 40 mmHg Cvo = 15 ml % 2 CCO = 22 ml% 2

CaO2= 18.5 ml% PaO2= 60 mm Hg

Figure 145-2 Diagram of a two-compartment model of lung perfusion and ventilation demonstrating basis for failure of oxygenation in ALI and ARDS. When large portions of the lung are nonventilated due to alveolar collapse or flooding (hatched area), blood flow to these units with mixed venous PO2 (P¯vO2 ) of 40 mmHg and content of 15 vol percent is effectively ‘‘shunted” through the lungs without being resaturated. Thus, despite a high concentration of supplemental oxygen (100 percent in this example) and high alveolar PO2 in ventilated unit, these blood flows mix in accord with their oxygen contents, i.e., the resulting left atrial blood has an oxygen content that is the weighted mean of the oxygen content of the shunted and non-shunted blood. In this example of a 50 percent shunt, the left atrial and systemic arteries have an arterial PO2 of 60 mmHg. CaO2 = arterial oxygen content; CCO2 = capillary oxygen content; C¯vO2 = mixed venous oxygen content; PA = alveolar pressure; PaO2 = arterial PO2 ; P v¯ O2 = partial pressure of oxygen in the mixed venous blood. (Reproduced with permission Christie JD, Lanken PN: Acute Lung Injury and The Acute Respiratory Distress Syndrome, in Hall JB, Schmidt GA, Wood LDH (eds.): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2005; p 516.)

Pathologists refer to this constellation of findings as diffuse alveolar damage (DAD).

Pathophysiologically, in the exudative phase, alveolar edema and alveolar collapse, i.e., atelectasis due to loss of normal surfactant-related stabilization of alveoli, interfere with oxygenation. Surfactant is both washed out of alveoli and inactivated by the alveolar edema. The hypoxemia in ALI/ARDS is typically resistant to supplementary oxygen, reflecting an increased right-to-left shunt (Fig. 145-2). Continued perfusion of alveoli that lack ventilation because of alveolar edema ˙ Q) ˙ ratios of zero, thereby results in ventilation-perfusion (V/ defining physiological shunt. Furthermore, the effects of this type of shunt are exacerbated by shuntlike contributions from alveoli with very low ventilation-perfusion ratios.

Disordered healing and proliferation of fibrous tissue dominate the late phase of ARDS or persistent ARDS, i.e., the proliferative or fibroproliferative phase. Type II alveolar cells, fibroblasts, and myofibroblasts proliferate in this phase, which can occur as early as 7 to 10 days after initial injury.

The late phase of ARDS is characterized by an increased dead space fraction, high minute ventilation requirement,

2540 Part XVII

Acute Respiratory Failure

pulmonary hypertension, and further reduction in lung compliance.

Table 145-5

Clinical Presentation

Differential Diagnosis of Acute Hypoxemic Respiratory Failure (AHRF)

The development of ALI and ARDS usually follows a rapid course, occurring most often within 12 to 48 hours of the predisposing event. At its onset, patients with ALI and ARDS often become anxious, agitated, and dyspneic. Inflammatory changes in the lung decrease lung compliance, which, in turn, leads to an increased work of breathing, small tidal volumes, and tachypnea. Marked tachypnea and dyspnea are invariably present in subjects with ALI. If breathing ambient air or lowflow supplementary oxygen, patients with ALI typically have initial arterial blood gas results showing a PaO2 less than 50 to 55 mm Hg and pulse oximetry recordings of less than 85 percent arterial O2 saturation. The hallmark of ALI and ARDS is hypoxemia that is resistant to oxygen therapy because of the large right-to-left shunt (Fig. 145-2).

Initially, patients may be able to compensate by hyperventilating, thereby maintaining an acceptable PaO2 with an acute respiratory alkalosis. Typically, patients deteriorate over several hours, requiring endotracheal intubation and mechanical ventilation. However, the need for mechanical ventilation is not necessary for establishing the diagnosis of ALI or ARDS. Selected patients with milder lung injury and a normal level of consciousness can be treated successfully with high-flow oxygen therapy, with or without a continuous positive airway pressure (CPAP) mask, or noninvasive assisted ventilation.

Differential Diagnosis The differential diagnoses for acute hypoxemic respiratory failure, in general (Table 145-5), and for ALI and ARDS, in particular (Table 145-6), are extensive. Identifying the specific etiology of the diffuse infiltrates in ALI or ARDS is important because several, e.g., acute eosinophilic pneumonia or diffuse alveolar hemorrhage, have specific therapies. Table 145-6 lists the major clinical and diagnostic characteristics of these disorders.

The setting in which respiratory failure occurs usually provides important diagnostic information. ALI and ARDS commonly arise following development of a typical predisposing factor (Table 145-4). Sepsis, pneumonia, trauma, transfusion of blood products, and gastric aspiration account for the majority of cases.

When an inciting event is obvious and diagnostic criteria (Table 145-1) are met, establishment of a clinical diagnosis of ALI or ARDS is not difficult. Under such circumstances, management can be instituted immediately. However, in the absence of a clear predisposing event, or when conflicting or ambiguous information exists, the other causes listed in Table 145-6 should be considered and relevant clues from the history and physical examination sought. For example, cardiogenic edema is most often accompanied by systolic left ventricular or valvular dysfunction, and the appropriate

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

ALI or ARDS Acute (or “flash”) cardiogenic pulmonary edema Bilateral aspiration pneumonia Lobar atelectasis of both lower lobes Severe unilateral lower lobe atelectasis, especially when patient is receiving vasodilators, such as intravenous nitrates, calcium-channel blockers, or sodium nitroprusside, that blunt hypoxic vasoconstriction Acute loss of ventilation to one lung due to complete or near-complete obstruction of its mainstem bronchus, e.g., due to a mucus plug or blood clot Loss of ventilation to one or both lungs due to large pneumothorax/pneumothoraces Loss of ventilation to one or both lungs due to large pleural effusion(s) Diffuse alveolar hemorrhage, especially in patients post–bone marrow transplantation Massive pulmonary embolus Acute opening of a patent foramen ovale in patient with preexisting pulmonary hypertension

Abbreviations: ALI = acute lung injury; ARDS = acute respiratory distress syndrome.

Source: Christie JD, Schmidt G, Lanken PN: Acute respiratory distress syndrome: http://pier.acponline.org/physicians/diseases/d349/ d349.html, July 2004. Physicians’ Information and Education Resource.

Philadelphia, American College of Physicians, reproduced with permission.

history and physical findings (e.g., a heart murmur or ventricular gallop) are often present. Electrocardiographic and laboratory-based evidence (e.g., serum troponin I levels) of cardiac ischemia suggest cardiogenic edema as a likely cause.

Additional important tests that help to differentiate ALI and ARDS from other causes of acute hypoxemic respiratory failure are discussed below.

Approach to Clinical Diagnosis A number of diagnostic methods are extremely valuable in evaluating suspected ALI or ARDS. Each is briefly described below.

Chest Radiograph The chest radiograph is a simple and widely available test used to assess patients with acute hypoxic respiratory failure.

In cases of established ALI or ARDS, the chest radiograph typically demonstrates findings of diffuse, bilateral alveolar infiltrates consistent with pulmonary edema (Fig. 145-3).

However, especially early in the course of the disorder, the infiltrates associated with ALI and ARDS may be variable: mild or dense, interstitial or alveolar, patchy or confluent.

2541 Chapter 145

ALI and ARDS

Table 145-6 Differential Diagnosis of ALI and ARDS Disorder

Characteristics

Comments

Pulmonary edema due to left heart failure.

History of cardiac disease, enlarged heart on chest radiograph, third heart sound.

Rapid improvement with diuresis and/or afterload reduction.

Noncardiogenic pulmonary edema

History of one or more precipitating causes (Table 145-4), crackles absent or not prominent, normal cardiac size on chest radiograph.

Usual etiology for ALI and ARDS. Rarely some patients with ALI or ARDS have no obvious precipitating cause.

Diffuse alveolar hemorrhage (DAH)

Often associated with autoimmune diseases (e.g., vasculitis) or following bone marrow transplantation. Often patients do not have bloody sputum. Renal disease or other evidence of systemic vasculitis may be present. Hemosiderin-laden macrophages in bronchoalveolar lavage fluid can confirm diagnosis of DAH. May respond to apheresis, corticosteroids, or cyclophosphamide, depending on etiology.

May meet diagnostic criteria for ARDS (Table 145-1), but has different pathophysiology and management.

Acute eosinophilic pneumonia

Cough, fever, pleuritic chest pain, and myalgia are often present. Patients often do not have peripheral blood eosinophilia, but generally have greater than 15% eosinophils in bronchoalveolar lavage fluid. Usually responds rapidly to high-dose corticosteroid therapy.

May meet diagnostic criteria for ARDS (Table 145-1), but has diffeent pathophysiology and management.

Lupus pneumonitis

Usually associated with active lupus. May respond to high-dose corticosteroid therapy or cyclophosphamide

May meet diagnostic criteria for ARDS, but has different pathophysiology and management.

Acute interstitial pneumonia (AIP)

Slower onset than ARDS (over 4–6 weeks) with progressive course. However it may present in advanced state, mimicking ARDS.

Associated with >90% mortality. AIP includes Hamman-Rich syndrome.

Pulmonary alveolar proteinosis (PAP)

Slower onset than ARDS (over 2–12 months) with progressive course. Can be treated with whole lung lavage.

Characteristic “crazy paving” pattern on high-resolution CT scan of chest.

Bronchiolitis obliterans with organizing pneumonia (BOOP) or cryptogenic organizing pneumonia

May be precipitated by viral syndrome. Slower onset than ARDS (over >2 weeks) with progressive course. However it may present in advanced state, mimicking ARDS. May respond to high-dose corticosteroid therapy.

(Continued )

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Acute Respiratory Failure

Table 145-6 (Continued ) Disorder

Characteristics

Comments

Hypersensitivity pneumonitis

Typically slower onset than ARDS (over weeks) with progressive course. However, it may present in advanced state, mimicking ARDS. May respond to high-dose corticosteroid therapy and removal from offending agent.

Leukemic infiltration

May be rapid in onset during active disease states. Usually leukemia is clinically apparent.

Drug-induced pulmonary edema and pneumonitis

May follow use of heroin, other opioids, overdose of aspirin, tricyclic antidepressants, or exposure to paraquat.

May progress to overt ARDS.

Acute major pulmonary embolus (PE)

Occurs acutely, occasionally accompanied by severe hypoxemia that may be resistant to O2 therapy like ARDS, and by hypotension, requiring pressors, mimicking ARDS with sepsis. Patients typically have risk factors for acute PE and may not have common precipitating causes of ARDS.

Chest radiograph in ARDS should have bilateral infiltrates consistent with pulmonary edema. Chest radiograph in acute major PE may have unilateral or no infiltrates. Acute major PE needs a confirmatory study, e.g., CT scan with pulmonary embolism protocol.

Sarcoidosis

The onset is not acute, but its clinical recognition may be. Oxygenation is often impaired and the chest radiograph can be diffusely abnormal.

Historical features and the frequent presence of hilar adenopathy in sarcoidosis usually eliminate confusion with ARDS.

Interstitial pulmonary fibrosis

The onset is not acute, but its clinical recognition may be. Oxygenation is often impaired and the chest radiograph can be diffusely abnormal.

Prior chest radiographs and a history of chronic and progressive dyspnea characterize the collection of diseases causing interstitial pulmonary fibrosis.

Abbreviations: AIP = acute interstitial pneumonia; ARDS = acute respiratory distress syndrome; CT = computed tomography; DAH = diffuse alveolar hemorrhage.

Source: Christie JD, Schmidt G, Lanken PN: Acute respiratory distress syndrome. http://pier.acponline.org/physicians/diseases/d349/d349.html, July 2004.

Physicians’ Information and Education Resource. Philadelphia, American College of Physicians, reproduced with permission.

In addition, the radiographic infiltrates may not correlate well with the degree of hypoxemia. For example, a patient with early ALI and ARDS may have profound hypoxemia in the setting of patchy asymmetrical infiltrates that may be interpreted as pneumonia or segmental atelectasis. Routine chest radiographs cannot reliably distinguish hydrostatic edema, i.e., cardiogenic edema, from ALI and ARDS. Nonetheless, several criteria suggest cardiogenic edema: increased heart size, increased width of the vascular pedicle, vascular redistribution toward upper lobes, the presence of septal lines, or a perihilar (“bat’s wing”) distribution of the edema. Lack of these findings, in conjunction with patchy peripheral infiltrates that extend to the lateral lung margins, suggests ALI

or ARDS. In the proper clinical setting, despite a variable radiographic appearance, the presence of bilateral infiltrates and moderate or severe hypoxemia (PaO2 /FiO2 less than or equal to 300 mmHg) should raise the possibility of ALI or ARDS. Laboratory Studies Although no laboratory test is specific for the diagnosis of ARDS, arterial blood gas analysis is essential for confirming the diagnosis of ALI or ARDS. PaO2 /FiO2 is markedly abnormal in patients with ALI and ARDS (Table 145-1). In addition to the profound oxygen therapy–resistant hypoxemia that is the hallmark of ALI and ARDS, acute respiratory alkalosis

2543 Chapter 145

A

ALI and ARDS

B

Figure 145-3 Chest CT and plain radiograph in ARDS. A. Chest CT scan reveals asymmetric lung injury, with dense consolidation at the right base, patchy alveolar infiltrates in the right anterior lung field, and patchy ground-glass infiltrates throughout the right lung. B . Chest radiograph obtained concurrently with chest CT scan shown in panel (A). Dense infiltrates at right base, patchy infiltrates in the right upper lung zone, and more subtle infiltrates in the left lung are demonstrated. The panels illustrate the subtle findings of lung injury that are more apparent on the CT scan than on the chest radiograph.

may also occur in the early stage. If a patient with ALI and ARDS then develops respiratory muscle fatigue, hypercapnia results. In late-stage ALI, patients typically have increased minute ventilation requirements due to an increasing deadspace fraction, despite possible improvement in oxygen exchange.

In addition to arterial blood gas measurements, several other laboratory studies may be helpful in investigating other causes of respiratory failure and evaluating additional aspects of critical illness associated with ALI or ARDS. For example, cardiac enzymes (creatine phosphokinase and troponins) are useful for evaluating the presence of myocardial infarction or cardiac ischemia in patients at risk because of increased age or other factors. The results should be interpreted in conjunction with electrocardiographic findings, since elevations in cardiac enzymes, especially troponins, have been reported in patients with sepsis or septic shock in the absence of coronary artery disease.

Another cardiac-related laboratory test that may be useful in this clinical context is plasma brain natriuretic peptide (BNP), which is secreted by the cardiac ventricles, and, to a lesser extent, the atria. BNP measurements are often utilized in the evaluation of acute shortness of breath in patients presenting to an emergency department. In this group, a BNP greater than 500 pg/ml indicates that congestive heart failure (CHF) is likely with a positive predictive value greater than 90 percent. In the same group, a BNP less than 100 pg/ml suggests that congestive heart is unlikely with a negative predictive value greater than 90 percent. However, interpretation of an elevated BNP in patients who are critically ill is problematic. Reports indicate that BNP increases with renal failure, and that elevations of BNP greater than 500 pg/ml may occur

in patients with sepsis and normal left ventricular function.

Nonetheless, one can reasonably exclude a cardiac cause for acute pulmonary edema in patients in the intensive care unit if BNP is less than 100 pg/ml.

Echocardiography Echocardiography is a useful noninvasive method to evaluate potential cardiac causes of acute hypoxemic respiratory failure. Cardiogenic pulmonary edema is suggested by echocardiographic findings of mitral valve stenosis or regurgitation, left ventricular dilatation and systolic dysfunction, or regional left ventricular wall motion abnormalities. Although these findings do not rule out coexisting lung injury, they are helpful in the initial evaluation and management, even in the presence of ALI or ARDS. Invasive Hemodynamic Monitoring Although right-heart catheterization has been performed often in patients with pulmonary edema, the benefits of the procedure are controversial and the topic of recent investigations (see Chapter 152). Several studies have demonstrated that physician interpretation of data obtained from right heart catheters is inconsistent and often erroneous. Furthermore, one observational study suggested that routine right-heart catheterization is harmful in critically ill patients with acute hypoxemic respiratory failure.

The utility of the pulmonary artery occlusion pressure, also known as pulmonary artery wedge pressure (PCWP), in the diagnosis of ALI or ARDS is questionable. Studies have shown that many patients who originally met criteria for ALI or ARDS (i.e., had a pulmonary artery occlusion pressure less

2544 Part XVII

Acute Respiratory Failure

than or equal to 18 mm Hg) often have subsequent measurements with the PAOP greater than 18 mm Hg. Finally, recent results from the ARDSNet Fluid and Catheter Treatment Trial (FACCT) support the contentions that the AECC’s decision to use a PAOP of greater than 18 mmHg to exclude ALI/ARDS was arbitrary and that the threshold of greater than 18 mmHg needs re-examination.

FACTT was a large, randomized clinical trial that used a two-by-two factorial design to test a fluid-conservative management strategy against a fluid-liberal management strategy in ALI and ARDS and to assess safety and efficacy of a central venous catheter (CVC) or pulmonary artery catheter (PAC) to guide fluid management. In FACTT, 29 percent of 513 patients enrolled in the PAC arm of the trial were found to have a PAOP greater than 18 mm Hg at the time of initial measurement (following passage of the catheter shortly after enrollment and randomization). Before enrollment, FACTT investigators believed that these patients lacked a primary cardiogenic cause for their pulmonary edema. Approximately one half of these subjects had PAOPs of 19 or 20 mmHg. Since the vast majority (97 percent) of this group had a normal cardiac index (greater than or equal to 2.5 L/m2 /min), and a mortality similar to other subjects in FACTT, the elevated PAOP (greater than 18 mmHg) likely reflected intravascular volume loading rather than cardiogenic pulmonary edema.

Bronchoalveolar Lavage Bronchoscopy with bronchoalveolar lavage (BAL) is an important tool in the evaluation of patients who have ALI or ARDS of unclear origin. In general, BAL can be performed safely in patients with ALI or ARDS, except in those with a very low PaO2 or requiring high levels of PEEP. The principal reason for performing bronchoscopy in ALI or ARDS is to rule in or rule out acute processes that may have specific therapies.

For example, acute eosinophilic pneumonia is a rare disorder characterized by diffuse eosinophilic infiltrates in the lungs (Table 145-6). When the precipitating cause for ALI or ARDS is uncertain, performance of BAL and measurement of the percent eosinophil count in the lavage fluid is helpful in establishing a diagnosis of this corticosteroid-responsive disorder.

Likewise, BAL can be diagnostic for diffuse alveolar hemorrhage (see Chapter 77). In this case, the bronchoscopy may or may not reveal fresh blood in the trachea and major bronchi. However, BAL generally demonstrates a bloodtinged fluid, which contains red blood cells and hemosiderinladen macrophages. Diffuse alveolar hemorrhage may occur following bone marrow transplantation or as a result of rheumatologic or other immunologic disorders, including Goodpasture’s syndrome, Wegener’s granulomatosis, systemic lupus erythematosus, or anti-phospholipid antibody syndrome.

APPROACH TO TREATMENT Goals of Management Management of patients with ALI or ARDS can be complicated and challenging because clinicians are often faced with simultaneous failure of both respiratory and nonrespiratory organ systems (Table 145-7). Unfortunately, only a limited set of controlled clinical trials are available to support an evidenced-based approach. For example, even large, multicenter, randomized clinical trials, such as those done by ARDSNet, are limited in the number of variables that can be tested.

As a result, patient management rests on a combination of relevant evidence-based medicine, extrapolations from basic and clinical research, and experience-based approaches.

Diagnosis and Treatment of Precipitating Causes and Other Comorbidities The first step in the therapy of ALI or ARDS is identification and treatment of the precipitating cause(s) and any other life-threatening medical or surgical issues (Fig. 145-4).

Table 145-7 Goals of Management of Patients with ALI and ARDS Treatment of respiratory system abnormalities Diagnose and treat the precipitating cause of ALI/ARDS, if possible (Table 145-8) Maintain oxygenation, preferably using nontoxic FiO2 (<0.7), PEEP, or mechanical ventilation Prevent ventilator-induced lung injury (VILI) by using a low tidal volume ventilatory strategy (Table 145-9) with a limit (≤30 cm H2 O) on static end-inspiratory airway pressure (plateau pressure) Keep pH in normal range without compromising goal to prevent VILI (but reverse a life-threatening acidosis, even if it prevents meeting goal to prevent VILI) Enhance patient-ventilator synchrony and patient comfort by use of sedation, amnesia, opioid analgesia, and pharmacological paralysis, if necessary Liberate or wean from mechanical ventilation when patient can breathe without assisted ventilation Treatment of non-respiratory system abnormalities Support or treat other organ system dysfunction or failure General critical care (preventive and homeostatic measures) Adequate early nutritional support

2545 Chapter 145 Patient presents with ALI/ARDS

ALI and ARDS

Table 145-8 Treatable Inciting Causes of ALI and ARDS

Treat precipitating cause(s) of ALI/ARDS and other serious comorbidities

Provide other ICU supportive care

Ventilatory management of respiratory abnormalities

Provide adjuncts to ventilator management as needed

Treat inflammation and coagulation abnormalities as appropriate

Monitor patient during the course of ALI/ARDS

Death

Rehabilitation and Recovery

Figure 145-4 Summary of treatment approach to ALI and ARDS. Note that, ‘‘Treat inflammation and coagulation abnormalities as appropriate,” is currently limited. Examples include treatment of patients with severe sepsis and multiple organ dysfunction using recombinant drotrecogin alpha (activated) and administration of replacement-dose corticosteroids in patients with severe sepsis and septic shock who have relative adrenal insufficiency. In the ARDSNet ‘‘LaSRS”clinical trial, physiological improvement, but no mortality benefit, was found with high-dose corticosteroid therapy for persistent (late phase) ARDS (see text for details). (Reproduced with permission Christie JD, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2004; p 525.)

Since ALI and ARDS are syndromes based on nonspecific radiographic and physiologic criteria, establishing a diagnosis of ALI or ARDS is not equivalent to diagnosing the precipitating cause. The fact that early identification and treatment directed at the inciting cause(s) of ALI and ARDS are imperative for resolution of lung injury and respiratory failure cannot be overemphasized. Treatable inciting causes of ALI and ARDS include a variety of infectious and noninfectious disorders (Table 145-8).

Management of Respiratory Failure Management of respiratory failure in ALI or ARDS rests on assurance of adequate oxygenation and carefully crafted ventilatory strategies, as outlined below.

Infectious etiologies Bacterial or other sepsis, e.g., fungemia, responsive to antimicrobial therapy Diffuse bacterial pneumonias, e.g., Legionella species Diffuse viral pneumonias, e.g., cytomegalovirus, influenza A Diffuse fungal pneumonias, e.g., Candida species, Cryptococcus Pneumocystis carinii pneumonia Other diffuse lung infections, e.g., military tuberculosis Noninfectious etiologies Diffuse alveolar hemorrhage post–bone marrow transplantation Diffuse alveolar hemorrhage due to vasculitis, e.g., Goodpasture syndrome Acute eosinophilic pneumonia Lupus pneumonitis Toxic drug reactions, e.g., aspirin Source: Christie JD, Lanken PN: Acute lung injury and the acute respiratory distress syndrome, in Hall JB, Schmidt GA, Wood LDH (eds.): Principles of Critical Care, 3rd ed. New York, McGraw-Hill, 2004; p 525, reproduced with permission.

Maintaining Adequate Oxygenation As noted, the pathophysiological hallmark of ALI and ARDS is hypoxemia that is resistant to oxygen therapy. Maintaining adequate arterial oxygenation is the primary goal of both traditional and newer (“lung protective”) approaches to assisted ventilation.

As expected with shunt physiology, administration of supplementary oxygen provided by high-flow oxygenation systems, e.g., a non-rebreather face mask, is generally ineffective in reversing the oxygenation deficit. Exceptions to this rule are some patients with mild or transient cases of ALI or ARDS that are otherwise uncomplicated by other organ system failures.

In order to reduce the shunt, positive end-expiratory pressure (PEEP) is employed. When utilized in sufficient amounts, PEEP generally results in correction of the hypoxemia to patients with ALI, thereby allowing FiO2 to be lowered from high potentially toxic concentrations. Although PEEP is usually used in conjunction with mechanical ventilation, in selected cases it may be effective when applied by means of a continuous positive airway pressure (CPAP) mask or as the lower level of bilevel noninvasive ventilation. The effect of PEEP-induced improvement in arterial oxygenation is attributed predominantly to recruitment of collapsed alveoli.

However, application of PEEP may also mediate a redistribution of alveolar fluid into the interstitium and decrease the absolute magnitude of shunt by reducing cardiac output.

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Acutely ill patients in intensive care units typically receive assisted ventilation via an endotracheal tube. In selected non-ARDS disorders, e.g., COPD or acute cardiogenic pulmonary edema, noninvasive ventilation has been shown to be as effective as invasive ventilation. Although the routine use of noninvasive ventilation for patients with ALI or ARDS lacks compelling evidence, the data are limited. One reason for limited study of noninvasive ventilation in ALI or ARDS is concomitant nonrespiratory organ failure (e.g., due to septic shock). Except for select subgroups, e.g., immunosuppressed patients with hypercapnic respiratory failure who are hemodynamically stable, one should generally avoid use of noninvasive ventilation for patients with ALI and ARDS.

In summary, the goals of lung-protective ventilation are to avoid injury due to overexpansion of alveoli during inspiration (so-called “volu-trauma”) and injury due to repetitive opening and closing of alveoli during inspiration and expiration (so-called “atelecta-trauma”) (Fig. 145-5).

The injurious effects of mechanical ventilation on the lung have been referred to as “ventilator-induced lung injury or VILI.” The term “bio-trauma” encompasses the direct lung injury and the concomitant release of inflammatory cytokines that produce remote cell death or organ injury. Clinical strategies underlying contemporary applications of mechanical ventilation in treatment of ALI or ARDS are described below.

Lung-Protective Mechanical Ventilation As described in Chapter 153, over the past 30 years investigators have convincingly shown that large tidal volumes delivered during mechanical ventilation can injure lungs of normal animals, producing a pathologic pattern resembling ALI in humans. In animal models of acute lung injury, use of large tidal volume ventilation has been found to augment preexisting injury. In addition, repetitive opening and closing of alveoli during inspiration and expiration induces acute lung injury in normal animals. The injury can be prevented by application of sufficient PEEP. Finally, overexpansion of alveoli in normal lungs of sheep induces multiorgan failure, with recent studies of other species showing that lung overexpansion results in systemic release of proinflammatory cytokines—providing a likely mechanism for these remote deleterious effects. These observations support the concept that the lung, rather than the gut, is the “engine of inflammation.”

Concurrent with the previously described observations, clinical investigators studying patients with ALI or ARDS using computed tomography observed that, in contrast to the typical diffuse-appearing pattern noted on plain chest radiographs, the pattern of consolidation, atelectasis, and normal alveoli is actually heterogeneous (Fig. 145-3). The key physiological implication of these observations is that a ventilator-delivered tidal volume is preferentially distributed to the open alveoli, which represent only a small fraction of the entire lung. Reference by Gattinoni, Pesenti and coworkers to this fraction as “the baby lung” emphasized the potential danger of delivering traditional tidal volumes of 10 to 15 ml/kg actual body weight and the associated risk for alveolar overexpansion and lung injury. Notably, tidal volumes of 10 to 15 ml/kg actual body weight (equivalent to approximately 12 to greater than 15 ml/kg predicted body weight) were used originally in critically ill patients with ALI or ARDS as a complementary strategy to PEEP in recruiting atelectatic alveoli.

These productive lines of basic and clinical research strongly support the hypothesis that mechanical ventilation using limited tidal volumes should be less injurious to the lungs of patients with ALI and ARDS and should result in better outcomes (i.e., decreased mortality) compared with use of traditional, large tidal-volume ventilation.

Based on the aforementioned considerations, the ARDSNet conducted a randomized trial (ARMA) in the mid-to-late 1990s to test the hypothesis that low tidal volume ventilation, combined with limited end-inspiratory (plateau) pressure, would lower mortality and ventilator days among survivors of ARDS compared with use of traditional tidal volumes.

The trial included 861 subjects. The low tidal volume arm consisted of a tidal volume of 6 ml/kg predicted body weight, as long as the end-inspiratory pressure (Pplat) was 30 cm H2 O or less; if Pplat exceeded 30 cm H2 O, the tidal volume could be decreased to as low as 4 ml/kg. The traditional tidal volume arm used a tidal volume of 12 ml/kg predicted body weight, as long as the Pplat remained less than 50 cm H2 O. Both arms included explicit goals and protocols as the bases for ventilator adjustments and determination of the time and means of weaning (Table 145-9).

Important results of this clinical trial are summarized in Table 145-10. The difference in actual tidal volumes resulted from protocol-driven target tidal volumes in each study arm.

As expected, the mean plateau pressure for the lower tidal volume group was less than 30 cm H2 O (25 cm H2 O), since the protocol required decreasing the tidal volume from 6 ml/kg predicted body weight to as low as 4 ml/kg if Pplat exceeded 30 cm H2 O. Of note, the traditional tidal volume group had a mean Pplat of 33 cm H2 O on study day one—a value less than the threshold of 35 cm H2 O that some clinicians had believed represented a safe threshold.

Despite the fact that the clinical trial used an arbitrary threshold of 30 cm H2 O for Pplat in the lower tidal volume arm, it should not be assumed that any Pplat at or below 30 cm H2 O is safe. If a “safe” upper limit of Pplat exists, its value is unknown. Lack of such a safe threshold is supported by the finding of an absence of any significant interaction between differences in mortality and quartiles of static respiratory compliance (Fig. 145-6A) or quartiles of plateau pressures (Fig. 145-6B). These results suggest that the lower tidal volume ventilatory strategy tends to be effective across a wide range of baseline static compliances and plateau pressures.

Likewise, a statistical model of mortality proportion vs. Day 1 Pplat that combined data from both arms of this clinical trial suggests that, in general, the lower Pplat the lower the associated mortality (Figure 145-7).

ARDSNet Ventilator Strategies: Low vs. Traditional Tidal Volumes

2547 Chapter 145

ALI and ARDS

A C

B D

Figure 145-5 A. Schematic inspiratory static pressure-volume (P-V) curve of the respiratory system (lung and chest wall combined) in ARDS. Lower inflection point (LIP) is approximately 14 cm H2 O, and upper inflection point (UIP) is approximately 35 cm H2 O. Abscissa is respiratory system recoil pressure; ordinate is lung volume above functional residual capacity (FRC) B. Same static P-V curve as (A), plus dynamic P-V curve of 600 mL tidal volume starting below the LIP (PEEP = 0). This tidal volume results in a plateau pressure (closed arrow) below the UIP (24 cm H2 O).

Static compliance (Cstat = "V/"P = 600 ml/24 cm H2 O) is 25 ml/cm H2 O. C . PEEP of 15 cm H2 O has moved the starting point for the 600 ml tidal volume up the static P-V curve to a new FRC (open arrow), which is at the LIP. The tidal volume results in a plateau pressure of 27.5 cm H2 O (closed arrow), which is well below the UIP. Cstat ("V/"P = 600 ml/12.5 cm H2 O) is increased to 48 ml/cm H2 O. D. Dynamic P-V curve of a 1000 ml tidal volume, starting at 14 cm H2 O PEEP, results in a plateau pressure of 37.5 cm H2 O (closed arrow). Despite an increase in Cstat ("V/"P = 1000 ml/24 cm H2 O = 41.5 ml/cm H2 O), compared with Cstat derived from the 600 mL tidal volume in (B ), the plateau pressure associated with the 1000 ml tidal volume exceeds the UIP. Delivery of an inflation volume that results in a plateau pressure exceeding the UIP implies alveolar overdistension and is believed to put the lung at risk for ventilator-induced lung injury (see text). (Reproduced with permission from Lanken PN: Acute respiratory distress syndrome, in Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual. Philadelphia, Saunders, 2001, pp 824â&#x20AC;&#x201C;825.)

These considerations are important, since some clinicians may believe that they can achieve the improved mortality rate simply by lowering tidal volumes to the point where Pplat is at or slightly less than 30 cm H2 O, instead of following the ARDSNet low tidal volume strategy of using a tidal volume of 6 ml/kg predicted body weight. In addition, recognition of the need to use predicted, rather than actual, body weight is important, since the latter has been estimated to be about 20 percent greater than the former (due to fat and extravascular fluid). In summary, clinicians should employ the entire ARDSNet protocol (Table 145-9) rather than

selected parts in attempting to achieve comparably favorable mortality results.

Lung Protection due to Higher PEEP

The initial ARDSNet trial (ARMA) described above did not address the question of whether application of higher levels of PEEP than used traditionally is beneficial. The possibility of improved outcomes using higher levels of PEEP was suggested by both basic and clinical studies conducted by Amato and colleagues in the early 1990s. To address whether higher levels of PEEP combined with low tidal volumes decreases

2548 Part XVII

Acute Respiratory Failure

Table 145-9 NIH NHLBI ARDS Clinical Trials Network Low Tidal Volume Ventilation Strategy Part I: Ventilator setup and adjustment 1. Calculate ideal body weight (IBW)∗ (also known as predicted body weight [PBW]) 2. Use Assist/Control mode and set initial TV to 8 ml/kg IBW (if baseline TV >8 ml/kg) 3. Reduce TV by 1 ml/kg at intervals ≤2 h until TV = 6 ml/kg IBW ˙ (but not >35 bpm) 4. Set initial rate to approximate baseline Ve 5. Adjust TV and RR to achieve pH and plateau pressure (Pplat) goals below.

6. Set inspiratory flow rate above patient demand (usually >80 L/min); adjust flow rate to achieve goal of I:E ratio of 1:1.0–1.3 Part II: Oxygenation goal: PaO2 = 55–80 mmHg or SpO2 = 88–95% 1. Use these incremental FiO2 -PEEP combinations to achieve oxygenation goal: FiO2

0.3

0.4

0.4

0.5

PEEP

5

5

8

8

FiO2

0.7

0.8

0.9

0.9

PEEP

14

14

14

16

0.5 10 0.9 18

0.6 10

0.7 10

1.0 20

1.0 22

0.7 12 1.0 24

Part III. Plateau pressure (Pplat) goal: ≤ 30 cm H2 O 1. Check Pplat (use 0.5-sec inspiratory pause), SpO2 , total RR, TV and ABG (if available) at least every 4 h and after each change in PEEP or TV. 2. If Pplat >30 cm H2 O, decrease TV by 1 ml/kg steps (minimum 4 ml/kg IBW) 3. If Pplat <25 cm H2 O and TV < 6 ml/kg, increase TV by 1 ml/kg until Pplat > 25 cm H2 O or TV = 6 ml/kg.

4. If Pplat < 20 cm H2 O and breath stacking occurs, one may increase TV in 1 ml/kg increments (to a maximum of 8 ml/kg) Part IV. pH goal: 7.30–7.45 Acidosis management: pH < 7.30 1. If pH = 7.15–7.30, increase RR until pH > 7.30 or PaCO2 < 25 mmHg (maximum RR = 35); if RR = 35 and PaCO2 < 25 mmHg, may give NaHCO3 .

2. If pH < 7.15 and NaHCO3 considered or infused, TV may be increased in 1 ml/kg steps until pH > 7.15 (Pplat goal may be exceeded) Alkalosis management: pH > 7.45: Decrease RR, if possible ∗ Male

IBW = 50 + 2.3 [height (inches) − 60]; female IBW = 45.5 + 2.3 [height (inches) − 60] Abbreviations: ABG = arterial blood gas; RR = respiratory rate on ventilator; SpO2 = Oxygen saturation by pulse oximetry; TV = tidal volume; V˙E = minute ventilation.

From the NIH NHLBI ARDS Clinical Trials Network (Complete protocol is available at www.ardsnet.org).

Source: Lanken PN: Acute respiratory distress syndrome, in Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual, Philadelphia, Saunders Co., 2001, p. 828, reproduced with permission.

mortality, the ARDSNet conducted a second ventilator clinical trial (ALVEOLI) in which each of two groups received the same low tidal volume ventilatory strategy, but one group was treated using an additional 4 to 5 cm H2 O of PEEP. Mortality rates at day 60 were below 30 percent for both groups and were not significantly different, even after adjustment for imbalances in baseline variables. Similarly, ventilator-free days were not significantly different. Therefore, at present, whether maintenance of PEEP above a certain point (corresponding to the lower inflection point in Fig. 145-5) improves clinical outcome is unknown. Recent studies by Gattinoni and

co-workers showed that, while some patients with ALI have little or no recruitment (opening previously collapsed or fluid filled airspaces) with increased levels of PEEP, in others PEEP shows marked recruitment. This suggests that future clinical trials using higher PEEP be restricted to subjects with ALI in whom PEEP increments can reliably result in recruitment.

Recommended Core Ventilator Management

We recommend that as the core ventilator management in ALI and ARDS clinicians follow the ARDSNet low tidal volume ventilatory strategy (Table 145-9). Because higher levels of

2549 Chapter 145

ALI and ARDS

Table 145-10 Results of NIH NHLBI ARDS Clinical Trials Network Low Tidal Volume vs. Traditional Tidal Volume Clinical Trial (“ARMA”)

Variable or Outcome

Units

Low Tidal Volume Ventilatory Strategy Mean ± SD

Tidal volume on day 1

mL/kg PBW

6.2 ± 0.9

11.8 ± 0.8

<0.05

Plateau pressure on day 1

cm H2 O

25 ± 7

33 ± 9

<0.05

PEEP on day 1

cm H2 O

9.4 ± 3.6

8.6 ± 3.6

<0.05

158 ± 73

176 ± 76

<0.05

PaO2 :FiO2 on day 1

Traditional Tidal Volume Ventilatory Strategy Mean ± SD

p Value

PaCO2 on day 1

mmHg

40 ± 10

35 ± 8

<0.05

Death before discharge or 180 days

%

31.0

39.8

0.007

Breathing without assistance at day 28

%

65.7

55.0

<0.001

No. of ventilator-free days by day 28

12 ± 11

10 ± 11

0.007

No. of days without failure of nonpulmonary systems by day 28

15 ± 11

12 ± 11

0.006

Abbreviations: PBW = predicted body weight (see footnote of Table 145-9 for details); PEEP = positive end expiratory pressure; SD = standard deviation; ventilator-free days by day 28, number of days alive and not receiving assisted ventilation between days 1 and 28.

Source: Acute Respiratory Distress Syndrome Network. New Engl J Med 342:1301, 2000.

PEEP have not yet been found to improve outcomes, unless new evidence arises to the contrary, we also recommend that clinicians follow the same combinations of FiO2 and PEEP used in the first ARDSNet trial, ARMA (Table 145-9).

Because of constraints of sample size, the ARDSNet trial tested the low-volume strategy only against use of tidal volumes of 12 ml/kg predicted body weight. Notably, a strategy using 6 ml/kg has not been shown to be superior to a strategy using tidal volumes of 8 to 10 ml/kg. However, based on the previous descriptions of ventilator-induced lung injury and bio-trauma, we believe it is prudent for clinicians to strictly follow the ARDSNet protocol as their core management strategy in ALI or ARDS. Modifications should be considered only in special cases, e.g., when contraindications for permissive hypercapnia exist (Table 145-11).

Other Approaches to Ventilator Management In addition to the low-volume protocol described, several additional approaches may be used in the management of ALI or ARDS and are discussed briefly below.

Pressure Control Mode

The ARDSNet low tidal volume strategy used the volumeassist-control mode—a familiar device setting and the only

ventilator intervention that has been shown thus far to improve long-term survival in patients with ALI and ARDS. However, other modes of ventilation can also provide low tidal volume ventilation, including pressure control ventilation (PCV).

PCV can limit maximal peak airway pressure as well as end-inspiratory pressure (Fig. 145-8A) and, hence, is favored by some clinicians. However, the end-inspiratory pressure in PCV can be underestimated. For example, using PCV with an inspiratory pressure of 30 cm H2 O and a PEEP of 10 cm H2 O, the end-inspiratory pressure is 40 cm H2 O (the sum of the two pressures). Some may misinterpret this combination as equivalent to a Pplat of 30 cm H2 O and assume that it is a “safe” value according to interpretation of ARDSNet results.

As discussed previously, however, no Pplat is known to be safe, even when end-inspiratory pressure is calculated correctly. Furthermore, use of PCV to mimic both tidal volume and Pplat used in the ARDSNet trial remains problematic.

The benefit seen from using the ARDSNet strategy may have been due as much to the use of low tidal volume as to lower Pplat.

Inverse ratio ventilation (IRV) with PCV is based upon an inspiratory time (I) greater than expiratory time (E), i.e., I:E greater than 1 (Fig. 145-8B). Some case reports identify

2550 Acute Respiratory Failure 0.6

Lower tidal volumes Traditional tidal volumes

0.5

Mortality

0.4 0.3 0.2 0.1 0.0 0.15–0.40

0.41–0.50

0.51–0.62

0.63–1.5

Quartile of Static çompliance (ml/cm of water/kg of predicted body weight) A

Vt = 6 ml/kg

60

Mortality %

Part XVII

45

ARR = 15.3% 95%Cl: 2 to 30%

Vt = 12 ml/kg

ARR = 9.4% 95%Cl: −3 to 22%

ARR = 4.3% 95%Cl: −9 to 17%

ARR = 2.9% 95%Cl: −11 to 17%

30

15

Pplat 16.0 to 26.0 (101)

Pplat 10.0 to 20.0 (99)

Pplat 20.3 to 24.7 (95)

Pplat 26.3 to 31.0 (104)

Pplat 25.0 to 28.3 (97)

Pplat 31.7 to 37.3 (95)

Pplat 29.0 to 47.0 (97)

Pplat 37.7 to 69.0 (99)

0 1

2 3 Quartile of Pplat

4

B

Figure 145-6 ARDSNet ARMA study. A. Mortality rates (mean ± SE) according to quartile of static respiratory system compliance before randomization and subsequent treatment group. Data represent a subset of 861 subjects enrolled, including 257 patients assigned to the low tidal volume ventilatory strategy and 260 to the high tidal volume strategy. Mortality in the low tidal volume group was at least 30 percent lower than for those receiving traditional tidal volumes in each of the lowest three quartiles. Although the low tidal volume strategy was not advantageous for patients in the quartile with the highest static compliance, a test for interaction between treatment group and static compliance quartile at baseline was not statistically significant. Results support the concept that the low tidal volume ventilation strategy is beneficial for patients with ALI or ARDS across a spectrum of static compliances, not just for those with the stiffest lungs. (Reproduced with permission from Acute Respiratory Distress Syndrome Network. N Engl J Med 342: 1301, 2000.) B. Mortality according to quartiles of end-inspiratory pressure (plateau pressure, Pplat) and treatment group on study day 1 in 787 subjects for whom Pplat data are available (including 270 subjects for whom pre-randomization static compliance measurements were not available). Pplat was measured using protocol-dictated tidal volumes (rather than clinician-determined tidal volumes, as used in assessing static respiratory system compliance). Subjects with the stiffest lungs are likely to have Pplat in the fourth quartile (far right). Range of Pplat (cm H2 O) and number of subjects (parentheses) are shown in each bar of the graph (ARR = absolute risk reduction; CI = confidence interval). Lower tidal volume ventilation appears to benefit patients with ALI or ARDS across a range of Pplat.

The hypothesis that a ‘‘safe” upper limit exists for Pplat, below which ventilator-induced lung injury does not occur, is not supported by the data. (Reproduced with permission from Hager DN, Krishnan JA, Hayden DL, et al: Am J Respir Crit Care Med 172:1241, 2005.)

2551 Chapter 145 1

Table 145-11

.9 Mortality Proportion

ALI and ARDS

.8

Contraindications for Permissive Hypercapnia and Acute Respiratory Acidosis

.7 .6 .5 .4

Increased intracranial pressure from any cause (trauma, mass lesion, malignant hypertension)

.3 .2 .1

Acute cerebrovascular disorders, e.g., stroke 0

20 40 60 Day 1 Plateau Pressure (cm H2O)

80

Figure 145-7 Lowess (locally weighted regression and smoothing) plot (bandwidth, 0.4) of mortality proportion and day 1 plateau pressure (Pplat, cm H2 O) for 787 patients enrolled in the ARDSNet ARMA study. Plot includes same subjects and Pplat shown in Fig. 145-6B. When expressed using this estimating method, the data do not support a safe upper limit for Pplat, the presence of which would be suggested by a leveling in mortality proportion, rather than a further decrease, as the plot demonstrates. The Lowess method is a nonparametric smoother that uses overlapping neighborhoods of data to estimate a local effect. A bandwidth of 0.4 means that 20 percent of the data on either side of a given Pplat contribute to a local estimate of mortality at that Pplat; data at the high and low ends of the curve represent fewer observations. As data are smoothed using a tricubic weight function, points furthest from the Pplat of interest are assigned the least weight and approach zero. (Reproduced with permission from Hager DN, Krishnan JA, Hayden DL, et al: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 172:1241, 2005.)

patients with refractory hypoxemia who responded to PCVIRV. This may be due to effects of auto-PEEP (intrinsic PEEP) or other mechanisms involving alveolar recruitment following prolonged exposure to IRV. IRV with auto-PEEP plus applied PEEP may compromise cardiac output and increase the risk of nonpulmonary organ dysfunction. Clinicians should consider using PCV-IRV only as a “salvage” mode of ventilation (Table 145-12).

Acute or chronic myocardial ischemia Severe pulmonary hypertension Right ventricular failure Uncorrected severe metabolic acidosis Sickle cell anemia Tricyclic antidepressant overdose Patients taking beta-blockers Pregnancy (due to potential for decreased fetal blood flow from vasodilation-induced steal syndrome; in addition, shift to the right of the O2 dissociation curve decreases the maternal-fetal gradient for O2 )

BIPAP and APRV can be expected to decrease the use of neuromuscular blocking agents in patients with ALI or ARDS since both allow spontaneous breathing and potentially less patient-ventilator dyssynchrony. However, whether such newer modes of ventilation are better than, equal to, or worse than the ARDSNet lower tidal volume ventilatory strategy remains unknown. Until more clinical evidence supports their superiority or equivalency, their routine use cannot be recommended.

Modes That Allow Spontaneous Breathing during Positive Pressure Ventilation

High Frequency Oscillatory Ventilation Mode

Two ventilatory modes of modern microprocessor-based devices that permit spontaneous breathing to occur at any phase of the respiratory cycle during assisted ventilation include biphasic airway pressure (BIPAP) and airway pressure release ventilation (APRV). In each, airway pressure cycles between higher and lower levels of PEEP at preset time intervals. Controlled studies using these ventilator modalities are limited. One report found that use of APRV in patients with ARDS decreased intrathoracic pressure, improved ventilation-perfusion mismatch and cardiac output, and decreased shunt and dead space fractions compared with pressure support ventilation (matched for the same airway pressure limits or minute ventilation). However, clinically important outcomes were not compared.

The U.S. Food and Drug Administration has approved an adult high frequency oscillatory ventilator (HFOV) for management of patients with ARDS. Theoretically, HFOV may be regarded as the ultimate low tidal volume ventilator with a capacity to ventilate a patient using a very small tidal volume midway between the upper and lower inflection points of the pressure-volume curve (Fig. 145-5).

Clinically, use of HFOV has been shown to be equivalent to “usual” care. However, the trial comparing HFOV with usual care was conducted at a time when usual care did not include low tidal volume ventilation. Since its application generally requires neuromuscular paralysis, HFOV is unlikely to be utilized in patients with mild ALI or ARDS because of the risk of paralytic agent–related quadriparesis and lack of

2552 Part XVII

Acute Respiratory Failure

ALI and ARDS. In some cases, the physiological or pharmacologic basis for the measure’s beneficial effect is apparent; in others, the mechanism is unknown.

Overview

A

Use of adjuncts to lung protective ventilation is generally based on extrapolations from animal or basic studies, or from clinical studies using physiological markers as surrogates for clinically meaningful endpoints, e.g., mortality or ICU length of stay or ventilator-free days. However, extrapolation from such studies to clinical practice is problematic. For example, the only intervention that thus far proved to result in improved survival in ALI and ARDS—the ARDSNet low tidal volume ventilatory strategy—also resulted in patients in the low-volume group with significantly lower PaO2 /FiO2 after enrollment compared with those receiving traditional tidal volume ventilation (Table 145-10). If the trial had used improvement in PaO2 /FiO2 as a surrogate marker for better survival, the results would have been interpreted as showing that low tidal volume ventilation results in higher not a lower mortality.

In general, both efficacy and safety data supporting use of the following adjunctive therapies in ALI or ARDS are lacking. Thus, these interventions should be used cautiously, if at all.

Permissive Hypercapnia

B

Figure 145-8 Schematic depiction of pressure, flow, and volume waveforms during pressure control ventilation (PCV) with applied PEEP. Abscissa is time and ordinates (from top to bottom) are proximal airway pressure (Pprose ), inspiratory flow and volume above functional residual capacity (FRC). Other abbreviations: I, inspiration, "FRC, change in FRC. A. The inspiratory-to-expiratory (I:E) time is about 1:2. The pressure waveform resembles pressure support ventilation, and the flow pattern is characterized by marked deceleration. Applied PEEP increases FRC (PEEP effect).

B. I:E time is reversed (I > E), representing pressure-controlled inverse ratio ventilation (PC-IRV). As a result, the next breath starts before expiratory flow has returned to zero (open arrows), resulting in auto-PEEP and dynamic hyperinflation. The latter is superimposed on the increased FRC due to the applied PEEP. (Reproduced with permission from Lanken PN: Acute respiratory distress syndrome, Lanken PN, Hanson CW III, Manaker S (eds): The Intensive Care Unit Manual. Philadelphia, Saunders, 2001, p 829.)

efficacy data comparable to the ARDSNet protocol used in ARMA (Table 145-9). Some clinicians may use high frequency ventilation as a “salvage” mode (Table 145-16). However, its use, even in those circumstances, is not supported by controlled clinical trials.

Adjuncts to Lung Protective Mechanical Ventilation A number of adjunctive measures to mechanical ventilation have assumed importance in the management of patients with

Permissive hypercapnia is defined as clinician-allowed hypercapnia during assisted ventilation, despite an ability to achieve a level of minute ventilation sufficient to maintain a normal PaCO2 (36 to 44 mmHg). Because patients may develop hypercapnia during lower tidal volume ventilation, which is recommended as the core ventilator strategy, permissive hypercapnia should no longer be considered an “adjunct.” (Although the ARDSNet lower tidal volume strategy did stipulate maintenance of minute ventilation while decreasing tidal volume in order to decrease the secondary rise in PaCO2 , permissive hypercapnia was allowed as a consequence of the protocol.

The response to the resulting respiratory acidosis was left to the local investigator’s discretion.)

Fluid Management

The ARDSNet Fluid and Catheter Treatment Trial (FACTT), which used a two-×-two factorial design, tested the hypothesis that a management strategy of fluid restriction (conservative fluid management) would improve clinically important outcomes in ALI compared with more generous fluid management strategy (liberal fluid management). Although the strategy of liberal fluid management was based upon a protocol to determine fluid balance, patients’ net fluid balance during the first 7 days of the trial resembled that resulting from the non–protocol-directed care in the first two ARDSNet clinical trials (ARMA and ALVEOLI).

FACTT investigators developed a detailed fluid management protocol that, except for patients in shock (MAP less

2553 Chapter 145

than 60 mmHg or on vasopressors for hypotension), used four basic input variables (assessed every 1 to 4 hours) to determine the fluid management instructions: (1) mean arterial blood pressure (MAP); (2) urine output; (3) effectiveness of circulation; and (4) intravascular pressure (central venous pressure [CVP] or pulmonary artery occlusion pressure [PAOP]). In both arms of the study, the protocol goals were MAP greater than 60 mmHg (or vasopressor independence); urine output greater than 0.5 ml/kg predicted body weight/hour; and evidence for effective circulation, including a cardiac index greater than or equal to 2.5 L/min/m2 in patients with pulmonary artery catheters (PACs) or, in those with central venous catheters (CVCs), absence of physical examination findings indicating hypoperfusion of extremities.

In the group randomized to conservative fluid strategy, the target intravascular pressure was a CVP less than 4 mmHg or PAOP less than 8 mmHg. In contrast, for those randomized

ALI and ARDS

to the liberal fluid strategy, targets were a CVP of 4 to 8 mmHg or PAOP of 8 to 12 mmHg. Despite marked differences in cumulative net fluid balance between the conservatively and liberally managed groups, the two showed no statistically significant difference in mortality at 60 days, which was the study’s primary outcome (Table 145-12). Nonetheless, compared with the liberal strategy, the conservative strategy resulted in statistically significant improvements in several clinically important outcomes, including decreased duration of assisted ventilation and length of stay in the intensive care unit (Table 145-12).

Moreover, the conservative strategy did not worsen the incidence of shock, number of days in shock, frequency or extent of other organ system failures, or rate of use of dialysis.

These results support the use of a conservative fluid strategy in managing patients with ALI or ARDS who are not in shock.

Table 145-12 Results of ARDSNet FACTT (Fluids and Catheter Treatment Trial): Conservative Fluid Management Stategy vs. Liberal Fluid Management Strategy Result Cumulative net fluid balance from day 1 to day 7 (ml) All patients Patients in shock at entry Patients not in shock at entry

Conservative Strategy (n = 503) −139 ± 491 2904 ± 1008 −1576 ± 519

Liberal Strategy (n = 497)

p Value

6992 ± 502 10, 138 ± 922 5287 ± 576

<0.001 <0.001 <0.001

Death at 60 days (%)

25.5

28.4

0.30

Ventilator-free days from day 1 to Day 28∗

14.6 ± 0.5

12.1 ± 0.5

<0.001

ICU-free days from day 1 to day 28∗

13.4 ± 0.4

11.2 ± 0.4

<0.001

3.9 ± 0.1 3.4 ± 0.2 5.5 ± 0.1 5.7 ± 0.1 5.6 ± 0.1

4.2 ± 0.1 2.9 ± 0.2 5.6 ± 0.1 5.5 ± 0.1 5.37 ± 0.1

0.04 0.02 0.45 0.12 0.23

10 11.0 ± 1.7

14 10.9 ± 1.4

0.06 0.96

Organ-failure-free days from day 1 to day 7∗,† Cardiovascular failure‡ CNS failure§ Renal failure‡ Hepatic failure‡ Coagulation abnormalities‡ Dialysis to day 60 Patients (%) Days of dialysis

Plus-minus values are means ± SE. Abbreviations: CNS = central nervous system. was an a priori secondary outcome. Death at 60 days was the primary outcome. † Definitions of organ failure: Cardiovascular failure = systolic blood pressure <90 mmHg or receiving a vasopressor other than dopamine at 5 µg/kg/min or less; CNS failure = Glasgow Coma Scale of 12 or less; renal failure = serum creatinine ≥ 2 mg/dl (177 µmol/L); hepatic failure = serum bilirubin ≥ 2 mg/dl (34 µmol/L); coagulation abnormalities = platelet count of 80,000/µl or less. Number of days without organ failure is determined by subtracting the number of days with organ failure from the lesser of 28 or from number of days until death. ‡ This difference was not significant from day 1 through day 28. § This difference was still statistically significant from day 1 through day 28. ∗ This

2554 Part XVII

Acute Respiratory Failure

Table 145-13 Results of ARDSNet FACTT (Fluids and Catheter Treatment Trial): Use of Pulmonary Arterial Catheter (PAC) vs. Use of Central Venous Catheter (CVC) to Direct Fluid and Hemodynamic Management Protocols

Result

Pulmonary Artery Catheter Group (n = 513)

Central Venous Catheter Group (n = 487)

Death at 60 days (%)

27.4

26.3

0.69

Ventilator-free days from day 1 to day 28∗

13.2 ± 0.5

13.5 ± 0.5

0.58

ICU-free days from day 1 to day 28∗

12.5 ± 0.5

12.0 ± 0.4

0.4

Number of catheters inserted†

2.47 ± 0.05

1.64 ± 0.04

<0.001

Number of complications per catheter

0.08 ± 0.01

0.06 ± 0.01

0.35

Total number of catheter-related complications per group†

100

p Value

41

±values are means ± SE. ∗ This was an a priori secondary outcome. Death at 60 days was the primary outcome. † This includes the sheath for PAC, PAC, and CVC for subjects in the PAC group and sheath (n = 6) and CVC for subjects in the CVC group.

Hemodynamic Management

Using the trial’s two-×-two factorial design, the ARDSNet FACTT investigators also compared the safety and efficacy of PACs with CVCs in directing fluid and hemodynamic protocols, as described. Mortality and other important clinical outcomes, such as ventilator-free days, ICU-free days, and organfailure-free days by study day 28 were no different in patients managed with a PAC versus a CVC (Table 145-13). However, use of the PAC was associated with a significantly higher complication rate during catheter insertion—primarily, cardiac arrhythmias. The excess events were attributed principally to the need for passing both a sheath and catheter; none of the adverse events was fatal.

Based on the results, the FACTT investigators recommend using a CVC to guide a hemodynamic and fluid management. However, in specific cases, clinicians may elect to use a PAC in selected circumstances, e.g., in addressing the response to volume resuscitation, determining the adequacy of cardiac output, measuring the oxygen saturation of mixed venous blood, calculating the degree of intrapulmonary shunt, or searching for equalization of diastolic pressures during suspected cardiac tamponade.

Prone Positioning

About two-thirds of patients with ALI or ARDS improve their oxygenation after being placed in a prone position.

Mechanisms that may explain the improvement include: (1) increased functional residual capacity; (2) change in regional diaphragmatic motion; (3) perfusion redistribution;

and (4) improved clearance of secretions. Studies of the distribution of ventilation-to-perfusion ratios in animal models suggest that gravity is less influential on the distribution of perfusion in the prone rather than supine position. This finding, coupled with the observation that edema fluid migrates to the dependent portions of the lung (as demonstrated on computed tomography) in patients with ALI who have been turned prone, suggested that ventilation-perfusion relationships might be favorably altered in the prone position.

Patients managed in the prone position need special attention to prevent pressure necrosis of the nose, face, and ears. Extra care is also needed to ensure security and patency of the endotracheal tube. Pressure on the eye may result in retinal ischemia, especially in hypotensive patients. Others may experience cardiac arrhythmias or hemodynamic instability when turned prone.

In a large clinical trial of prone positioning in patients with ALI and ARDS published in 2001 by Gattinoni and colleagues, subjects were randomly placed prone for 6 or more hours daily for 10 days or were left in the supine position. Although the investigators found that oxygenation was transiently improved with prone positioning, they demonstrated no survival advantage. A more recent study of prone positioning in children with ALI also demonstrated lack of benefit.

Because no controlled clinical trial has showed improved survival with prone positioning, and because the technique carries known risks, even in experienced hands, it cannot be recommended for routine use in patients with ALI or ARDS. However, some clinicians may opt to use

2555 Chapter 145

prone positioning as salvage therapy for severe hypoxemia (Table 145-16).

ALI and ARDS

ported that recruitment maneuvers improve oxygenation in patients on relatively low levels of PEEP, receiving large tidal volumes, or maintained on paralytics.

Because no controlled clinical trials demonstrate efficacy in clinically relevant end points and there are potentially adverse effects, routine use of recruitment maneuvers is not recommended in ALI or ARDS. Likewise, in the absence of data showing efficacy, routine use of ventilator “sighs” exceeding peak pressures of 30 cm H2 O (the threshold used in the ARDSnet clinical trial that showed improved survival) is also not recommended. Some clinicians may use recruitment maneuvers with higher pressures as part of salvage therapy for patients with severe refractory hypoxemia (Table 145-16).

Recruitment Maneuvers

Lung recruitment maneuvers are defined as the application of continuous positive airway pressure (CPAP) aimed at “recruiting” or opening totally or partially collapsed alveoli. The alveoli are then kept inflated during expiration using an appropriately high level of PEEP. In one study of a “lung protective” strategy utilizing low tidal volume ventilation and extra-high PEEP, recruitment manuvers were performed by maintaining a CPAP level of 35 to 40 cm H2 O for 30 seconds.

Others advocate application of equivalent or higher pressures for longer periods.

No controlled clinical trial supports the efficacy of recruitment maneuvers alone to improve clinically important outcomes, such as mortality or ventilator-free days. Studies of recruitment maneuvers have generally used physiological end points, e.g., improvement in oxygenation. In a subset of patients treated with high levels of PEEP in the ARDSnet trial comparing high versus low PEEP in ARDS, no clinically relevant improvements in arterial saturation were noted.

However, complications such as transient hypotension and slight drops in arterial saturation during the manuver were reported. On the other hand, other clinical studies have re-

Inhaled Nitric Oxide

In 1993 Roissant and colleagues published a study of inhaled nitric oxide (NO) as a novel therapy for ARDS. Given via inhalation, NO selectively vasodilates pulmonary capillaries and arterioles that subserve ventilated alveoli, diverting blood flow to these alveoli and away from areas of shunt. Lowering of the pulmonary vascular resistance, accompanied by lowering of the pulmonary artery pressure, appears maximal at very low concentrations (0.1 ppm) in patients with ARDS. Beneficial effects on oxygenation take place at somewhat higher inspired concentrations of NO (1 to 10 ppm).

Table 145-14 Results of ARDSNet Late Steriod Rescue Study (“LaSRS”) in Patients with Persistent ARDS: A Priori Protocol-Defined Outcomes and Adverse Events MethylprednisoloneTreated Group

Placebo-Treated Group

Mortality at day 60 (%) (95% CI)

28.6 (20.8–38.5)

29.2 (20.8–39.4)

No. of ventilator-free days at day 28

11.2 ± 9.4

6.8 ± 8.5

<0.001

No. of ICU-free days at day 28

8.9 ± 8.2

6.2 ± 7.8

0.02

No. of serious adverse events associated with myopathy or neuropathy

0

9

0.001

27 66 35 23

36 66 8 25

0.26

Variable or Outcome

60-Day mortality according to time from onset of ARDS (means) 7–13 days (%) No. of patients >14 days (%)∗ No. of patients ± values

p Value 1.0

0.02

are mean ± SD. = 0.02 for the interaction with treatment-group assignment (Wald’s test).

Abbreviations: SD = standard deviation; ventilator-free days by day 28, number of days alive and not receiving assisted ventilation between days 1 and 28; ICU-free days by day 28, number of days alive and not in ICU between days 1 and 28 Source: Acute Respiratory Distress Syndrome Network. N Engl J Med 354:1671, 2006.

∗p

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Rapid inactivation of NO by hemoglobin prevents unwanted systemic hemodynamic side effects, but also requires continuous delivery of gas through the ventilator circuit. Thus, if continuous delivery of NO is interrupted (e.g., during patient transport or due to NO supply exhaustion), precipitous and life-threatening hypoxemia and right-sided heart failure may occur.

Inhaled NO has been studied in one large contolled clinical trial in patients with ALI and ARDS (not due to sepsis) who had no other organ failures. Inhaled NO did not improve survival, although some patients experienced transient improvements in oxygenation. Based on this trial, the routine use of inhaled NO in ALI is not recommended.

Some clinicians may consider using inhaled NO as a salvage intervention (Table 145-16). However, a much less costly alternative, inhaled prostacyclin (epoprostenol/ilo- prost), is available. The initial daily cost of inhaled NO is several thousands of dollars, while the daily cost of inhaled prostacyclin is several hundreds of dollars. Although less well studied than inhaled NO, inhaled prostacyclin seems to improve oxygenation to the same degree in a majority of patients with ALI or ARDS. Tracheal Gas Insufflation

Tracheal gas insufflation (TGI) consists of delivering fresh gas through a modified endotracheal tube at a point just above the carina. The additional gas flow (i.e., flow provided in addition to the standard tidal volumes delivered by the ventilator) tends to remove CO2 -rich gas from the trachea and smaller airways. It has the effect of reducing anatomic dead space.

Although acute lung injury decreases the ability of TGI to reduce PaCO2 , permissive hypercapnia and higher PaCO2 values increase its relative effectiveness. For example, in one study of patients with ARDS, TGI using 100 percent humidified oxygen, delivered throughout the respiratory cycle at a flow of 4 L/min, lowered PaCO2 from 108 to 84 mmHg. Because TGI carries a number of potential risks (e.g., tracheal erosion, oxygen toxicity related to an increased FiO2 , and hemodynamic compromise or barotrauma due to TGIinduced auto-PEEP and a larger tidal volume than the ventilator is set to deliver), its routine use is not recommended.

However, once again, some clinicians may employ it as a salvage intervention for patients with high levels of PaCO2 (e.g., greater than 100 mmHg).

Extracorporeal Membrane Oxygenation (ECMO) or Extracorporeal CO2 Removal (ECCO2 R)

The use of extracorporeal gas exchange, such as ECMO or ECCO2 R, is based on the hypothesis that more patients will survive if the lung is allowed to recover from its injury by â&#x20AC;&#x153;restingâ&#x20AC;? it by using extracorporeal gas exchange temporarily. Although this hypothesis was initially stimulated by the desire to decrease the risk of pulmonary oxygen toxicity, its assessment can now be justified in regard to the techniquesâ&#x20AC;&#x2122; potential roles in reducing ventilator-induced lung injury (VILI).

In the 1970s, a large-scale study on use of ECMO in patients with severe ARDS demonstrated that it offered no

survival benefit to patients whose mortality was extremely high (approximately 90 percent). Similarly, a randomized controlled trial in severely ill patients with ARDS reported in 1994 did not find improved survival using ECCO2 R. Despite these findings, some clinicians believe that ECMO, with its continually improving technology, may be beneficial in subgroups of patients with ARDS when treated before 7 days of mechanical ventilation. A number of related techniques also have been utilized, including veno-venous ECMO to assist in CO2 elimination. Some specialized centers continue to offer ECMO to adults with severe ARDS and consider the technique as a safe life-saving salvage intervention (Table 145-16).

Corticosteroids

The general consensus among intensivists is that corticosteroids have little or no role to play in treating the acute phase of ALI or ARDS. However, the role of corticosteroids in later phases of ALI or ARDS has been controversial.

A number of small case series suggest that high-dose corticosteroid therapy may be beneficial during the proliferative phase of ARDS, based on the rationale of preventing lung scarring that occurs during this phase of ALI as a result of alveolar inflammation. Potential risks include immunosuppression of debilitated, instrumented patients managed in environments harboring multiple antibiotic-resistant organisms and potential long-term neuromuscular weakness associated with use of high-dose corticosteroids and paralytic agents.

In 2006, the ARDSNet investigators published results of a double blind, random, controlled clinical trial (Late Steroid Rescue Study or LaSRS) designed to evaluate benefits and risks of moderately high doses of corticosteroids in 180 patients with persistent ARDS (ARDS lasting 7 to 21 days) (Tables 145-15 and 145-16). It found no differences in 60- or 180-day mortality rates. Although parameters of respiratory function, including PaO2 /FiO2 , plateau pressure, respiratory system compliance, and time to, and rate of, liberation from mechanical ventilation improved after corticosteroid administration, the corticosteroid treated group included more patients who returned to assisted ventilation. Furthermore, no statistically significant differences between treated and untreated groups in ICU or hospital days by 180 days were observed. In addition, more adverse events related to weakness occurred in the treated group than in those receiving placebo.

Finally, patients treated with corticosteroids after 14 days of persistent ARDS had a significantly increased mortality (Table 145-15). Hence, the results of this study do not support the routine use of steroids for late-phase ARDS in general, and they argue against their use if ARDS has been present for 14 days or longer.

Beta-Agonists

Basic research supports the hypothesis that beta-agonists may improve the outcomes of patients with ALI or ARDS. Betaagonists stimulate removal of fluid from flooded alveoli by stimulating the epithelial sodium pump and promoting active

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Table 145-15 Results of ARDSNet Late Steroid Rescue Study (“LaSRS”) in Patients with Persistent ARDS: Post-hoc Analyses of Outcomes and Adverse Events at 180 Days Variable or Outcome

MethylprednisoloneTreated Group

Placebo-Treated Group

180-Day mortality (%) (mean) (95% CI)

31.5 (22.8–41.7)

31.9 (23.2–42.0)

1.0

No. of days of assisted ventilation in survivors up to 180 days (median) (interquartile range)

11

18

0.006

(6–22)

(10–33)

No. of days of ICU stay in survivors up to 180 days (median) (interquartile range)

17

20

(10–31)

(11–31)

No. of days of hospitalization in survivors up to 180 days (median) (interquartile range)

26

29

(19–43)

(19–40)

180-Day mortality according to time from onset of ARDS (means) 7–13 days (%) No. of patients >14 days (%)∗ No. of patients

27 66 44 23

39 66 12 25

p Value

0.29

0.73

0.14 0.01

∗p

= 0.006 for the interaction with treatment-group assignment (Wald’s test).

Abbreviations: SD = standard deviation.

Source: Acute Respiratory Distress Syndrome Network. N Engl J Med 354:1671, 2006.

transport of sodium out of the alveoli (with water following passively according to osmotic gradients). This mechanism is possible, however, only with an intact epithelial membrane.

Following preliminary reports suggesting that use of betaagonists may be effective in fluid removal in patients with ALI or ARDS, the ARDSNet clinical investigators began a large, randomized, double-blinded, controlled clinical trial of inhaled albuterol to test the hypothesis in 2006. Their results are pending.

Experimental Adjuncts to Lung-Protective Ventilation Two experimental adjuncts to lung-protective ventilation deserve comment: use of exogenous surfactant and partial liquid ventilation.

Exogenous Surfactant

Both animal and human studies have shown that in ALI surfactant levels are decreased or proportions of various surfactants are abnormal, resulting in decreased surface tensionlowering activity. Surfactant therapy in infants with respiratory distress syndrome (RDS) due to prematurity improves

gas exchange and lung mechanics, decreases the requirement for CPAP, lessens barotraumas, and improves survival. However, results of trials using surfactant therapy in adults with ALI or ARDS have been disappointing to date.

The first large, prospective, randomized controlled trial of inhaled surfactant in patients with ARDS due to severe sepsis was reported in 1996 and showed no benefit. Concerns about appropriate dosing of the agent, alternative modes of agent delivery, timing of therapy, types of subjects treated, and the precise surfactant formulation employed prompted investigators to view the study as inconclusive with regard to advising against use of exogenous surfactant in adults with ARDS. However, another large randomized, controlled trial reported in 2004 also found no improvement in survival; additional trials are underway.

In contrast, in children (infants to adolescents), one encouraging report on use of exogenous surfactant in ALI or ARDS demonstrated improvement in overall mortality, but not in ventilator-free days, which was the study’s primary end point. Further positive studies in children likely will be necessary to gain FDA approval for this indication.

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Table 145-16 “Rescue” or “Salvage” Interventions Used in Patients with ARDS and Severe Hypoxemia Resistant to Conventional Mechanical Ventialation and PEEP Corticosteroids Extracorporeal CO2 removal (ECCO2 R) Extracorporeal membrane oxygenation (ECMO) High frequency oscillatory ventilation (HFOV) Inhaled nitric oxide (NO) or inhaled prostacyclin (epoprostenol/iloprost) Pressure controlled inverse ratio ventilation (PC-IRV) Prone positioning Recruitment maneuvers Tracheal gas insufflation (TGI)

Currently, exogenous surfactant for adults is available only as an experimental agent.

Partial Liquid Ventilation

Clinical studies on use of partial liquid ventilation using oxygen-carrying perfluorocarbons instilled into the trachea of adults and children with ALI suggest that this mode of therapy has the potential to improve gas exchange. Partial liquid ventilation may improve oxygenation in part because the perfluorocarbon, by virtue of the hydraulic column created, is able to recruit dependent alveoli that PEEP is not. A practical problem with the technique is that agent used (perflubron) is radiodense, thereby complicating interpretation of chest radiographs in detecting infection or in following resolution of the ALI or ARDS. One clinical trial reported in 2006 reported that patients treated with partial liquid ventilation showed trends to worse survival, longer ventilator-free days and more complications.

CLINICAL COURSE, OUTCOME, AND LONG-TERM SEQUELAE The clinical course and outcomes of ALI and ARDS have been better delineated in recent years. Both pulmonary and nonpulmonary outcomes have been investigated.

Clinical Course and Duration The course of illness varies considerably in severity and duration among patients. ALI and ARDS may last for a few days or even less (e.g., ARDS from opioid exposure, with the patient recovering rapidly after the initial insult). Alternately, ARDS from other causes may last several months and involve a prolonged ICU course. Patients can recover or die at any point in the course of ALI or ARDS. The median duration of mechanical ventilation is approximately 9 days. Up to 20 percent of patients remain on mechanical ventilation for longer than 2 weeks, and about 10 percent still require assisted ventilation at 28 days (representing approximately 15 percent of those still alive at 28 days). Notably, as shown in LaSRS, a longer duration of mechanical ventilation for ALI/ARDS does not translate into a higher mortality. Most ARDS-related deaths occur within the first 2 weeks, with one-third occurring by day 7, two-thirds by day 14, and three-fourths to four-fifths by day 28.

The mortality rate of patients on mechanical ventilation after 2 to 4 weeks of persistent ARDS is about 30 percent over the ensuing 2 to 6 months. These rates are similar to the overall mortality rate (at 180 days) for patients enrolled in ARDSNet clinical trials in which low tidal volume ventilation was used. The findings highlight the importance of continued supportive care in the ICU and vigilance aimed at reducing nosocomial complications.

Trends in Mortality Rates Mortality rates for patients with ARDS have decreased since the early 1980s. In one hospital using the same definition of ARDS throughout the period analyzed, the mortality rate was 68 percent in 1982, 29 percent in 1996, and in the mid–30 percent range in 1997 and 1998. Obviously, the decrease cannot be ascribed to widespread application of low tidal volume ventilation strategies, since the decline was observed prior to publication of the ARDSNet ARMA study in May 2000.

The improvement is likely attributable to improvements in general ICU care, including prevention of nosocomial pneumonias and other infections, earlier institution of enteral nutrition, routine use of stress ulcer prophylaxis, and improved ICU teamwork. Notably, however, the case fatality rate for patients with ARDS due to sepsis remained the same over this time frame, while that for patients with ARDS due to trauma or other causes decreased significantly.

Mortality rates for patients with ALI but without ARDS (see previously described definitions in Table 145-1) are lower by about one-third than for those with ARDS. The decreased mortality presumably reflects the decreased severity of the oxygenation defect in ALI compared with ARDS (Table 145-1).

Causes of Death Approximately one-third of ARDS-related deaths occur in the first 7 days. Most are related to the underlying disease

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or injury, i.e., to events occurring before the onset of ARDS. The majority of patients who die succumb after 7 days, with these late deaths also commonly due to the underlying injury or illness. Other causes include complications occurring contemporaneously with or after the onset of ARDS. The most common cause of death in this group of patients is sepsis and associated multiple organ system failure. Of note, only a relatively small fraction of patients—10 to 20 percent of all patients with ARDS—die a respiratory death due to irreversible hypoxemia or refractory respiratory acidosis. Therefore, not surprisingly, clinical trials of interventions aimed selectively at improving gas exchange (e.g., use of inhaled nitric oxide or exogenous surfactant) have not demonstrated improved survival.

Long-Term Sequelae Recent studies indicate that many survivors of ALI have medical problems and a compromised quality of life both of which persist well beyond their initial ICU stay. Impaired pulmonary, neurologic, musculoskeletal, cognitive, and psychosocial functions have been documented in ALI survivors.

Furthermore, survivors have a poorer quality-adjusted survival than do critically ill subjects without ALI. Research into these disorders is in the early stages; the etiology and pathophysiology of are incompletely understood. Recognition of the problems affecting ALI survivors and referral for appropriate evaluation and therapy constitute important components of overall care. With improved therapy of ALI resulting in greater survival rates, clinicians should anticipate an increase in the prevalence of long-term sequelae.

Health-Related Quality of Life Health-related quality of life (HRQL) has become increasingly recognized as important to the evaluation of patient-centered outcomes in recovery from a variety of illnesses. A number of studies have evaluated HRQL in ALI survivors. Tools used to assess HRQL include the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), St. George’s Respiratory Questionnaire, Quality of Well Being Scale, and Sickness Impact Profile. Each has illustrated impaired quality of life in survivors of ALI compared with various control populations, including critically ill subjects without ALI and patients with chronic diseases (including cystic fibrosis). In general, impairments in HRQL improve over the first 3 months following discharge from the ICU and appear to plateau by 1 year.

Studies of interventions to improve HRQL are under way.

Pulmonary Sequelae Studies of pulmonary function following ALI and ARDS are affected by inconsistent disease definitions, methodological problems due to lack of patient follow-up, and heterogeneity of preexisting pulmonary diseases. Consequently, a range of lung function impairments has been reported following recovery. Although a proportion of survivors of ALI may have

ALI and ARDS

impaired diffusion capacity or restrictive or obstructive abnormalities, restoration of normal lung function occurs in a substantial proportion. In the Toronto ARDS Outcomes study, restrictive and diffusion abnormalities observed at 3 months improved toward normal by 1 year. Given the severely impaired physical function domains reported in HRQL surveys and the relatively mild pulmonary impairment, investigation has more recently focused on other limitations and causes of symptoms in ALI survivors (see below).

Physical and Neuromuscular Sequelae In the previously noted Toronto ARDS Outcomes study, persistent physical impairment in survivors of ARDS was assessed. Despite improvement in pulmonary function at 1 year following their ICU stay, this cohort had low exercise capacity, weakness, and decreased muscle mass. Risk factors for these findings included multiorgan dysfunction in the ICU, prolonged duration of ARDS, treatment with corticosteroids during the ICU stay, and increased co-morbid disease burden.

Although the basis for many of the abnormalities is not clear, a number of patients demonstrated a range of abnormalities, including critical illness polyneuropathy, ICU-acquired myopathy (critical illness myopathy), entrapment neuropathy, and heterotopic ossification.

Cognitive and Psychological Sequelae Cognitive impairments can cause major limitations in the ability to return to work, affect mood, and lead to increased health care expenditures. Study of long-term cognitive function in ARDS survivors indicates that many have impaired memory, reduced attention, and decreased concentration and processing speed. The abnormalities were associated with the number and severity of hypoxemic episodes in the ICU. Similar to physical abnormalities, cognitive dysfunction seemed to be worse in the first 3 months following hospital discharge; it improved until 1 year and then reached a plateau.

Depression and anxiety are frequent following ARDS. Several studies indicate that the prevalence of depression symptoms is as high as 50 percent following recovery. These emotional problems are likely multifactorial, including prior hypoxic brain injury and delirium and subsequent limitation of physical function. In addition, some authors have suggested the presence of a major component of post-traumatic stress disorder (PTSD) in survivors of ALI. Because these disorders are potentially treatable using pharmacological, behavioral, and cognitive therapies, clinicians should ask ARDS survivors about possible depression and anxiety, which, in turn, may improve HRQL. Finally, in accord with the concept that the ICU team treats patients as well as their families, clinicians need to be aware that familial caregivers of patients who are survivors of ALI or ARDS experience long-term health effects. In particular, they are at increased risk for emotional distress (associated with various factors, including patient depression) and a lower HRQL over all domains tested on the Medical

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Outcomes Short Form 36. Clinicians providing long term follow-up care for patients with ALI or ARDS should aim to ensure adequate social and other support for their familial caregivers.

SUGGESTED READING Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301, 2000.

Ammann P, Fehr T, Minder EI, et al: Elevation of troponin I in sepsis and septic shock. Intensive Care Me 27:965, 2001.

Ashbaugh DG, Bigelow DB, Petty TL, et al: Acute respiratory distress in adults. Lancet 2:319, 1967.

Bernard GR AA, Brigham KL, et al: The American-European Consensus Conference of ARDS: Definitions, mechanisms, relevant outcomes, and clinical trial coordination.

Am J Respir Crit Care Med 149:818, 1994.

Bernard GR: Acute respiratory distress syndrome: A historical perspective. Am J Respir Crit Care Med 172:798, 2005.

Cameron JI, Herridge MS, Tansey CM, et al: Well-being in informal caregivers of survivors of acute respiratory distress syndrome. Crit Care Med 34:81, 2006.

Chan KPW, Stewart TE, Mehta S: High-frequency oscillatory ventilation for adult patients with ARDS. Chest 131:1907, 2007.

Duane PG, Colice GL: Impact of noninvasive studies to distinguish volume overload from ARDS in acutely ill patients with pulmonary edema: Analysis of the medical literature from 1966 to 1998. Chest 118:1709, 2000.

Fan D, Needham M, Stewart TE: Ventilatory management of acute lung injury and acute respiratory distress syndrome.

JAMA 294:2889, 2005.

Gattinoni L, Caironi P, Pelosi P, et al: What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 164:1701, 2001.

Gattinoni L, Pesenti A: The concept of “baby lung”. Int Care Med 31:776, 2005.

Hager DN, Krishnan JA, Hayden DL, et al: Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med 172:1241, 2005.

Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683, 2003.

Hopkins RO, Weaver LK, Collingridge D, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 171:340, 2005.

Jefic D, Lee JW, Jefic D, et al: Utility of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide in evaluation of respiratory failure in critically ill patients.

Chest 128:288, 2005.

Moss M, Mannino DM: Race and gender differences in acute respiratory distress syndrome in the United States: An analysis of multiple-cause mortality data (1979–1996).

Crit Care Med 30:1679, 2002.

Murray JF, Matthay MA, Luce JM, et al: An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138:720, 1988.

Rubenfeld GD, Caldwell E, Peabody E, et al: Incidence and outcomes of acute lung injury. N Engl J Med 353:1685, 2005.

Perkins GD, McAuley DF, Thickett DR, et al: The betaagonist lung injury trial (BALTI): A randomized placebocontrolled clinical trial. Am J Respir Crit Care Med 173:281, 2006.

Stapleton RD, Wang BM, Hudson LD, et al: Causes and timing of death in patients with ARDS. Chest 128:525, 2005.

The National Heart, Lung, and Blood Institute ARDS Clinical Trials Network: Higher versus lower positive endexpiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327, 2004.

The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 354:1671, 2006.

The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: The fluid and catheter treatment trial (FACTT): pulmonary artery catheter versus central venous catheter guided treatment of acute lung injury. N Engl J Med 354: 2213, 2006.

The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network: Comparison of two fluid management strategies in acute lung injury: the fluid and catheter treatment trial (FACTT). N Engl J Med 354:2564, 2006.

Ware LB, Matthay MA: Acute pulmonary edema. N Engl J Med 353:2788, 2005.

146 Sepsis, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome Stuart F. Sidlow Clifford S. Deutschman

I. DEFINITIONS, NATURAL HISTORY, AND EPIDEMIOLOGY II. STRESS RESPONSE, SIRS, SEPSIS, AND MODS III. CLINICAL PATTERNS OF SIRS AND MODS IV. EPIDEMIOLOGY V. PATHOPHYSIOLOGY VI. HYPOTHESES OF UNDERLYING MECHANISMS Cytokine Hypothesis Microcirculatory Hypothesis Gut Hypothesis

The systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) are diseases of medical progress. Prior to advances in critical care medicine that have characterized the past three decades, SIRS and MODS were unknown. However, our ability to treat shock, manage acute renal insufficiency, support patients in pulmonary failure, and even to transplant organs such as the liver has unmasked these new syndromes. Indeed, initial reports on MODS, which, at the time was called sequential system failure or multiple system organ failure, heralded the ability to rescue patients from such diverse catastrophic events as ruptured abdominal aortic aneurysm, severe trauma, pancreatitis, multiple transfusions, and progressive infections.

Attempts to manage MODS have led, in turn, to a host of important biochemical, metabolic, and physiological discoveries.

This chapter defines the clinical findings that constitute sepsis, SIRS, and MODS and places these disorders in con-

‘‘ Two-Hit’’ Hypothesis Connectionist Hypothesis Other Hypotheses VII. MANAGEMENT Pulmonary Dysfunction Source Control Perfusion Management Rational Use of Inotropes and Vasopressors Metabolic Management Novel Medications VIII. CONCLUSION

text by relating them to a continuum of clinical abnormalities and syndromes. In addition, the natural history of these disorders is reviewed briefly. Several pathogenic hypotheses, management strategies, and intriguing new forms of therapy are examined.

DEFINITIONS, NATURAL HISTORY, AND EPIDEMIOLOGY The characteristic response to inflammatory stimuli, including surgery and trauma, classically has been referred to as the stress response (Fig. 146-1)—the evolutionary importance of which is facilitation of survival and tissue repair. Initially, an orchestrated neural-endocrine-humoral response directs substrate delivery to the most vital organs— the heart and brain. This response is accomplished through

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 146-1 Diagnostic Criteria SIRS Temperature >38◦ C or <36◦ C Heart rate >90 beats/minute Respiratory rate >20 breaths/min or Pco2 <32 mmHg WBC >12×109 /L or <2×109 /L or >10% immature forms Sepsis SIRS + identified or suspected infection Sever Sepsis Sepsis + dysfunction of 1 or more organ systems Septic Shock Sepsis + hypotension (BP <90 mmHg or a reduction of >40 mmHg from baseline in the absence of other causes) despite adequate fluid resuscitation and perfusion abnormalities (e.g., lactic acidosis, oliguria, altered mental status) MODS No current definitions Figure 146-1 Diagrammatic representation of the two classic patterns of MODS pathogenesis. Percentages indicate the proportion of patients following the pathway. Patients develop respiratory insufficiency after an initial insult. In some cases (left side of diagram) this persists for 2 to 3 weeks, and the patients then rapidly develop abnormalities of other organ systems. Over the course of the next week, patients either recover or die. In a second group of patients, multiple-organ dysfunction rapidly follows the onset of respiratory insufficiency. These abnormalities persist for 2 to 3 weeks. Over the next week, patients then either recover or die.

vasoconstriction, fluid retention, and translocation of intracellular water to the vasculature. In the absence of exogenous support, death from shock ensues if these endogenous mechanisms are inadequate. Following resuscitation from the initial period of shock, hypermetabolism develops. The driving force behind this second phase is repair of damaged tissue, with white blood cells serving as the primary effectors of the process. To support the increased white blood cell mass, substrate is mobilized from endogenous sources and glucose reserves are rapidly depleted. Because white blood cells are obligate glucose users, muscle (both skeletal and smooth) is broken down to provide precursors for hepatic gluconeogenesis. In addition, amino acids are used to synthesize structural proteins and enzymes. Energy to support the liver, heart, and other organs is derived from fat and amino acids, since utilization of glucose by tissues other than blood cells and neurons is blocked. Generalized capillary recruitment and leak allows glucose delivery to the avascular tissue of the wound.

The amount of fluid in the extracellular compartment, par-

From Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250–1256, 2003.

ticularly in the extravascular matrix, increases dramatically.

Continued fluid retention and movement of water out of cells fill the dilated, leaky vasculature. Vasodilatation is accompanied by an increase in cardiac output, which further facilitates delivery of substrate.

By the fourth day after injury or surgery, neovascularization of damaged tissue occurs. Along with a sharp increase in substrate delivery to the tissue of the newly vascularized wound, a decrease occurs in capillary leak accompanied by generalized increases in vascular tone and in the mobilization and excretion of fluid in the matrix. Water also returns to cells. In most cases, the patient recovers uneventfully.

In an unknown percentage of patients, the inflammatory process becomes persistent, progressing to the systemic inflammatory response syndrome, or SIRS. This process is defined by the presence of two or more of the criteria listed in Table 146-1. Because these are normal responses postsurgery or following trauma, these criteria must persist beyond days 3 to 5 for the disorder to be termed SIRS. Although SIRS is a useful term in comparing studies in the literature, some have challenged the notion that it is a useful diagnostic entity. One alternative approach is the socalled “PIRO” classification system (Table 146-2), which considers Predisposition, Infection, Response, and Organ Dysfunction in evaluating patients in the context of a systemic

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Table 146-2 The PIRO system for Staging Sepsis Domain

Present

Future

Rationale

Predisposition

Premorbid illness with reduced probability of short-term survival.

Cultural or religious beliefs, age, sex.

Genetic polymorphisms in components of inflammatory response (e.g., TIR, TNF, IL-1, CD14): enhanced understanding of specific interactions between pathogens and host diseases.

In the present, premorbid factors impact on the potential attributable morbidity and mortality of an acute insult; deleterious consequences of insult heavily dependent on genetic predisposition (future).

Insult infection

Culture and sensitivity of infecting pathogens; detection of disease amenable to source control.

Assay of microbial products (LPS, mannan, bacterial DNA): gene transcript profiles.

Specific therapies directed against inciting insult require demonstration and characterization of that insult.

Response

SIRS, other signs of sepsis, shock, CRP.

Nonspecific markers of activated inflammation (e.g., PCT or IL-6) or impaired host responsiveness (e.g., HLA-DR); specific detection of target of therapy (e.g., protein C, TNF, PAF).

Both mortality risk and potential to respond to therapy vary with nonspecific measures of disease severity (e.g., shock); specific mediator-targeted therapy is predicated on presence and activity of mediator.

Organ dysfunction

Organ dysfunction as number of failing organs or composite score (e.g., MODS, SOFA, LODS, PEMOD, PELOD).

Dynamic measures of cellular response to insult—apoptosis, cytopathic hypoxia, cell stress.

Response to preemptive therapy (e.g., targeting micro-organism or early mediator) not possible if damage already present; therapies targeting the injurious cellular process require that it be present.

TLR, Toll-like receptor; TNF, tumor necrosis factor; IL, interleukin; LPS, lipopolysaccharide; SIRS, systemic inflammatory response syndrome; CRP, C-reactive protein; PCT, procalcitonin; HLA-DR, human leukocyte antigen-DR; PAF, platelet-activating factor; MODS, multiple-organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; LODS, logistic-organ dysfunction system; PEMOD, pediatric multiple-organ dysfunction; PELOD, pediatric logisticorgan dysfunction. source: Table created using data from Angus et al (2003); Gerlach et al (2003); Vincent, Opal et al (2003); and Vincent, Wendon et al (2003).

inflammatory response. While not yet widely accepted, this classification system has the potential to address some of the concerns over the SIRS designation.

Whatever one calls the syndrome that develops when inflammation becomes persistent, the clinical entity does exist, often driven by an underlying source, such as a nidus of infection or in undrained hematoma. Such occurrences generally reflect extensive trauma, delayed resuscitation, surgery complicated by extensive, rapid blood loss, or inflammation, as occurs with pancreatitis or aspiration pneumonitis. If a clear source of infection is present, the disorder is classified as sepsis. Further details are summarized in Table 146-3. Although sepsis or SIRS may be complicated by hypotension, lactic acidosis, acute lung injury, or oliguria, obvious organ dysfunction is not present. When organ dysfunction does

arise, the syndrome is termed “multiple-organ dysfunction syndrome”, or MODS.

STRESS RESPONSE, SIRS, SEPSIS, AND MODS Virtually all organs become dysfunctional in MODS. However, defining which abnormalities in individual organs constitute dysfunction is problematic. Although many different criteria have been used, none are universally accepted. Indeed, two Consensus Conference Committees of the American College of Chest Physicians (ACCP) and the Society for Critical

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Table 146-3 General Criteria for Organ Dysfunction System

Mild

Severe

Pulmonary

Hypoxia/hypercarbia requiring assisted ventilation for 3–5 d

ARDS requiring PEEP >10 cm H2 O and Fio2 >0.5

Hepatic

Bilirubin 2–3 mg/dl or other LFTs twice normal, PT elevated to twice normal

Jaundice with bilirubin >8–10 mg/dl

Renal

Oliguria (<500 ml/d) or increasing creatinine (2–3 mg/dl)

Dialysis

Gastrointestinal

Intolerance of GI feeding >5 d

Stress ulceration with need for transfusion, acalculous cholecystitis

Hematologic

PTT >125% of normal, platelets <50,000–80,000 per mm3

DIC

CNS

Confusion

Coma

PNS

Mild sensory neuropathy

Combined motor and sensory deficit

Cardiovascular

Decreased ejection fraction, persistent capillary leak

Hypodynamic state not responsive to pressors

ARDs = acute respiratory distress syndrome; PEEP = positive end-expiratory pressure; LFTs = liver function tests; PT = prothrombin time; PTT = partial thromboplastin time; DIC = disseminated intravascular coagulation; CNS = central nervous system; PNS = peripheral nervous system. source: From Deitch EA: Multiple organ failure: Pathophysiology and potential future therapy. Ann Surg 216:117–134, 1992.

Care Medicine (SCCM) declined to recommend the adoption of specific definitions. The basis for this position may reflect the understanding that just as MODS falls along a continuum of abnormalities, so, too, is there spectrum of abnormalities in each organ system. Furthermore, the transition from adaptive response to organ dysfunction may be clinically obscure, and distinctions among sepsis, SIRS, and MODS are often simply semantic.

Some generally used criteria for organ dysfunction in other systems are detailed in Table 146-3. However, these criteria reflect the gaps in our understanding of MODS. More detailed investigations into the pathobiology of MODS should provide more useful diagnostic criteria.

CLINICAL PATTERNS OF SIRS AND MODS Two well-defined forms of SIRS/MODS are recognized (Fig. 146-1). In either, development of acute lung injury or the acute respiratory distress syndrome (ARDS) is of key importance to the natural history. ARDS is the earliest manifestation in almost all cases.

In the more common form of SIRS/MODS, damage to the lungs predominates and often is the only evidence of

organ dysfunction until very late in the disease. This predominantly pulmonary form of MODS is identical to ARDS, which is described in depth elsewhere (see Chapters 144 and 145).

However, it is important to point out that the natural history of patients with this type of MODS is well established. Most often, these patients present with an initiating pulmonary affliction (e.g., pneumonia, aspiration, lung contusion, neardrowning, exacerbation of COPD, lung hemorrhage, or pulmonary embolism) that progresses to a condition that meets the diagnostic criteria for ARDS. Ventilator-dependent pulmonary dysfunction, often accompanied by encephalopathy and a mild coagulopathy, persists for some time. At some point, the patient either begins to recover or progresses to develop fulminant dysfunction in other organ systems, most often hepatic, renal, or cardiovascular. A large proportion of patients with multiple organ involvement do not survive. The pulmonary origin of this form of SIRS/MODS is useful diagnostically since the population at risk can often be defined; data indicate a better prognosis in this subgroup.

Diagnosis of the second form of SIRS/MODS is more problematic. Although the earliest manifestation of the syndrome continues to be pulmonary, most often there is an underlying source that is remote from the lung. This group consists of patients who have experienced major trauma (including isolated head injuries, intra-abdominal sepsis,

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extensive blood loss, pancreatitis, vascular catastrophes, such as ruptured or dissecting aneurysms, and a host of other conditions). Acute lung injury and ARDS develop early, but dysfunction in other organs soon becomes evident.

Most studies have found the liver to be the next most commonly involved organ. Indeed, if one considers bleeding associated with an elevated prothrombin time to reflect a hepatic abnormality, the liver may well become dysfunctional even in cases classified as primary pulmonary MODS. Gastrointestinal, cardiovascular, and renal dysfunction are cited equally as the next most common signs of organs failure.

Compensated organ dysfunction persists for some time before the patient either recovers or deteriorates further and dies. The diversity of the population at risk makes early diagnosis of the second form of SIRS/MODS difficult. Furthermore, since many of these patients have undergone surgical procedures, development of mild hypoxemia and increased lung water—normal findings after surgery—may obscure early recognition of ARDS. Thus, SIRS/MODS may not be appreciated until dysfunction in several organ systems has become well established.

Improvements in our ability to support patients with MODS have led to recognition of a third syndrome—referred to (for lack of a better term) as “chronic critical illness.” At some point, critically ill patients may become quite stable (i.e., unchanging), but their physiology remains remarkably abnormal. Typically, they require exogenous support of major organ systems. A “hyperimmune” state gives way to one of immunosuppression. Most hormonal systems cease to work properly either because of resistance to hormonal effects or to depletion of hormonal synthesis and storage. These abnormalities reflect a state of endocrine “burn-out” that currently has no specific treatment.

EPIDEMIOLOGY Accurate determination of the incidence of SIRS/MODS is difficult, predominantly a reflection of the diverse etiologies of the syndromes. The incidence of primary pulmonary SIRS/MODS (i.e., ARDS) is estimated to be in excess of 150,000 cases per year. With regard to the second form of SIRS/MODS, the estimated number of cases in the United States is 750,000 per year. The incidence of MODS following trauma that necessitates admission to the ICU may be as high as 14 percent.

Mortality from MODS remains distressingly high. Estimated mortality from ARDS per se is approximately 35 to 40 percent. Involvement of additional organ systems increases the likelihood of a poor outcome; the presence of dysfunction in three or more organ systems virtually ensures death.

Some investigators have reported lower mortality rates; others have shown that mortality is a function of the duration of organ failure. The incidence and mortality of MODS may be increasing. Although there is a lack of consensus in this

regard, clearly, once the disease has progressed to the point of multi-organ failure, the patient is at substantial risk for death.

PATHOPHYSIOLOGY The major factor limiting treatment of MODS is the lack of a clear understanding of the underlying pathophysiological defect. In fact, if not viewed carefully, the changes associated with SIRS/MODS may simply resemble an extension of those observed after uncomplicated stress. Thus, patients recovering from major surgery undergo increases in metabolic rate, oxygen consumption, and carbon dioxide production.

Relative glucose intolerance and hyperglycemia also occur.

The vasculature is dilated, and the cardiac output increases to promote oxygen transport. In fact, lactate production may increase, reflecting the overall increase in metabolism rather than tissue hypoxia.

Although simple stress and SIRS/MODS have in common altered intermediary metabolism, a hyperdynamic circulation, and systemic signs of inflammation, two important distinctions have been consistently observed. First, noted previously, they differ in time course. Whereas postoperative hypermetabolism runs its course over 5 to 7 days and resolves with neovascularization, the time course of SIRS/MODS is longer, usually 3 to 4 weeks. The second distinction consists of subtle differences in metabolic and physiological parameters. In simple stress and early SIRS, the increase in metabolic demand can be met by an increase in oxygen supply or in oxygen extraction. However, as the disease progresses toward MODS, the ability to extract, and possibly, utilize, oxygen is lost in some tissue beds. This situation is unstable, because oxygen demand on the cellular level is increased. Similarly, in simple stress there appears to be a block in peripheral glucose utilization.

Glucose intolerance becomes more pronounced in SIRS/MODS, possibly because of a defect in the enzyme pyruvate dehydrogenase, which catalyzes conversion of pyruvate to acetyl coenzyme A (acetyl CoA). As a result, increases in tissue metabolic demand cause an increase in the activity of the Krebs cycle and in the generation of lactate (aerobic glycolysis). Consequently, serum lactate increases in direct proportion to the increase in pyruvate. If a microcirculatory perfusion deficit develops, increases in lactate exceed increases in pyruvate. These changes in glucose metabolism become progressively less responsive to modulation by insulin. Ultimately, futile cycling occurs of alanine and lactate between the liver and periphery.

The onset of hepatic dysfunction is heralded by increments in serum lactate that are disproportionate to the increments in pyruvate. Fat metabolism is markedly altered as well. Stress is characterized by levels of ketosis that are disproportionately low for the degree of starvation. It also elicits an increase in hepatic gluconeogenesis, which, in turn, causes hyperinsulinemia.

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Stress is associated with lipolysis, decreased lipogenesis, and increased oxidation of long- and medium-chain triglycerides. In early SIRS/MODS, lipogenesis undergoes further decrease. However, oxidation of long-chain triglycerides by the liver also decreases, in association with a decrease in expression of key beta-oxidative enzymes. Ultimately, fat intolerance arises as the liver continues to fail.

In the setting of SIRS/MODS, with significant abnormalities of both glycolysis and beta-oxidation, amino acids become an important source of fuel. As oxidation of amino acids increases, so does urea production. Exogenous protein can be an important energy source, but ultimately, hepatic failure compromises ureagenesis and limits this energy source, as well.

On the physiological level, vasodilatation and peripheral edema become more pronounced. Cardiac output increases as afterload decreases, but ultimately, the heart also fails as energy sources are depleted. Renal mechanisms are then called upon to conserve fluid and to excrete urea. The generalized edema limits the ability to concentrate the urine maximally, thereby leading to two incompatible goals. As a result, the renal system also becomes dysfunctional. One additional hallmark of progressive SIRS/MODS is a loss of the normal hormonal modulation of cellular processes. Thus, insulin-mediated glucose uptake decreases and blood pressure becomes unresponsive to all but the most potent vasopressors, while a glucagon-induced alteration in gluconeogenesis disappears. The mechanisms by which these changes occur are unknown.

A large number of hypotheses have been advanced to explain the pathophysiology of SIRS/MODS. From these have emerged two general concepts concerning etiology.

In one, the predominant effect is in the microcirculation: along with an overall decrease in peripheral vascular tone, demand and supply at the microcirculatory level are mismatched, resulting in misdistribution of flow. In the second, the defect is predominantly one of cellular and, indeed, mitochondrial, metabolism. All hypotheses invoke a process that “activates” an inflammatory cascade that “mediates” end-organ responses. In time, these responses become dysfunctional. It is generally accepted that dysfunction in some way results from an inability to meet metabolic demands because of either inadequate flow or direct metabolic block.

HYPOTHESES OF UNDERLYING MECHANISMS A number of hypotheses have been advanced regarding the underlying basis of SIRS/MODS.

Cytokine Hypothesis Cytokines are mediators produced and secreted by a number of cells, most notably inflammatory and endothelial cells.

These mediators bind to receptors on the cell membrane and initiate intracellular events that alter cell behavior. The cell whose behavior is altered may be the same cell that produces the cytokine (autocrine), a nearby cell (paracrine), or a distant cell (endocrine). Cytokines activate a number of intracellular signal transduction pathways. The ultimate effect may be direct (e.g., activation of membrane channel or an intracellular protein) or may result in stimulation of gene expression.

Cytokines that have been implicated in SIRS/MODS include tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-γ (INF-γ).

Following simple stress, TNF-α or IL-1 are produced by inflammatory cells drawn to the site of injury or inflammation and by local endothelial cells. These cytokines are then released into the circulation and affect distant organs. The behavior of TNF-α on the liver serves as a useful paradigm.

A 26-kD form of TNF-α is produced by local cells and is expressed on the cell surface. This form of TNF-α is, through unknown mechanisms, active in control of debridement and infection at the local level. Ultimately, however, 26-kD TNF-α is cleaved by a matrix metalloproteinase to a 17-kD circulating form. The blood carries the 17-kD form from remote organs. The 17-kD form is capable of not only producing vasodilatation (perhaps, via a nitric oxide-linked pathway), but also of stimulating other inflammatory and noninflammatory cells. For example, in the liver, TNF-α stimulates resident macrophages (Kupffer cells) to produce more TNF-α, as well as other cytokines, such as IL-1 and especially IL-6. TNF-α, IL-1, and IL-6 then induce hepatocytes to express the genes for a number of proteins called acute-phase reactants. These secreted proteins have diverse activities that help control the inflammatory response. Since low levels of TNF-α (and IL-1) are released from the initial site of inflammation, the process should be self-limited.

In the cytokine theory of MODS, over-production of TNF-α, IL-1, or IL-6 and resultant uncontrolled inflammation are postulated. The net result is prolonged, uncontrollable vasodilatation and damage to viable organs by activated macrophages and other inflammatory cells.

In support of this theory, high levels of circulating TNFα, IL-1, IL-6, and INF-γ have been found in fulminant septic shock (e.g., as in disseminated meningococcemia). Similarly, in animal models in which endotoxin is administered intravenously, serum levels of TNF-α and IL-1 are increased. Studies in animals and human volunteers indicate that TNF-α is probably the most proximal mediator, initiating the expression and release of the other cytokines. TNF-α is cytotoxic to a number of cells, initiating programmed cell death (apoptosis) in culture. Antibodies to TNF-α are protective in lethal endotoxemic and bacteremic animal models, while certain intracellular proteins can block TNF-α–induced apoptosis.

Finally, administration of TNF-α to animals results in a syndrome that mimics septic shock, whereas giving low doses of this cytokine to humans mimics certain metabolic aspects of SIRS. Substantial data indicate, however, that this view of SIRS/MODS is simplistic.

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In animal models of bacterial peritonitis, neutralizing TNF-α in the serum increases mortality. Reported levels of cytokines in the blood of septic patients vary considerably among studies. Also, clinical trials of anti-TNF-α in human SIRS have been disappointing. Recent data indicate that serum levels do not reflect tissue levels, and that the cellassociated, 26-kD form (and not the 17-kD circulating form) of TNF-α mediates organ injury. Evidence from studies of IL6 knockout mice indicates that this cytokine is an important component of hepatic regeneration; therefore, it may be protective, rather than injurious. Since a host of other mediators and pathways are activated in SIRS, a reasonable conclusion is that cytokines are important mediators of certain aspects of SIRS/MODS, but that other factors are at work.

Microcirculatory Hypothesis The common link in the microcirculatory hypothesis is that the failure of cells or organs to receive adequate levels of oxygen or some important nutrient or substrate triggers SIRS/MODS. Low blood flow, as is likely to occur in hypotension or shock, contributes to cellular dysfunction. However, the release of vasoactive mediators and vascular congestion secondary to microthrombi and leukocytes are also held to be important.

Reperfusion of ischemic tissue may be as important a determinant of tissue injury as decreased flow itself. In particular, the generation of oxygen free radicals and peroxidation of membrane lipids following reperfusion may contribute to tissue injury. Sources of free radicals include the conversion of molecular oxygen to superoxide by xanthene oxidase, activated leukocytes, mitochondria, and prostaglandin synthase. The first two sources are probably the most important.

Circulatory shock, microvascular compromise, and free radical generation are likely to affect the endothelium directly.

Endothelial cells are active in free radical formation, provide a point of attachment for leukocytes, and may be exquisitely sensitive to hypoxia. Furthermore, they not only produce, but are also affected by, vasoactive mediators. These interactions provide the link between the cytokine and microvascular hypotheses.

Cytokines activate endothelial cells to elaborate other vasoactive substances and to express surface proteins that promote leukocyte adhesion; endothelial cells are also important participants in the formation of microthrombi. In support of the microvascular hypothesis, circulatory shock often occurs before MODS; autopsy data indicate the presence of microvascular injury in patients with MODS; and microthrombi containing platelets, neutrophils, and fibrin are common in MODS. Antibodies to CD18, which block leukocyte adhesion, do occur in circulatory shock and are protective in some forms of ischemia-reperfusion injury; they are not protective against liver injury or leukocyte adherence in experimental sepsis. The microthrombi, microvascular constriction, and free radicals are valuable in limiting the spread of infection.

Gut Hypothesis The syndrome that is now designated as SIRS once was believed to be the result of uncontrolled infection, presumably due to the endotoxin released by gram-negative bacteria.

However, organisms other than gram-negative bacteria have been implicated, and in many patients, neither microorganisms nor a source of bacteria can be identified.

The gut hypothesis contends that inflammation is due, in part, to bacteria in the gastrointestinal tract (or their associated endotoxin) that translocate to the mesenteric lymph nodes, liver, and circulation. Various insults have been shown to lead to such translocation of bacteria or endotoxin, and the intestinal barrier is disrupted in many clinical situations that can precede MODS. As a rule, translocation involves a combination of insults, including an alteration in the indigenous gastrointestinal flora, that results in bacterial overgrowth, impaired host defenses, and physical disruption of the intestinal barrier.

The gut hypothesis overlaps the cytokine and microcirculatory hypotheses. Bacteria or endotoxin activates white blood cells and induces production of cytokines. Each can alter the behavior of both endothelial cells and the coagulation system, leading to microvascular aggregation and production of free radicals, which can, in turn, create a self-sustaining cycle that culminates in MODS. Exposure to intestinal flora activates hepatic macrophages (Kupffer cells), releases cytokines, and damages hepatic cells, reinforcing the hypothesis that translocated bacteria are important in the pathogenesis of SIRS/MODS.

‘‘Two-Hit’’ Hypothesis A second insult, subsequent to an initial “hit,” may be of major importance in the pathogenesis of SIRS/MODS. According to this hypothesis, an initial period of hypotension “primes” the trauma patient for SIRS/MODS (i.e., the initial insult activates other processes that amplify the effects of the initial event, however mild).

Priming could involve activation of white blood cells or platelets, disruption of the intestinal mucosal barrier, or the induction of free radicals and the enzymes (such as xanthene oxidase) that produce these reactive species. Although this hypothesis overlaps with others, such as the cytokine, microcirculatory, and gut hypotheses, animal studies in which a single insult is followed by a second, more severe insult have shown that the first “hit” is actually protective.

Connectionist Hypothesis By viewing biologic systems as composed of oscillators, with the oscillations reflecting a continuously changing series of external events, we can regard the loss of either the external stimuli or the ability to respond to these stimuli as pathological. On the basis of this approach, and with the application of nonlinear modeling, the transition from SIRS to MODS has been depicted as an erosion in the ability of different organs to

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communicate with each other. For example, in experimental sepsis, hepatocellular metabolic pathways, such as glucogenesis, respond inadequately to hormonal stimulation. Similarly, beat-to-beat cardiac variability in human volunteers is lost during experimental endotoxemia. The connectionist hypothesis supplements, rather than substitutes for, the hypotheses presented above.

Other Hypotheses Other hypotheses are being explored. For example, one possibility under investigation is that the seemingly diffuse abnormalities in SIRS and MODS may be related to deficits in hepatic metabolism. Consistent with this hypothesis is the observation that gluconeogenesis, beta-oxidation, and ureagenesis are impaired in septic animals. These alterations are due, in part, to a decrease in the transcription of genes coding for key enzymes in each pathway. Furthermore, when important transcription factors are examined, a potential link between pulmonary and hepatic dysfunction becomes clear.

Similarly, another theory holds that dysfunction at the mitochondrial level may be responsible for the improper response in MODS—specifically, inadequate oxygen utilization by cells may be operative. This mechanism, coupled with inadequate oxygen delivery (as described in the microcirculatory hypothesis) results in a mismatch between oxygen demand or supply and oxygen utilization. Recent studies reveal a defect in cytochrome oxidase, the terminal complex in the electron transport chain, in septic myocardium.

Regardless of which is the dominant “cause” or “effect” of SIRS or sepsis, the net result is that dysfunction of multiple systems results in physiological detriment to the patient and threatens survival.

MANAGEMENT Management of patients with SIRS/MODS is challenging and focuses on treatment of major end-organ damage.

Pulmonary Dysfunction Pulmonary dysfunction most often takes the form of secondary ARDS. This topic is covered in depth in Chapter 145.

Source Control The key to prevention and elimination of SIRS/MODS is source control. The clinician must exhaustively search for and eliminate the nidus of inflammation, whether it is a hematoma, abscess, wound infection, or sinusitis. This is critical to reversing the process. While conducting the search for the offending source or microorganism, empiric use of broadspectrum antibiotics is advised; subsequently, the regimen is

tailored based on culture and sensitivity reports from the microbiology laboratory.

Perfusion Management In the face of inflammation, perfusion should be optimized.

It is nearly impossible to restore the body to pre-insult hemodynamic status until the inflammatory response has run its course. Supportive care is key. That inadequate tissue perfusion potentiates SIRS and may catalyze progression to MODS should be recognized. This is especially true for the kidneys, which are sensitive to hypoperfusion, even in the absence of underlying renal pathology. Moreover, hypoperfusion of the kidneys activates the renin-angiotensin-aldosterone system.

Since angiotensin II is the major determinant of portal perfusion of the liver, and since hepatic dysfunction figures prominently in MODS, disturbances in the renin-angiotensinaldosterone system may contribute to disturbance in hepatic function. Disturbances in ventilation-perfusion relationships secondary to pulmonary hypoperfusion may contribute to arterial hypoxemia.

Fluids should be administered liberally in SIRS/MODS. Determination of the appropriate volume of fluid to administer is problematic, however, largely because end-organ function, the best index of adequate perfusion, is already impaired.

One practical rule of thumb is to achieve a stroke volume of approximately 1 ml/kg of body weight. If the administration of fluid does not increase stroke volume, cardiac dysfunction is probably present and administration of additional fluid is not likely to be helpful.

Rational Use of Inotropes and Vasopressors Animal and human studies indicate that SIRS/MODS renders the cardiovascular system relatively resistant to the effects of native and synthetic catecholamines. Therefore, powerful agents are required to achieve any hemodynamic effect. Also, the vasodilatation may represent a compensatory response to a metabolic defect; hence, induced vasoconstriction may worsen this defect.

One practical expedient is to treat hypotension when evidence of myocardial ischemia develops, usually at a diastolic pressure of about 40 mmHg. Norepinephrine is the drug of choice. This agent constricts somatic (muscle) beds, but it appears to spare the splanchnic circulation, thereby transferring fluid from the periphery to the central, visceral compartment. As a second-line therapy to increase visceral tone once maximum effect using norepinephrine has been achieved, a low, nontitrated dose of vasopressin at 0.01 to 0.04 units/h may be added. Endogenous vasopressin release is diminished in sepsis, suggesting a role for vasopressin “replacement,” rather than “therapy.” Dopamine, which had long been a preferred agent in sepsis, is no longer advocated, since it is a nonspecific agonist and may cause maldistribution of flow.

Dopamine has been demonstrated to be detrimental to renal function. If cardiac output remains low despite adequate fluid resuscitation and vasopressor therapy, an inotrope,

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Supplemental oxygen ± endotracheal intubation and mechanical ventilation

Central venous and arterial catheterization

Sedation, paralysis (if intubated), or both

<8 mm Hg

CVP

Crystalloid Colloid

8–12 mm Hg

MAP

<65 mm Hg >90 mm Hg

Vasoactive agents

>65 and <90 mm Hg

ScvO2

<70%

>70% Transfusion of red cells until hematocrit >30%

<70%

>70% Inotropic agents

No

Goals achieved Yes Hospital admission

Figure 146-2 Goal-directed therapy for septic shock. (From Clinical Practice Guidelines, Hospital of the University of Pennsylvania.)

Resuscitation in Septic Shock: Hemodynamic Considerations in Goal-Directed Therapy Resuscitation should continue with predetermined end points: 1.

2.

3.

4.

Target mean arterial pressure (MAP) of 65 mmHg Urinary output of >0.5 ml/kg/h Central venous pressure (CVP) of 12–15 mmHg Stroke volume (SV) of 0.7–1.0 ml/kg

If early aggressive fluid resuscitation does not restore MAP within 30 min (refractory shock), add norepinephrine.

If norepinephrine dose exceeds 10 µg/min, add nontitrated dose of vasopressin at 0.04 µg/min.

If patient remains hyperdynamic with impaired myocardial contractility, add inotrope with goal SV of 0.7–1.0 ml/kg.

Dobutamine is first line, followed by epinephrine. Impaired myocardial contractility is defined as decreased ejection fraction (EF), ventricular dilation, impaired contractile response to volume loading, or low peak systolic/end-systolic volume ratio.

End points for assessing resuscitation are arterial blood pressure, heart rate, urinary output, and skin perfusion.

From Clinical Practice Guidelines, Hospital of the University of Pennsylvania, Philadephia, PA.

such as dobutamine, may be added to increase cardiac contractility.

Recent studies emphasize goal-directed therapy in the management of sepsis (Fig. 146-2). This includes promptly achieving a mean arterial pressure (MAP) greater than 65 mmHg, a central venous pressure (CVP) of 8 to 12 mmHg,

a venous oxygen saturation (SvO2 ) greater than 70 percent, a hemoglobin concentration greater than 10 g/dl, and a lactate concentration less than 4.0 mm. After initial resuscitation, unless there is active cardiac disease, acute hemorrhage, or continuing lactic acidosis, a hemoglobin concentration of 7 g/dl is acceptable.

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Metabolic Management As SIRS progresses to MODS, the intrinsic metabolic defect associated with the disorder worsens. Although glucose intolerance is apparent very early in the course of the disease, progressive hyperglycemia may develop. Additionally, there is progressive azotemia as amino acids are deaminated and carbon skeletons enter the Krebs cycle. Ultimately, hepatic dysfunction becomes so severe that even this process becomes impaired. The intrinsic defect appears to be a decrease in the transcription of genes encoding certain key enzymes in metabolic pathways. Although compensation can occur early in the course, ultimately this fails.

To meet caloric needs, most clinicians rely on a formula that is relatively hypocaloric and protein-rich. The resultant increase in blood urea nitrogen is generally well tolerated in adequately hydrated patients. This contrasts with the results of overfeeding with fat or glucose. However, if the increase in blood urea nitrogen is a manifestation of uremia, rather than an isolated consequence of protein overfeeding, dialysis may become necessary.

We believe that administration of exogenous insulin should be avoided early in SIRS/MODS. Most often, the need is precipitated by use of fluids that contain exogenous glucose. Employment of tight glycemic control is controversial in sepsis, although it has been shown to be effective overall in critically ill patients. These studies show an improvement primarily in patients in the ICU for more than 5 days. Thus, it is our belief that “insulin resistance” represents one additional manifestation of “endocrine burn out” in chronic critical illness.

In the acute phase of critical illness, insulin may lower serum glucose levels, but it does so by driving glucose into fat cells. Insulin does not increase glucose oxidation in any tissue. Moreover, even though insulin may block catabolism of skeletal muscle, it does not have this effect on smooth muscle. Therefore, vascular and gastrointestinal smooth muscle may be mobilized, worsening the defects in these organ systems.

Use of corticosteroids in sepsis is another controversial topic. Patients requiring high doses of vasopressors may have a component of adrenal insufficiency. However, the criteria for defining adrenal insufficiency in critically ill patients are difficult to define. If normal diagnostic criteria are met (low baseline cortisol or failure to increase serum levels 30 to 60 minutes following administration of adrenocorticotropic hormone [ACTH] or an ACTH analogue), corticosteroid administration is reasonable. Adrenal insufficiency, too, may be a manifestation of endocrine burnout in chronic critical illness.

Novel Medications Recent studies have evaluated the use of recombinant human Activated Protein C (rhAPC) in patients who are in severe sepsis or MODS. The rationale for use is that the inflammatory response results in a procoagulant state. By reversing this response, patients may have a greater survival rate. Indeed,

in carefully selected subgroups (those who are less severely ill, with Acute Physiology, Age, and Chronic Health Evaluation (APACHE) scores under 25), administration of rhAPC modestly increases survival. Furthermore, low-risk patients do not benefit.

The specifics of renal replacement therapy are beyond the scope of this chapter. However, in acute renal failure from MODS, the replacement of choice is early continuous venovenous hemodialysis (CVVHD). Hemodynamic stability is greater with CVVHD than with intermittent hemodialysis.

In addition, animal studies have demonstrated a shortened course of sepsis using hemodiafiltration. Unfortunately, these results have not been confirmed in human studies.

CONCLUSION SIRS/MODS represent a major cause of mortality and morbidity. The nature of the underlying pathological defect is unknown. Current treatment is supportive and centers on assurance of adequate ventilation and oxygenation, appropriate fluid resuscitation, metabolic support, an intensive search for an excisable or drainable inflammatory site, and avoidance of secondary organ injury.

SUGGESTED READING Abraham E, Laterre PF, Garg R, et al: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death.

N Engl J Med 353:1332–1341, 2005.

Andrejko KM, Deutschman CS: Altered hepatic gene expression in fecal peritonitis: Changes in transcription of gluconeogenic, beta-oxidative, and ureagenic genes. Shock 7:164–169, 1997.

Angus DC, Burgner D, Wunderink R, et al: The PIRO concept: P is for predisposition. Crit Care 7:248–251, 2003.

Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310, 2001.

Annane D, Sebille V, Troche G, et al: A 3-level prognostic classification in septic shock based on cortisol levels and cortisol response to corticotropin. JAMA 283:1038–1045, 2000.

Beale RJ, Hollenberg SM, Vincent JL, et al: Vasopressor and inotropic support in septic shock: An evidence-based review. Crit Care Med 32:S455–S465, 2004.

Bernard GR, Margolis BD, Shanies HM, et al: Extended evaluation of recombinant human activated protein C United States Trial (ENHANCE US): A single-arm, phase 3B, multicenter study of drotrecogin alfa (activated) in severe sepsis. Chest 125:2206–2216, 2004.

Dellinger RP, Carlet JM, Masur H, et al: Surviving Sepsis Campaign guidelines for management of severe

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Sepsis, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome

sepsis and septic shock. Crit Care Med 32:858–873, 2004.

Deutschman CS, De Maio A, Clemens MG: Sepsis-induced attenuation of glucagon and 8-BrcAMP modulation of the phosphoenolpyruvate carboxykinase gene. Am J Physiol 269:R584–R591, 1995.

Gerlach H, Dhainaut JF, Harbarth S, et al: The PIRO concept: R is for response. Crit Care 7:256–259, 2003.

Godin PJ, Fleisher LA, Eidsath A, et al: Experimental human endotoxemia increases cardiac regularity: Results from a prospective, randomized, crossover trial. Crit Care Med 24:1117–1124, 1996.

Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 348:138–150, 2003.

Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31:1250–1256, 2003.

Levy RJ, Piel DA, Acton PD, et al: Evidence of myocardial hibernation in the septic heart. Crit Care Med 33:2752– 2756, 2005.

Levy RJ, Vijayasarathy C, Raj NR, et al: Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis. Shock 21:110–114, 2004.

Pelosi P, D’Onofrio D, Chiumello D, et al: Pulmonary and extrapulmonary acute respiratory distress syndrome are different. Eur Respir J Suppl 42:48s–56s, 2003.

Regel G, Grotz M, Weltner T, et al: Pattern of organ failure following severe trauma. World J Surg 20:422–429, 1996.

Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377, 2001.

Van den Berghe G, Wilmer A, Hermans G, et al: Intensive insulin therapy in the medical ICU. N Engl J Med 354:449– 461, 2006.

Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patients. N Engl J Med 345:1359–1367, 2001.

Vincent JL, Mercan D: Dear Sirs, what is your PCT? Intensive Care Med 26:1170–1171, 2000.

Vincent JL, Opal S, Torres A, et al: The PIRO concept: I is for infection. Crit Care 7:252–255, 2003.

Vincent JL, Wendon J, Groeneveld J, et al: The PIRO concept: O is for organ dysfunction. Crit Care 7:260–264, 2003.

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147 Acute Respiratory Failure in the Surgical Patient Robert M. Kotloff

I. IDENTIFICATION OF THE HIGH-RISK PATIENT Type of Operative Procedure Chronic Obstructive Pulmonary Disease Smoking Predicting Risk of Respiratory Failure II. IMPACT OF ANESTHESIA AND POSTOPERATIVE ANALGESIA ON PULMONARY FUNCTION General Anesthesia Neuraxial Anesthesia Postoperative Analgesia

IV. CAUSES OF POSTOPERATIVE RESPIRATORY FAILURE Atelectasis Pneumonia Acute Lung Injury Phrenic Nerve Injury and Diaphragmatic Dysfunction Pulmonary Embolism Obstructive Sleep Apnea V. USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION

III. IMPACT OF SURGERY ON POSTOPERATIVE PULMONARY FUNCTION Upper Abdominal Surgery Cardiac Surgery Lung Resection

Advances in surgical technique, anesthesia and analgesia, and postoperative supportive care have facilitated application of sophisticated surgical procedures to an expanding spectrum of patients. Emboldened by diminished operative mortality rates, clinicians are increasingly willing to subject older and sicker patients to rigorous, but potentially life-saving, surgical interventions. In most instances, the success or failure of the surgery is defined not in the operating room, but postoperatively, when the adverse effects of surgery may first become apparent and when intercurrent complications may jeopardize the patient’s well-being.

The respiratory system is particularly vulnerable to the effects of general anesthesia and surgery, and postoperative respiratory impairment is common. While generally mild and well-tolerated in otherwise healthy, young patients, postoperative respiratory compromise may have serious consequences in the elderly and in patients with preexisting lung disease. Potentially devastating postoperative complications,

such as pneumonia, aspiration, and acute respiratory distress syndrome (ARDS) may lead to respiratory failure independent of the patient’s presurgical status. Overall, pulmonary complications account for approximately 25 percent of postoperative deaths. This figure is, in fact, conservative, since many patients with respiratory failure can be supported on mechanical ventilation, only to die of other nonrespiratory complications (e.g., sepsis, gastrointestinal bleeding, and multi-organ failure). In addition to their effect on mortality, respiratory complications exact a toll in lengthening ICU and hospital stay, delaying convalescence, and escalating the cost of care. Therefore, clinicians who provide preoperative evaluation and postoperative care must be familiar with the factors that predispose to pulmonary impairment in the surgical patient. Many of these concepts are considered in Chapter 38. This chapter focuses on the most serious of the perioperative respiratory complications—acute respiratory failure.

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IDENTIFICATION OF THE HIGH-RISK PATIENT In a review of over 7000 patients undergoing various gastrointestinal, urological, gynecological, and orthopedic procedures, respiratory failure requiring mechanical ventilation beyond 24 h occurred in only 0.8 percent. Among 81,719 patients undergoing both elective and emergency noncardiac procedures in hospitals belonging to the Veterans Affairs (VA) health system, respiratory failure (defined as mechanical ventilation beyond 48 h after surgery or need for reintubation) occurred in 3.4 percent. Though the overall risk of respiratory failure in these studies is relatively low, it is clear that risk varies markedly, depending on a number of factors related to the procedure and the patient. While risk of postoperative respiratory failure is negligible in the young, healthy nonsmoker undergoing elective knee surgery, it is significant in the elderly patient with underlying chronic obstructive pulmonary disease (COPD) undergoing emergent repair of a thoracoabdominal aortic aneurysm. Factors that have been most thoroughly studied in association with postoperative respiratory failure are discussed in greater detail below.

Type of Operative Procedure Procedures that involve the upper abdomen or thorax are associated with the highest rates of postoperative pulmonary complications, including respiratory failure (Table 147-1).

In large part, the risk is attributable to the profound derangement in pulmonary mechanics that accompanies these procedures (see below). Thoracoabdominal aneurysm repair carries the greatest risk of postoperative respiratory failure.

Given the need for both abdominal and thoracic incisions, as well as division of the diaphragm and costal margin, this observation is not surprising. Other procedures with significant risk include abdominal aortic aneurysm repair, upper gastrointestinal surgery, thoracotomy, and open heart surgery.

Lower abdominal procedures carry a much smaller risk than those involving the upper abdomen; procedures involving the extremities carry a negligible risk.

In some cases, the surgical approach can be modified to lessen the risk of postoperative pulmonary complications in patients who are marginal operative candidates because of advanced age or co-morbid conditions. For example, use of a transverse abdominal incision appears to carry less risk than a vertical midline incision. Cholecystectomy performed by laparoscopic technique is associated with a lower incidence of pulmonary complications compared with the conventional open approach. For thoracic procedures, median sternotomy and muscle-sparing lateral thoracotomy are better tolerated than posterolateral thoracotomy. However, these approaches provide more limited access to the thorax than does the standard thoracotomy incision, and they are generally inadequate for resection of the left lower lobe or for tumors involving the posterior chest wall, diaphragm, or superior sulcus. Additionally, removal of bulky tumors via the muscle-sparing approach may be problematic. Video-assisted thoracoscopic surgery (VATS) also appears to be a less morbid thoracic procedure (Chapter 37). Studies suggest that VATS results in reduced postoperative pain and hospital length of stay compared with thoracotomy and may cause less early impairment in lung function. Whether this procedure carries a diminished risk of postoperative pulmonary complications has not been definitively established.

Chronic Obstructive Pulmonary Disease

Table 147-1 Incidence of Respiratory Failure Following Various Surgical Procedures Procedure

Incidence of Postoperative Respiratory Failure

TAAA repair

8–33%

AAA repair

5–24%

Lung resection

4–15%

CABG

5–8%

All types∗

0.8%

TAAA = thoracoabdominal aortic aneurysm; AAA = abdominal aortic aneurysm; CABG-coronary artery bypass grafting. ∗Refers to general survey of gastrointestinal, urological, gynecological, and orthopedic procedures.

In the previously noted study of over 80,000 patients undergoing noncardiac surgery in VA hospitals, multivariate analysis revealed that a history of COPD was an independent risk factor for postoperative respiratory failure. Overall, the risk of respiratory failure associated with COPD (odds ratio of 1.8) was considerably lower than that associated with the type of surgery (odds ratio of 14.3 for abdominal aortic aneurysm repair and 8.1 for thoracic surgery). Notably, preoperative pulmonary function parameters were not examined in this study, precluding assessment of the relationship between severity of COPD and risk of postoperative respiratory failure.

Studies focusing on outcomes following specific, highrisk procedures shed additional light on the risks posed by COPD. The incidence of respiratory failure following thoracotomy and lobectomy or pneumonectomy exceeds 50 percent for patients with COPD and a predicted postresection forced expiratory volume in 1 sec (FEV1 ) less than 40 percent of normal, but it is minimal for those with more adequate pulmonary reserve. Within the subset of patients with a predicted postresection FEV1 less than 40 percent, those who maintain an acceptable functional status (as indicated by peak oxygen consumption of greater than or equal to 10 to

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15 ml/kg/min on cardiopulmonary exercise testing) appear to have a low risk of respiratory failure following definitive lung resection procedures. The use of VATS in combination with less extensive resection of lung tissue (e.g., wedge resection or segmentectomy) appears to be well tolerated by patients with severe lung disease, with only a 4 percent incidence of respiratory failure and a 1 percent mortality rate documented in one recent study of 100 patients with an FEV1 less than 35 percent predicted.

Studies of the risk posed by COPD among patients undergoing thoracoabdominal aortic aneurysm repair have yielded conflicting results. In one prospective study of over 1400 patients, COPD was found to be an independent risk factor for respiratory failure, defined as the need for mechanical ventilation in excess of 48 h. Respiratory failure developed in 53 percent of patients with COPD and in only 23 percent of patients without this disorder. The risk of respiratory failure correlated linearly with preoperative spirometry, precluding identification of a particular set of “threshold” values.

In contrast, two other studies of thoracoabdominal aneurysm surgery employing similar statistical methods did not identify COPD as a significant predictor of postoperative respiratory failure.

The impact of COPD on outcome following coronary artery bypass grafting (CABG) has also been examined. In one study, patients with a history of COPD had higher rates of mechanical ventilation exceeding 48 h (18.9 percent vs. 3.7 percent) and reintubation (13.5 percent versus 3.7 percent) compared with age-matched controls. In a recent study of over 8000 consecutive patients undergoing CABG, the incidence of postoperative respiratory failure was 5.6 percent. Among preoperative characteristics, COPD was identified as a risk factor for respiratory failure, with an odds ratio (OR) of 1.9.

This was, nonetheless, considerably less than the risk posed by such factors as renal insufficiency (OR 3.9), congestive heart failure on admission (OR 4.1), and emergency (rather than elective) surgery (OR 5.8).

Following major abdominal vascular surgery, including abdominal aortic aneurysm repair and aortobifemoral bypass grafting, approximately 25 percent of patients require ventilatory support for more than 24 h. While an extensive smoking history and low preoperative Pao2 are predictive of the need for prolonged postoperative ventilatory support, the severity of COPD, as defined by preoperative spirometry, is not. Indeed, no prospective evaluation of patients undergoing abdominal surgery of any type has shown that pulmonary function studies can reliably identify patients at increased risk of serious postoperative pulmonary complications.

What conclusions can be drawn from this complex and conflicting body of literature? Clearly, the presence of severe COPD with a predicted postoperative FEV1 of less than 30 to 40 percent in association with poor functional status should be viewed as an absolute contraindication to thoracotomy and extensive lung resection (lobectomy or pneumonectomy).

COPD appears to increase the risk of respiratory failure to a far lesser degree following other types of surgical procedures.

Acknowledging current uncertainties about the full contri-

Acute Respiratory Failure in the Surgical Patient

bution of COPD to postoperative risk in these settings, the presence of significant lung disease should prompt a careful analysis of the necessity of the surgery planned. However, it should not preclude surgery deemed likely to extend patient survival or to markedly improve quality of life.

Patients with COPD scheduled for surgery should undergo a preparatory pulmonary regimen intended to optimize lung function and minimize airway secretions. This regimen should include smoking cessation, institution or intensification of inhaled bronchodilator therapy, and use of oral antibiotics in the presence of purulent secretions or a “loose” cough.

Patients should be instructed on the use of incentive spirometry or cough and deep breathing techniques prior to surgery.

A short course of oral corticosteroids should be considered in patients who have a significant bronchospastic component to their disease. Such a preparatory regimen is simple and inexpensive and has been shown to have a favorable impact on the incidence of postoperative pulmonary complications. Other than the assurance of strict compliance with the regimen, there is no reason to believe that hospitalization is superior to outpatient preparation of the patient.

Smoking Smoking has been shown to be a risk factor for postoperative pulmonary complications in general and for prolonged ventilatory support in particular. Smoking does not appear simply to be a surrogate marker of COPD; rather it poses risk that is independent of the magnitude of pulmonary impairment.

Detrimental effects of smoking include bronchial irritation with resultant excessive airway secretions, impairment in mucociliary clearance, and elevation of carboxyhemoglobin levels with consequent impairment in oxygen uptake and tissue oxygen utilization. While preoperative smoking cessation has been shown to diminish the risk of postoperative pulmonary complications, a minimum of 8 wk of abstinence is required to achieve this risk reduction (see Chapter 38 for additional details).

Predicting Risk of Respiratory Failure Recently, a multifactorial risk index for predicting postoperative respiratory failure was published. The model was derived from analysis of the VA population of over 80,000 patients undergoing noncardiac surgery and was validated in a second VA population of nearly 100,000 patients. Preoperative variables independently predictive of an increased risk of postoperative respiratory failure (mechanical ventilation for greater than 48 h or reintubation) were identified by multivariate analysis, and each variable was assigned a point value reflecting the relative risk that it posed (Table 147-2). Based upon the total number of points, patients were assigned to one of five risk classes that predict the overall probability of respiratory failure (Table 147-3). The model performed well when validated in the second cohort of patients. However, as it was derived from a population of male patients cared for at VA facilities and did not include cardiac procedures, its applicability to

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other patient populations is uncertain. Therefore, additional studies are required before use of this predictive index can be endorsed.

Table 147-2 Respiratory Failure Risk Index Preoperative Predictor

Point Value

Type of surgery Abdominal aortic aneurysm Thoracic Neurosurgical, upper abdominal, peripheral vascular Neck

27 21 14 11

IMPACT OF ANESTHESIA AND POSTOPERATIVE ANALGESIA ON PULMONARY FUNCTION An additional important consideration in patients undergoing surgical procedures is the effect of anesthesia on pulmonary function.

Emergency surgery

11

Albumin (<30 g/L)

9

General Anesthesia

Blood urea nitrogen (>30 mg/dL)

8

Partially or fully dependent functional status

7

History of COPD

6

Age (years) ≥70 60–69

6 4

Use of general anesthetic agents is associated with a number of well-characterized alterations in pulmonary mechanics, gas exchange, and respiratory drive. In the controlled environment of the operating room, these physiological derangements are clinically inconsequential and easily overcome by simple adjustments of the ventilator. However, lingering effects of general anesthesia after completion of surgery may impede efforts to extubate the patient or may precipitate respiratory failure in the recovery room.

Administration of general anesthesia, whether by the inhaled or intravenous route, results in an almost immediate loss of diaphragmatic and intercostal muscle tone, a cephalad shift of the diaphragm, and a decrease in the transverse thoracic diameter. These dimensional alterations in thoracic volume result in a 20 percent reduction in functional residual capacity (FRC) and in development of compressive atelectasis. As demonstrated using computed tomography (CT) to image patients during and after general anesthesia, patients develop crescent-shaped areas of atelectasis in dependent areas of the lung within 10 min of induction. Atelectatic areas comprise approximately 2 to 10 percent of total lung volume and disappear with the application of positive end-expiratory pressure (PEEP). Dependent atelectasis develops after administration of either inhalational or intravenous anesthetics. A notable exception is ketamine, a drug that is unique in its maintenance of respiratory muscle tone. The degree of atelectasis appears unaffected by whether the patient is breathing spontaneously or is mechanically ventilated.

Areas of dependent atelectasis perturb the normal balance of ventilation and perfusion in the lung. Persistent perfusion of nonventilated atelectatic areas results in an increase in the shunt fraction, which may approach 15 percent. The magnitude of shunt correlates directly with the volume of atelectatic lung and may be further magnified by impairment of hypoxic pulmonary vasoconstriction induced by certain inhalational anesthetics. Elderly patients, those who are obese, and patients with underlying COPD are most likely to develop clinically apparent hypoxemia in response to general anesthesia; the effect may persist into the early postoperative period.

Source: Adapted from Arozullah MA, et al: Multifactorial risk index for predicting, postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 22:242–253, 2000.

Table 147-3 Respiratory Failure Index Scores and Predicted Probability of Postoperative Respiratory Failure Class

Point Total

Predicted Probability of PRF

1

≤10

0.5%

2

11–19

2.2%

3

20–27

5.0%

4

28–40

11.6%

5

>40

30.5%

Source: Adapted from Arozullah MA, et al: Multifactorial risk index for predicting, postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 22:242–253, 2000.

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The inhaled anesthetic agents in common usage are respiratory depressants that blunt the response to both hypoxemia and hypercapnia. These agents depress the ventilatory response to CO2 in a dose-dependent fashion. They have a negligible effect on the hypercapnic response at the low concentrations encountered during emergence from anesthesia.

In contrast, hypoxemic drive is markedly attenuated even at very low, subanesthetic concentrations of the volatile agents.

As a result of deposition of these agents in muscle and fat, concentrations sufficient to depress hypoxic drive persist for several hours after termination of anesthesia. This can result in significant postoperative respiratory depression in patients who, by virtue of chronic hypercapnia, are dependent upon a hypoxic ventilatory drive to breathe.

Neuraxial Anesthesia It is common practice for those providing preoperative assessment of high-risk patients to recommend the use of neuraxial (i.e., spinal or epidural) anesthesia, predicated on the impression that this route of administration lessens the adverse impact of anesthesia on the respiratory system. Neuraxial anesthesia does possess a number of favorable physiological features. In contrast to the effects of general anesthesia, neuraxial anesthesia preserves diaphragmatic innervation and function. External intercostal muscle paralysis is induced by thoracic levels of neuraxial anesthesia, but the level is generally two dermatomes below the sensory level because of the lesser sensitivity of motor neurons to the effects of the anesthetic agent. Hypoxic pulmonary vasoconstriction is unaffected by neuraxial anesthesia, and the ventilatory response to CO2 is unimpaired; indeed, the CO2 response may be heightened.

Despite the ostensibly favorable effects of neuraxial anesthesia on respiratory mechanics and respiratory drive, a clinically significant benefit over general anesthesia has not been consistently demonstrated. Pending further studies, neuraxial anesthesia should not be viewed as clearly superior to general anesthesia in the compromised patient.

Postoperative Analgesia Postoperative analgesia is an essential component of the care of the surgical patient. Analgesia is important not only in ensuring patient comfort, but also in mitigating the adverse effects of pain on respiratory function and airway clearance.

Inadequate pain relief can lead to splinting and patient reluctance to cough and deep breathe; the end result is promotion of retained secretions, atelectasis, hypoxemia, and, possibly, pneumonia. For major surgical procedures, particularly those involving the chest and upper abdomen, administration of opiates via the parenteral or epidural route has become the analgesic method of choice. Studies comparing the effect of epidural and parenteral opiates on pulmonary function are conflicting. While most have documented the superior analgesic effect of the epidural route, this has not invariably translated into improvement in respiratory mechanics and gas exchange or a lower incidence of postoperative

Acute Respiratory Failure in the Surgical Patient

pulmonary complications. This suggests that factors other than pain (see below) contribute significantly to alterations in pulmonary function that accompany thoracic or abdominal surgery. Nonetheless, this should not lead to the false impression that pain control is superfluous; failure to adequately control pain will exacerbate postoperative pulmonary dysfunction.

The use of narcotic analgesia in the postoperative period is associated with a small, but not insignificant, risk of precipitating respiratory depression. The reported incidence of respiratory depression varies based on the criteria employed. A meta-analysis of published studies revealed an incidence of 0.3 percent defined by the need to administer naloxone, 3.3 percent defined by the presence of hypercapnia, and 17 percent defined by oxygen desaturation. The risk may be slightly lower in association with the epidural, as opposed to parenteral, route of administration. Elderly patients are particularly susceptible to the respiratory depressant effects of opiates, likely reflecting an impaired ability to metabolize these agents. Respiratory depression in the postoperative patient is most likely to occur during the initial 24 h following surgery. It is typically accompanied by a decreased level of consciousness and a slow respiratory rate. Treatment consists of administration of naloxone in 0.1 to 0.4 mg aliquots. Ventilation should be supported with a face mask and Ambu bag, reserving intubation for failure of naloxone to swiftly rectify the problem.

IMPACT OF SURGERY ON POSTOPERATIVE PULMONARY FUNCTION Surgery involving the upper abdomen and thorax results in a pronounced impairment in pulmonary function in the postoperative period. The impairment is more severe and prolonged than that due to administration of general anesthesia alone. Typically, upper abdominal and thoracic procedures are associated with a fall in lung volumes, development of atelectasis, and hypoxemia. These adverse effects commonly necessitate short-term administration of low-flow, supplemental oxygen, but when severe, or when accompanied by underlying lung disease, may precipitate respiratory failure.

Upper Abdominal Surgery Vital capacity declines by 50 percent within 24 h following upper abdominal surgery. Although the vital capacity improves with time, marked impairment persists for as long as 7 d after the surgery. In contrast, vital capacity falls by only 25 percent following lower abdominal procedures; it returns to normal by the third postoperative day. Underlying these profound changes after upper abdominal surgery is the development of diaphragmatic dysfunction, as reflected in a reduction in transdiaphragmatic pressure with tidal respirations and in a shift from abdominal to rib cage breathing.

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Two main theories have been proposed to explain the observed impairment in diaphragmatic function. One theory is that there is a primary alteration in diaphragmatic contractility induced by local irritation, inflammation, surgical trauma, or pain. This theory has been rendered improbable with the demonstration that external stimulation of the phrenic nerves produces normal peak transdiaphragmatic pressure in patients recovering from upper abdominal surgery. In other words, when maximally stimulated, the diaphragm functions in a normal fashion.

The alternative, and currently favored, theory proposes that diaphragmatic dysfunction results from diminished phrenic nerve output. The basis for the attenuation in neural drive remains a matter of speculation, although several putative pathways can be rationally eliminated. For example, general anesthesia is known to depress output from the central respiratory centers, as well as to inhibit synaptic transmission. However, as noted previously, the effects of general anesthesia on diaphragmatic tone are transient and modest.

Additionally, the degree of dysfunction observed after upper abdominal procedures is not seen following general anesthesia for procedures on the lower abdomen and extremities. An inhibitory arc initiated by abdominal nociceptors for pain is unlikely, given that achievement of adequate pain control by epidural opiates fails to consistently improve pulmonary function or to normalize diaphragmatic performance. In contrast, the epidural administration of anesthetic agents such as bupivacaine does ameliorate diaphragmatic dysfunction following upper abdominal surgery. Since these agents produce sympathetic blockade in addition to pain control, it has been argued that visceral sympathetic afferents are responsible for providing an inhibitory signal that downgrades central neural drive and phrenic nerve activity, thereby leading to impaired diaphragmatic function. Supporting the notion of a reflex inhibitory arc mediated by visceral afferents is the demonstration in experimental animals that mechanical gallbladder stimulation strongly inhibits electromyographic activity and motion of the diaphragm.

Cardiac Surgery Although CABG—the most commonly performed cardiac surgical procedure—has been most intensively scrutinized with respect to its impact on the respiratory system, other related cardiac procedures (e.g., valve replacement) are likely to have similar effects. Lung volumes decrease by approximately 30 percent after CABG; their return to preoperative values may take several months. Lung function may decline to a greater degree when internal mammary harvesting and grafting are employed. Gas exchange is also impaired after CABG, as evident in the development of hypoxemia and significant widening of the alveolar-arterial oxygen gradient. In 125 patients who had daily room air arterial blood gas determinations prior to and following CABG, Pao2 fell from approximately 75 mmHg preoperatively to a nadir of 55 mmHg on postoperative day 2. The PaO2 improved, but remained below preoperative values, at the end of the first postoper-

ative week. A similar pattern and magnitude of decline in oxygenation have been demonstrated in other studies, with the development of hypoxemia associated with an increase in calculated shunt fraction from 3 percent preoperatively to a peak of 19 percent postoperatively. The increase in shunt fraction is readily accounted for on the basis of atelectasis, which is invariably present postoperatively, especially on the left side.

A number of factors have been implicated in the development of post-CABG pulmonary dysfunction and atelectasis. Alterations in chest wall compliance and motion may result from division of the sternum, harvesting of the internal mammary artery, and traumatic injury to the costovertebral joints and first rib induced by retraction. Intraoperative lung retraction may directly injure the left lower lobe, leading to contusion and atelectasis, and, perhaps, accounting for the predilection for radiographic infiltrates on the left side. An alternative explanation for post-CABG left lower lobe atelectasis is intraoperative injury to the left phrenic nerve and consequent diaphragmatic paralysis or paresis. The phrenic nerve is vulnerable to stretch and ischemic injury during sternal retraction, dissection of the left internal mammary artery, or prolonged distention of the pericardium. Additionally, thermal injury to the nerve may occur with the cardioplegic technique of instilling iced slush into the open pericardial sac. The actual incidence of phrenic nerve dysfunction after CABG is best defined in studies employing electrophysiological techniques, which have documented unequivocal evidence of phrenic nerve injury in 10 percent of patients. This suggests that phrenic nerve injury accounts for only a minority of the observed cases of left lower lobe atelectasis.

Finally, cardiopulmonary bypass (CPB) may contribute to pulmonary impairment after cardiac surgery. The duration of CPB has been linked to the severity of postoperative atelectasis; whether this relationship is causal is unclear. It has been hypothesized that the use of CPB leads to abnormal surfactant production—possibly due to ischemic, thermal, or toxic injury to the alveolar epithelium—predisposing to the development of atelectasis. More clearly established is the ability of the bypass pump to induce a capillary leak syndrome, marked by extravasation of fluid into the alveolar interstitium and, rarely, into the airspaces. This process is thought to result from exposure of blood to nonendothelial surfaces, resultant activation of neutrophils, complement and other inflammatory cascades, and sequestration of neutrophils within the microvasculature. While this rarely may lead to full-blown ARDS (see discussion below), the consequences are usually more subtle, manifesting as a widened arterial-alveolar oxygen gradient and diminished lung compliance. The recent introduction of “off-pump” CABG has permitted a greater appreciation of the adverse impact of CPB on postoperative lung function. For example, a recent large, multicenter comparative analysis from the United Kingdom of CABG with or without CPB demonstrated significant reductions in the rates of prolonged mechanical ventilation (more than 24 h), reintubation or tracheostomy, and ARDS or pulmonary edema

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or pneumonia among the group that underwent off-pump CABG.

Lung Resection Unique to lung resection surgery is the immediate loss of lung function due to removal of lung parenchyma. The magnitude of the loss can be estimated reliably from preoperative quantitative lung scanning in conjunction with standard spirometry (Chapter 38). The impact of lung resection on pulmonary function is further magnified in the perioperative period by other factors. For example, the standard posterolateral thoracotomy incision represents significant chest wall trauma, with rib retraction and resection, and transection of intercostal, latissimus dorsi, trapezius, and serratus anterior muscles. As a result, total respiratory compliance may fall by as much as 75 percent; work of breathing increases; and lung volumes decline dramatically, out of proportion to the surgical loss of functional lung. Following standard thoracotomy and lung resection (either lobectomy or wedge resection), FEV1 and FVC fall to 25 percent of preoperative values at 1 hour, and to 30 percent at 24 h. When a more limited, muscle-sparing incision is used, the impact on pulmonary function is markedly attenuated.

As with cardiac and upper abdominal surgery, atelectasis is frequently present after lung surgery and results in impaired oxygenation. Phrenic nerve activity remains normal and diaphragmatic function during tidal breathing is preserved, although maximal diaphragmatic strength may be reduced.

CAUSES OF POSTOPERATIVE RESPIRATORY FAILURE The development of acute respiratory failure in the surgical patient should prompt a systematic assessment of the likely causes (Table 147-4). In approaching this life-threatening problem, one must consider the nature and magnitude of preexisting pulmonary disease, type of surgery performed, drugs administered intra- and postoperatively, and predominant derangement in gas exchange (i.e., hypoxemia or hypercapnia). In conjunction with important information derived from the physical examination and chest radiograph, the analysis should readily identify factors responsible for, or contributing to, respiratory failure. The following discussion focuses on the more common or unique causes of postoperative respiratory failure in the surgical setting.

Atelectasis Atelectasis is the most common pulmonary complication encountered in the surgical patient, particularly following thoracic and upper abdominal procedures. As discussed previously, anesthesia and surgical manipulation act in concert to produce regional atelectasis through incompletely defined

Acute Respiratory Failure in the Surgical Patient

Table 147-4 Causes of Postoperative Respiratory Failure Factors extrinsic to the lung Depression of central respiratory drive (anesthetics, opioids, sedatives) Phrenic nerve injury or diaphragmatic dysfunction Obstructive sleep apnea Factors intrinsic to the lung Atelectasis Pneumonia Aspiration of gastric contents Acute lung injury (ARDS) Volume overload or congestive heart failure (CHF) Pulmonary embolism Bronchospasm or COPD mechanisms, including diaphragmatic dysfunction and diminished surfactant activity. The atelectasis is typically basilar and segmental in distribution, obscuring the hemidiaphragms radiographically. A distinct and less common cause of postoperative atelectasis is plugging of central airways by retained secretions. This problem is encountered in the surgical patient whose efforts to clear secretions are compromised by depressed consciousness, inadequate pain control, or a weak, ineffective cough. When situated in a mainstem bronchus, mucus plugs can result in collapse of an entire lung; more distal obstruction leads to lobar collapse. An abrupt termination of the proximal bronchial air shadow and the absence of air bronchograms within the atelectatic portion of the lung are clues to the possible presence of mucus plugging.

While often clinically insignificant, postoperative atelectasis may lead to severe hypoxemia and respiratory distress. The magnitude of hypoxemia is dictated by the extent of atelectasis, the presence and severity of underlying lung disease, and the integrity of the hypoxemic pulmonary vasoconstrictive response. Impairment of hypoxemic pulmonary vasoconstriction by vasodilatory drugs, commonly administered to surgical patients for treatment of underlying hypertension or ischemic heart disease, prevents the compensatory diversion of blood flow away from nonventilated areas of the lung and magnifies the shunt fraction.

Respiratory distress due to atelectasis usually evolves insidiously over the first several postoperative days. Supplemental oxygen requirements increase in association with worsening basilar infiltrates noted on the chest radiograph. The clinicoradiographic picture may be indistinguishable from that of pneumonia. While fever and leukocytosis suggest infection, these signs are common and nonspecific. When atelectasis is due to central airway occlusion by mucus plugs, hypoxemia and respiratory distress may develop quickly. A chest radiograph obtained immediately after the onset of symptoms may be surprisingly unrevealing if sufficient time has

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not passed to permit resorption of gas from the airspaces of the nonventilated lung. Careful examination of the patient, however, will reveal an absence of breath sounds over the involved lung, providing an important clue to the presence of central airway obstruction and obviating pursuit of other considerations, such as pulmonary embolism.

Treatment of respiratory failure due to atelectasis is directed toward the combined goals of adequate oxygenation and re-expansion of lung segments. Supplemental oxygen should be titrated to achieve an arterial oxyhemoglobin saturation of at least 90 percent. Refractory hypoxemia, severe respiratory distress, progressive hypercapnia, or inability of the patient to clear copious airway secretions should prompt immediate intubation and mechanical ventilatory support.

This life-saving intervention permits more efficient delivery of oxygen, secures access for suctioning of the airways, and facilitates performance of bronchoscopy should it be necessary. Moreover, the positive pressure and large tidal volumes delivered by the ventilator are often effective in rapidly re-expanding collapsed lung segments. In less dire circumstances, noninvasive delivery of continuous positive airway pressure (CPAP) via a nasal or face mask may be equally effective.

Fiberoptic bronchoscopy has a limited role in the treatment of serious postoperative atelectasis; its indiscriminate use should be avoided. The immediate use of fiberoptic bronchoscopy does not result in more rapid or complete resolution of acute lobar atelectasis when compared with standard chest physiotherapy consisting of deep breathing, coughing, suctioning of the intubated patient, aerosolized bronchodilator treatments, chest percussion, and postural drainage. Resolution of atelectasis appears to be dictated not by the treatment modality employed, but by radiographic evidence of central airway patency. In this regard, both chest physiotherapy and bronchoscopy are highly effective in the absence of an air bronchogram. In contrast, the presence of an air bronchogram, which indicates that the atelectasis is not due to proximal airway obstruction, is associated with minimal response to either modality. Therefore, simple and standard respiratory therapy techniques applied to either the spontaneously or mechanically ventilated patient form the mainstay of treatment for lobar atelectasis. Fiberoptic bronchoscopy should be reserved for those situations where chest physiotherapy is contraindicated (e.g., chest trauma, immobilized patient), poorly tolerated, or unsuccessful. In these circumstances, the decision to employ bronchoscopy should be tempered by the presence of an air bronchogram.

A number of other measures are commonly employed in the treatment of atelectasis. Judicious use of analgesia is an essential adjunct, permitting the patient to breathe deeply, cough forcefully, and comfortably participate in chest physiotherapy maneuvers. Care must be taken to avoid excessive sedation which will offset the beneficial effects of pain control. In the setting of marked hypoxemia, attempts should be made to discontinue vasoactive drugs with the potential to influence the pulmonary vascular bed; examples include nitrates, nitroprusside, calcium channel blockers, angiotensin-

converting enzyme inhibitors, and hydralazine. Mucolytics, such as N-acetylcysteine, are commonly administered in an effort to promote clearance of tenacious secretions; however, their efficacy in this setting has not been well documented.

Some clinicians and respiratory therapists advocate the use of nasotracheal suctioning of the nonintubated patient with a weak and ineffective cough. However, this technique is associated with considerable discomfort and, in the opinion of this author, is an inefficient and highly transient means of clearing secretions from the tracheobronchial tree.

The important role of prophylactic maneuvers in reducing the incidence and magnitude of postoperative atelectasis in high-risk patients should not be overlooked. These techniques, intended to promote periodic full lung expansion, include intermittent positive pressure breathing (IPPB), cough and deep breathing exercises, and incentive spirometry.

All three techniques have been shown to be equally efficacious and superior to no therapy in the prevention of postoperative pulmonary complications following abdominal surgery, although their efficacy following cardiac surgery has recently been called into question. IPPB has largely been abandoned due to its expense, need for specially trained personnel and close patient supervision, and tendency to produce abdominal distention. For maximal benefit, prophylactic measures should be taught and instituted prior to surgery and used hourly in the postoperative period. Early ambulation of the postsurgical patient has been found to be as effective as respiratory therapy maneuvers in the prevention of postoperative atelectasis and should be strongly encouraged.

Pneumonia Pneumonia is the second most common nosocomial infection and the most lethal, with an associated mortality rate of 20 to 50 percent. Pneumonia represents a principal cause of postoperative respiratory compromise and may precipitate acute respiratory failure, as well as complicate respiratory failure in the patient who is ventilator-dependent for other reasons.

In epidemiological surveys, surgery has been identified as an independent risk factor for nosocomial pneumonia. In particular, the risk is greatest following standard thoracic and upper abdominal procedures, where an incidence of 15 to 20 percent has been documented. Lung transplant recipients represent an emerging population with a similarly high risk of postoperative pneumonia. In contrast, the risk of pneumonia is only 5 percent following lower abdominal surgery, and it is even less frequently encountered following procedures remote from the chest and abdomen. Overall, the incidence of nosocomial pneumonia is up to fivefold greater among patients in surgical ICUs than among patients in medical ICUs. Epidemiological studies have identified a number of other risk factors for nosocomial pneumonia, but these studies fail to fully distinguish those factors that are causally linked from those that are simply surrogate markers. Factors reflective of poor preoperative health, including a low serum albumin level, presence of COPD, extensive smoking history, advanced age, protracted preoperative hospital stay, and high

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status according to the American Society of Anesthesiologistsâ&#x20AC;&#x2122; (ASAs) preanesthesia classification, have been linked to an excessive risk of pneumonia. A direct relationship between duration of surgery and incidence of postoperative pneumonia has been demonstrated. Other identified risk factors include presence of a nasogastric tube, use of antacids or H2 -blockers for stress ulcer prophylaxis, immunosuppression, impaired consciousness, and witnessed aspiration. Perhaps the most important and consistently identified risk factor is the need for prolonged mechanical ventilatory support. Overall, mechanically ventilated patients have a 3- to 21-fold increased risk of pneumonia compared with nonventilated patients.

Moreover, the risk of pneumonia is linked to the duration of ventilatory support, approximating 1 percent per day on the ventilator.

The microbiological profile of nosocomial pneumonia is distinctly different from that of community-acquired infection. Gram-negative aerobic bacilli of the Enterobacteriaceae family prevail, collectively accounting for approximately one-third of all infections. Other highly virulent gram-negative rods which are commonly encountered are Pseudomonas aeruginosa and Acinetobacter species. Of the gram-positive organisms, Staphylococcus aureus predominates, while the pneumococcus, the most common bacterial respiratory pathogen in the community setting, plays an insignificant role. Often the pneumonia is polymicrobial; studies employing bronchoscopic culture techniques or postmortem cultures of lung tissue have identified more than one organism in up to 46 percent of cases.

While organisms may reach the lower respiratory tract by several routes, microaspiration of oropharyngeal secretions appears to be the predominant mechanism in the pathogenesis of nosocomial pneumonia. A critical initiating event in this pathway is colonization of the oropharynx with gramnegative aerobic bacilli, a process that characteristically occurs in response to serious illness or surgical stress. Clinically occult aspiration of these virulent organisms is facilitated by a number of iatrogenic measures imposed upon the surgical patient. Paramount among these is the placement of an endotracheal tube, which impairs swallowing, stents open the glottis, and permit pooling of secretions above the tube cuff. The inflated cuff is an imperfect barrier and allows intermittent seepage of secretions into the lower airways. Prolonged intubation has also been associated with postextubation swallowing dysfunction. Depressed consciousness as a consequence of general anesthesia and postoperative analgesia further contributes to the risk of aspiration.

Recent attention has focused on the stomach as an additional source of bacteria in the development of nosocomial pneumonia. While the acidic milieu of the stomach normally inhibits bacterial growth, the common use of H2 -blockers and antacids as stress ulcer prophylaxes overrides this natural barrier and promotes gastric colonization with gram-negative enteric organisms. Gastroesophageal reflux, a common feature of the critically ill patient, permits bacteria-laden gastric contents to enter the respiratory tract either directly or by first colonizing the oropharynx. This route of migration

Acute Respiratory Failure in the Surgical Patient

has been confirmed by recovery of technetium-99m (99m Tc)labeled gastric contents in endobronchial secretions and by the demonstration in some patients that organisms cultured from the airways first appeared in the stomach. Perhaps the most compelling, albeit circumstantial, evidence derives from several studies that have shown a higher incidence of nosocomial pneumonia in patients receiving H2 -blockers or antacids compared with those given sucralfate, a drug that does not result in alkalinization of gastric pH. However, conflicting data abound, and firm conclusions about the role of gastric colonization in the pathogenesis of nosocomial pneumonia await the outcome of larger and more methodologically rigorous studies.

The fate of organisms introduced into the lower respiratory tract is dependent upon the integrity of mechanical and immunologic pulmonary defense mechanisms. Impairment of the mucociliary escalator (e.g., due to recent cigarette smoking or underlying COPD), weak and ineffective cough, and use of immunosuppressive medications (e.g., corticosteroids) favor the proliferation of organisms and the development of pneumonia. It is widely held that postoperative atelectasis predisposes to pneumonia by entrapping bacteria. However, studies demonstrating a lack of concordance between the degree of atelectasis and the subsequent risk of pneumonia challenge this contention.

The constellation of fever, leukocytosis, purulent sputum, and radiographic infiltrates has traditionally defined the presence of pneumonia. While these diagnostic criteria are reasonably accurate in the previously healthy outpatient, they are notoriously nonspecific in the setting of recent surgery, particularly with prolonged use of mechanical ventilation.

In one autopsy series, traditional clinical and radiographic criteria provided the correct antemortem diagnosis in only 70 percent of cases. Alternative etiologies of radiographic infiltrates include atelectasis, pulmonary edema, infarction or hemorrhage due to pulmonary emboli, pulmonary contusion, and chemical pneumonitis. Cultures of sputum and tracheal aspirates are poorly reflective of the bacterial flora of the distal airways, since these specimens are contaminated by colonizing organisms in the oropharynx and upper respiratory tract. In an attempt to enhance diagnostic certainty, bronchoscopic sampling of the distal airways using a sterile sheathed brush or bronchoalveolar lavage has been advocated.

While the absence of a â&#x20AC;&#x153;gold standardâ&#x20AC;? for the diagnosis of pneumonia has complicated attempts to define the accuracy of these techniques, rates of false-positive and false-negative results have generally fallen in the range of 30 percent. It is questionable, therefore, whether the performance of bronchoscopy actually contributes significantly to a reduction in the degree of diagnostic uncertainty. These concerns, coupled with the need to perform the procedure prior to institution of antibiotics and to collect and process specimens in a fastidious and standardized fashion, have severely limited the use and acceptance of currently available bronchoscopic techniques.

Despite all of the pitfalls, most clinicians continue to rely on conventional assessment strategies in establishing a diagnosis of pneumonia and in determining the need for therapy.

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Empiric treatment of nosocomial pneumonia is broad in spectrum and includes effective coverage of gram-negative organisms (including Pseudomonas) and S. aureus. The initial choice of antibiotics is influenced by the particular epidemiological profile and microbiologic susceptibility patterns at a given institution; many ICUs are currently plagued by highly resistant organisms, such as Acinetobacter and methicillinresistant Staphylococcus, which have unusual, but predictable, susceptibilities.

Preventive strategies intended to diminish the risk of pneumonia are an important consideration in the care of the surgical patient. Prevention begins in the preoperative phase with emphasis on abstinence from cigarette smoking for a minimum of 8 wk prior to elective surgery. Following surgery, nasogastric and endotracheal tubes should be removed as soon as possible. Postoperative analgesia must be titrated to permit the patient to comfortably and vigorously cough, but excessive sedation impairing protection of the airway and enhancing the risk of aspiration must be avoided.

For the high-risk, ventilator-dependent patient, maintenance of a semierect position has been shown to diminish the magnitude of clinically occult aspiration of gastric contents and the incidence of pneumonia. While the use of sucralfate has been associated with a lower incidence of gastric colonization and nosocomial pneumonia compared with agents that raise gastric pH, additional corroborating studies are required before a firm recommendation to preferentially employ sucralfate in stress ulcer prophylaxis can be made.

An emerging approach to pneumonia prevention in the high-risk patient is selective digestive decontamination (SDD), intended to prevent or diminish the magnitude of gram-negative colonization of the aerodigestive tract. Regimens have varied among studies, but they typically consist of some combination of antibiotics applied topically to the oropharynx, instilled into the stomach as a slurry, and/or administered systemically. A recent meta-analysis of prospective, randomized trials concluded that SDD reduced the incidence of pneumonia and decreased overall mortality among critically ill surgical patients. Some studies have demonstrated emergence of resistant pathogens, while others have not. Despite the proven efficacy of this approach in high-risk surgical patients, SDD is not yet widely used.

Acute Lung Injury The hallmark of acute lung injury is the presence of noncardiogenic pulmonary edema resulting from widespread damage to the alveolar-capillary membrane. Referred to clinically as acute respiratory distress syndrome (ARDS), the syndrome is defined by the constellation of hypoxemic respiratory failure, diffuse pulmonary infiltrates, and a normal pulmonary artery occlusion pressure or absence of clinical evidence of elevated left atrial pressure. ARDS represents the end result of a variety of insults that either involve the lung directly (e.g., aspiration of gastric contents) or trigger pulmonary inflammation as part of a systemic process (e.g.,

Table 147-5 Incidence of ARDS by Risk Factor Risk Factor

Incidence of ARDS

Sepsis

41%

Massive transfusions

36%

Pulmonary contusion

22%

Aspiration

22%

Multiple fractures

11%

Sourc: Data adapted from Hudson LD, et al. Clinical risks for development of the acute respiratory distress dyndrome. Am J Respir Crit Care Med 151:293â&#x20AC;&#x201C;301, 1995.

sepsis). Many of the risk factors associated with development of ARDS are commonly encountered in surgical patients (Table 147-5). In decreasing order of risk, these include sepsis, massive blood transfusion, pulmonary contusion, aspiration of gastric contents, and multiple fractures. Causes of acute lung injury of particular relevance to the surgical patient, and, in some cases, unique to this population, are described in greater detail below.

Aspiration of Gastric Contents Aspiration of gastric contents can rapidly lead to widespread acute lung injury and is an important cause of ARDS in the surgical patient. It is the third leading cause of anesthesiarelated deaths, accounting for 10 to 30 percent of fatal outcomes. Aspiration typically occurs when the mechanisms of glottic closure and cough, which normally protect the airway, are compromised. In the surgical patient, the period of maximal vulnerability for aspiration spans from the induction of general anesthesia to full return of consciousness postoperatively. A number of factors combine to enhance the risk of aspiration during this period. Most important is the blunting of consciousness that accompanies induction and administration of general anesthesia. Insufflation of air into the stomach during induction may cause gastric distention and promote vomiting. Vomiting may also be provoked by noxious stimulation of the posterior oropharynx during intubation or extubation. Reflux of gastric contents is facilitated by medicationinduced relaxation of the lower esophageal sphincter, placement of the patient in a supine position, and manipulation of the bowel during abdominal procedures. At the completion of surgery, extubation is commonly performed at a time when the patient, while able to ventilate adequately, may not yet be capable of fully protecting the airway. Indeed, upperairway reflexes remain significantly impaired for up to 2 h after recovery from anesthesia, even at a time when mental alertness has returned. Moreover, translaryngeal intubation, even

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when brief, may cause residual glottic dysfunction for up to 8 hours following removal of the tube. While the risk of aspiration diminishes beyond the immediate perioperative period, it remains a concern in the patient receiving narcotic analgesia, which may not only induce vomiting, but also depress consciousness.

The risk of aspiration during the immediate perioperative period was delineated in a survey of over 215,000 general anesthetic procedures performed at the Mayo Clinic. Aspiration was defined as the presence of bilious or particulate matter in the airways or the development of a new infiltrate on the immediate postoperative chest radiograph. The overall incidence of aspiration was only 0.03 percent, but the incidence was nearly fourfold higher (0.11 percent) in the setting of emergency surgery. In addition to the use of general anesthesia, other predisposing factors were present in over one-half of the patients who aspirated. These included gastrointestinal obstruction, swallowing dysfunction, altered sensorium, previous esophageal surgery, and a recent meal. The majority of events occurred during laryngoscopy (in preparation for insertion of the endotracheal tube) and during tracheal extubation. Twenty percent of patients who aspirated required postoperative mechanical ventilation in excess of 6 h; 5 percent died as a direct result of this complication.

Acidic gastric content introduced into the airways is rapidly disseminated throughout the bronchial tree and lung parenchyma, producing an almost instantaneous chemical burn. In addition, acid aspiration triggers a more delayed inflammatory response, with release of inflammatory cytokines and recruitment of neutrophils into the lung. The result is injury to the alveolar-capillary membrane, with flooding of the interstitium and airspaces by proteinaceous edema fluid.

Surfactant levels drop precipitously due to both direct acid denaturation and diminished production, leading to alveolar instability and atelectasis. The magnitude of lung injury is directly related to the pH and volume of aspirated material. Initial studies in animals suggested that a pH of less than 2.5 and a volume in excess of 0.4 ml/kg are critical threshold values for the induction of lung injury. While these values are now often quoted in the literature, their validity has been challenged by more recent studies demonstrating significant injury in association with lower volumes and higher pH. In particular, aspiration of bile is capable of inducing widespread injury even at a pH as high as 7.19. The presence of large food particles may further exacerbate the problem by causing airway obstruction and atelectasis. Notably, infection does not normally play a significant role in the initial lung injury from aspiration of acidic gastric contents, as the low pH serves to maintain relative sterility of the inoculum. However, gastric colonization with bacteria can occur in patients maintained on acid suppressive agents, those receiving enteral feeds, and those with gastroparesis or small bowel obstruction.

The diagnosis of aspiration is most firmly established in the setting of witnessed vomiting or recovery of gastric contents from the airways. More often, the diagnosis is suspected circumstantially in a patient with risk factors and a compatible clinicoradiographic picture. Massive aspiration

Acute Respiratory Failure in the Surgical Patient

presents in a characteristic fashion, with the development of fever, tachypnea, and diffuse crackles within several hours of the event. Wheezing is appreciated in approximately onethird of patients and may be due either to obstruction of airways by particulate matter or, more commonly, to reflex bronchospasm. Hypoxemia is universally present with massive aspiration and is sufficiently severe in the majority of patients to mandate use of mechanical ventilation. The initial presence of apnea or shock is particularly ominous and portends a high risk of subsequent death. Initial radiographic patterns vary, depending upon the volume, causticity, and distribution of the aspirated material. However, three general patterns have been described: (1) extensive bilateral consolidation resembling diffuse pulmonary edema; (2) widespread, but discrete, patchy infiltrates involving dependent areas of the lung; and (3) focal consolidation, usually localized to one or both lung bases.

The clinical course following massive aspiration is variable, but it typically diverges along one of several pathways. A minority of patients follow a fulminant course marked by refractory hypoxemia and shock that eventuates in death within several days. More commonly, patients demonstrate progressive radiographic and clinical improvement over the first several days. Although most of these patients will go on to full recovery, a subset demonstrates secondary deterioration due to the development of ARDS or nosocomial pneumonia. The overall mortality rate associated with massive aspiration is approximately 30 percent and exceeds 50 percent in those patients with initial shock or apnea, secondary pneumonia, or ARDS. Treatment of respiratory failure secondary to aspiration is supportive and includes mechanical ventilatory strategies generic to other forms of ARDS (detailed below). Bronchoscopy is indicated only when large-airway obstruction by particulate matter is suspected on the basis of a localized wheeze or lobar atelectasis. Because acid is disseminated and endogenously neutralized within seconds, large-volume bronchoalveolar lavage is ineffective in attenuating the degree of injury and is not recommended. Studies of the administration of systemic corticosteroids in the treatment of aspiration pneumonitis have been inconclusive and do not currently justify their use. Similarly, use of prophylactic antibiotics is generally discouraged in the absence of supportive data and because of fear that this practice will preferentially select more highly resistant organisms. Some authors do advocate use of empiric antibiotics for that subset of patients at risk for gastric colonization with bacteria, as described above. Additionally, up to 40 percent of patients will develop a superimposed bacterial pneumonia within several days of the aspiration event, often heralded by a new fever, new or progressive infiltrates, and purulent sputum. Broad-spectrum antibiotic therapy is indicated at that time.

The high morbidity and mortality associated with aspiration and the lack of effective therapy once the event has occurred have focused attention on measures to prevent this complication. The most straightforward and widely used measure is the convention of overnight fasting prior to

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elective surgery. However, despite prolonged fasting, up to one-third of patients will maintain a gastric volume in excess of 0.4 ml/kg (approximately 25 to 30 ml in the average adult), and up to three-fourths will have a gastric pH below 2.5. Administration of H2 -blockers and proton-pump inhibitors can effectively raise the pH and reduce the volume of gastric contents, suggesting a potentially appealing strategy. Currently, prophylactic administration of antisecretory agents is recommended only for patients deemed to be at increased risk for aspiration. Unfortunately, there is generally insufficient time to allow these agents to act in the setting of emergency surgery, where the risk of aspiration is highest. In high-risk patients, rapid sequence induction of anesthesia should be employed to shorten the time between loss of consciousness and tracheal intubation. During induction, manual pressure should be applied to the cricoid cartilage (Sellick maneuver) and maintained until the endotracheal tube is in proper position and the cuff is inflated. Postoperatively, extubation should be performed only when consciousness and the gag reflex have returned to a level sufficient to permit adequate protection of the airway.

Postpneumonectomy Pulmonary Edema Over the past 25 years, a number of published reports have documented the rapid development of pulmonary edema in the remaining lung of some patients following pneumonectomy. Initially attributed to overzealous fluid administration in the operating room, it has since been demonstrated that this complication occurs in the face of a normal pulmonary artery occlusion pressure. In addition, the edema fluid is protein-rich, arguing that the driving force behind edema formation is increased vascular permeability, rather than increased hydrostatic pressure. Postmortem studies confirm the universal presence of pathological features of acute lung injury. The exact mechanism responsible for lung injury after pneumonectomy remains obscure. One theory suggests that mechanical stress due to single lung ventilation in the operating room may cause ultrastructural damage to the alveolar epithelium, while diversion of the entire cardiac output through this remaining lung may similarly cause endothelial injury. Other factors that may contribute to edema formation include surgical trauma and disruption of lymphatic drainage.

In a study employing stringent criteria for excluding patients with congestive heart failure (CHF) or known risk factors for ARDS, the incidence of postpneumonectomy pulmonary edema was 2.6 percent. Other studies employing variable criteria have documented an incidence of 1 to 7 percent. For unclear reasons, the complication is encountered more frequently following right pneumonectomy. The observed mortality rate associated with postpneumonectomy pulmonary edema is in the range of 50 to 100 percent.

Cardiopulmonary Bypass ARDS has been documented to develop immediately following use of cardiopulmonary bypass in approximately 1

percent of cases. While factors unrelated to the use of CPB may be at play, there is compelling evidence from both animal models and clinical studies to suggest that CPB activates a number of inflammatory mechanisms that could lead to acute lung injury. It is well established, for example, that CPB results in neutrophil activation, likely through mechanical sheer stress and exposure to the artificial surfaces of the bypass circuit. Additionally, an increased expression of cell surface adhesion molecules has been demonstrated, which may promote neutrophil binding to pulmonary endothelium and release of proteolytic enzymes and reactive oxygen species.

The central role played by neutrophils in causing acute lung injury following CPB is supported by several lines of evidence: (1) bronchoalveolar lavage fluid from patients undergoing CPB contains an increased number of neutrophils; (2) plasma levels of neutrophil elastase and myeloperoxidase are increased; and (3) inhibition of neutrophil activation with pentoxifylline as well as neutrophil depletion attenuate the degree of pulmonary dysfunction. A number of other inflammatory mediators are released in association with CPB, including complement, proinflammatory cytokines, and prostaglandins.

Post-CPB ARDS is frequently accompanied by evidence of a systemic inflammatory response including fever, leukocytosis, and multi-organ system failure. Mortality associated with this complication is in the range of 60 to 90 percent.

Amiodarone Amiodarone-induced pulmonary toxicity usually presents as a subacute illness characterized by cough, dyspnea, fever, and patchy pulmonary infiltrates. Less commonly, use of amiodarone has been linked to the development of ARDS immediately following cardiac and thoracic surgery. In most of the reported cardiac cases, amiodarone was administered preoperatively for varying periods of time for control of arrhythmias. The majority of patients had no evidence prior to surgery of the more indolent form of amiodarone pulmonary toxicity. More recently, development of ARDS has been described in patients whose only exposure to amiodarone occurred in the postoperative period, when the drug was initiated as prophylaxis or treatment for atrial arrhythmias following lung resection. In one report, postoperative ARDS developed in 11 percent of patients receiving amiodarone and in only 1.8 percent of untreated patients. The specific perioperative factors that act in concert with amiodarone to produce acute lung injury remain to be defined.

Some authors have suggested that exposure to high levels of supplemental oxygen may be a contributing factor. The diagnosis rests on exclusion of other causes, rather than on specific diagnostic tests or histology.

Transfusion-Related Acute Lung Injury The transfusion of blood and blood products has been linked to the development of ARDS in two ways. Epidemiologically, an association between massive blood transfusion (greater than 15 U/24 h) and ARDS has been noted, but it remains

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unclear whether this link is truly causal or is indirect and reflective only of the critically ill nature of the patient requiring such massive transfusion support. More clearly defined mechanistically is the induction of acute lung injury by leukoagglutinating antibodies, a process that has been termed “transfusion-related acute lung injury” (TRALI). These antibodies are typically contained in blood products derived from multiparous female donors, whose exposure to foreign human leukocyte antigen (HLA) or granulocyte antigens occurred during prior pregnancies. When transfused into a recipient with these same antigens, these antibodies result in leukoagglutination and activation of recipient granulocytes or monocytes within the pulmonary microvasculature, triggering increased capillary permeability and development of noncardiogenic pulmonary edema. Less commonly, TRALI can be caused by the interaction between leukoagglutinating antibodies from the recipient and donor-derived leukocytes.

TRALI has rarely been associated with infusion of biologically active mediators derived from breakdown of the cellular component of stored blood products.

The true incidence of TRALI is difficult to determine since this entity is underrecognized and frequently misdiagnosed. One study involving 36 cases over a 2-year period documented an incidence of 0.02 percent per unit and 0.16 percent per patient transfused. Most cases were detected in surgical patients in the immediate postoperative period, a fact that likely reflects the frequent need for transfusions in this setting and the close monitoring of cardiopulmonary function in the postanesthesia recovery area.

Mild episodes of TRALI may present as dyspnea and fever. More severe cases are characterized by the abrupt onset of respiratory distress, hypoxemia, and diffuse pulmonary infiltrates within 2 to 4 h of transfusion. Accompanying features include fever, chills, and hypotension; urticaria is present in a minority of patients. Respiratory distress and hypoxemia are of sufficient magnitude to require mechanical ventilatory support in most patients. The differential diagnosis includes volume overload, CHF myocardial infarction, and aspiration.

The reaction tends to be self-limited and is typically characterized by rapid clearing of infiltrates and improved oxygenation within several days. However, a more protracted course of greater than 1 wk can be seen in approximately 20 percent of patients; a mortality rate of 5 to 10 percent has been reported.

When TRALI is suspected, the blood bank should be notified and all units that have been transfused should be assayed for the presence of leukoagglutinating antibodies. Any blood product containing plasma or plasma proteins is capable of inducing this reaction. Indeed, packed red blood cells, which contain only 60 to 100 ml of plasma, are one of the more common culprits.

Ischemia-Reperfusion Injury The restoration of blood flow to previously ischemic tissue may, paradoxically, worsen tissue injury. This ischemiareperfusion effect involves a “two-hit” mechanism. Tissue is-

Acute Respiratory Failure in the Surgical Patient

chemia leads to formation of xanthine oxidase and its substrate, hypoxanthine, while reperfusion supplies molecular oxygen that fuels the reaction to produce oxygen free radicals injurious to cells. Neutrophils recruited to the site of ischemia-reperfusion serve as an additional source of oxygen free radicals, as well as proteolytic enzymes. Within the lung, ischemia-reperfusion produces diffuse injury to the alveolar epithelium and resultant noncardiogenic pulmonary edema.

This mechanism underlies the development of acute lung injury in two important clinical settings: lung transplantation (Chapter 101) and pulmonary thromboendarterectomy.

Noncardiogenic pulmonary edema is a nearly universal feature of the freshly implanted lung allograft, but it is usually mild and self-limited. In approximately 10 percent of cases, however, the allograft is severely injured, with widespread and persistent alveolar edema causing profound hypoxemia and low pulmonary compliance, necessitating mechanical ventilatory support beyond the immediate posttransplant period.

This entity, termed primary graft dysfunction, is nonimmunologic in nature and is believed to represent a severe form of ischemia-reperfusion injury. Primary graft failure occurs despite acceptable ischemic times below the perceived safe threshold of 6 h. Injury is manifest exclusively in the allograft, sparing the native lung in cases of single lung transplantation. The presence of unilateral lung injury may create difficulties in postoperative ventilator management. This is particularly true in the presence of underlying COPD, when positive-pressure breaths and PEEP are preferentially applied to the highly compliant emphysematous lung, leading to progressive hyperinflation, mediastinal shift, and potentially catastrophic impairment in gas exchange and hemodynamics. This situation can be effectively addressed with insertion of a double-lumen endotracheal tube, enabling use of independent lung ventilation and selective application of PEEP to the edematous allograft, while ventilating the native lung using low-airway pressures and a prolonged expiratory phase to minimize hyperinflation.

Pulmonary thromboendarterectomy is an established surgical technique for definitive treatment of chronic thromboembolic pulmonary hypertension (Chapter 82). Although operative mortality has decreased dramatically to less than 10 percent, reperfusion pulmonary edema remains a common postoperative complication. It is most often encountered within the initial 24 h after surgery, but its onset may occasionally be delayed for up to 72 h. A striking characteristic is the radiographic restriction of edema to those lung zones supplied by previously obstructed vessels. Exacerbating the degree of shunt and hypoxemia associated with this complication is the redistribution of blood from previously wellperfused segments to newly endarterectomized vessels supplying edematous areas of lung—a phenomenon referred to as “pulmonary artery steal.” Fortunately, the degree of reperfusion edema and attendant hypoxemia is mild in the majority of cases. In approximately 10 percent of cases, however, the presence of severe hypoxemia necessitates prolonged mechanical ventilatory support with high levels of oxygen and application of PEEP.

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Treatment and Outcome Detailed discussion of the management of ARDS is beyond the scope of this chapter but is covered elsewhere in this text (Chapter 145) and in recent reviews. However, several fundamental aspects of care should be underscored. First and foremost, clinical management remains supportive; specific therapies aimed at ameliorating lung injury or accelerating healing are presently lacking. Care largely centers on use of mechanical ventilation, adjusted to maintain adequate gas exchange, while minimizing potentially harmful effects of high concentrations of oxygen, high tidal volumes, and highairway pressures, all of which can induce further acute lung injury. To this end, efforts should be made to reduce the FIO2 to 0.6 or less, accepting an arterial saturation in excess of 90 percent and using PEEP to recruit atelectatic areas of the lung and improve oxygenation. A “low stretch” ventilatory pattern should be employed, using tidal volumes of less than or equal to 6 ml/kg and limiting maximum plateau airway pressures to less than or equal to 30 cm H2 O. This ventilatory strategy, to which clinicians should strictly adhere, has been shown to decrease mortality associated with ARDS. Inhaled nitric oxide preferentially vasodilates vessels supplying well-ventilated areas of the lung and has been shown to reduce shunt fraction and improve oxygenation in patients with severe ARDS. Unfortunately, these beneficial effects are typically short-lived, and multiple phase III clinical trials have failed to show a meaningful impact on duration of mechanical ventilation or mortality. Similarly, placing patients in the prone position can improve oxygenation but has not, to date, been shown to impact survival.

Sedatives should be administered to maintain patient comfort and promote synchronous breathing with the ventilator. Paralysis of the patient is occasionally required in the acute situation of life-threatening hypoxemia or hypercapnia, but prolonged use of neuromuscular blocking agents is discouraged because of the risk of a debilitating myopathy.

Despite aggressive support, the overall mortality from ARDS approximates 30 percent. The mortality rate is significantly higher in the elderly and in those with concurrent failure of other organ systems. On the other hand, patients with acute lung injury due to TRALI tend to have a more favorable prognosis.

Phrenic Nerve Injury and Diaphragmatic Dysfunction Phrenic nerve injury is a well-described complication of CABG. In the past, this complication arose chiefly from the use of iced saline slush placed in the pericardium for topical cooling of the heart. Thermal injury causes both demyelination and axonal degeneration of the nerve, with slowing of conduction and impaired activation of the diaphragm.

The use of topical cooling techniques has fallen out of favor largely because of this potential complication. However, the phrenic nerves can also be injured by traction, ischemia, use of diathermy, or transection during sternal retraction and harvesting of the internal mammary arteries. Unilateral phrenic

nerve injury, typically involving the left phrenic nerve, has been reported in up to 10 percent of patients undergoing CABG. Bilateral phrenic nerve injury was reported to occur in 1 to 3 percent of cases in the era of widespread topical cardioplegia usage but is now a rare event. Phrenic nerve injury is not restricted to CABG; it is also seen in association with other cardiac procedures, thoracic surgery, neck surgery, and liver transplantation.

Although typically inconsequential in the otherwise healthy patient, unilateral diaphragmatic paralysis can lead to significant respiratory compromise in patients with underlying chronic lung disease or those who are otherwise marginal. In patients with COPD, for example, the duration of postoperative mechanical ventilation and the rate of reintubation are higher for those with than those without unilateral phrenic nerve injury following CABG. Bilateral diaphragmatic paralysis results in marked impairment in pulmonary function and frequently leads to respiratory failure.

In the proper setting, phrenic nerve injury should be suspected when attempts to wean a postoperative patient from mechanical ventilation result in progressive hypercapnia or atelectasis. The spontaneously breathing patient will often complain of orthopnea, which may be misinterpreted by the unsuspecting clinician as indicative of CHF. However, orthopnea is actually due to further impairment in diaphragmatic function resulting from loss of gravitational assistance in the supine position. The detection of inspiratory thoracoabdominal paradox—an inward movement of the abdominal wall with simultaneous expansion of the thorax—is an important bedside clue to the presence of bilateral diaphragmatic paralysis and is best evoked in the supine position. The chest radiograph may also hold important clues, demonstrating either unilateral or bilateral elevation of the diaphragms and accompanying basilar atelectasis. However, these findings are not specific for phrenic nerve injury and may also be due to splinting or abdominal distention. A reduced maximum inspiratory pressure recorded at the mouth is another sensitive but nonspecific indication of significant diaphragmatic dysfunction.

Unilateral diaphragmatic paralysis can be readily diagnosed by fluoroscopic inspection, which reveals paradoxical upward movement of the affected hemidiaphragm with a maximal inspiratory effort (“sniff ”). The situation is more problematic with bilateral diaphragmatic dysfunction. In this setting, patients often assume an altered breathing pattern marked by active contraction of the abdominal muscles during expiration, forcing the flaccid hemidiaphragms upward. With subsequent inspiration, the abdominal muscles relax and the hemidiaphragms descend briefly, potentially creating the false impression that they are functional. Because of this, fluoroscopy may not be confirmatory in these patients.

The “gold standard” for confirmation of phrenic nerve injury is electrophysiological testing, although even this methodology is occasionally flawed. The phrenic nerve is stimulated transcutaneously in the neck, and the diaphragmatic electromyogram (EMG) is recorded by surface

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electrodes placed in the seventh intercostal space at the costochondral junction. Demonstration of a prolonged latency between nerve stimulation and diaphragmatic action potential confirms a diagnosis of demyelinating injury. It is more difficult to interpret the significance of diminished amplitude or complete absence of the surface recording of the diaphragmatic EMG. This finding could represent either phrenic nerve injury or transection or failure to properly localize the diaphragm, which is typically shifted caudally in the postoperative patient and, therefore, away from the surface electrodes.

Direct puncture of the diaphragm with a recording electrode may be employed to clarify this issue, but the technique requires a high level of expertise and carries a risk of pneumothorax.

Nontraumatic causes of phrenic nerve injury and diaphragmatic dysfunction can also lead to prolonged respiratory failure and delayed weaning in the surgical patient.

Phrenic neuropathy can be a component of a more generalized polyneuropathy of critical illness, commonly encountered in the wake of an episode of severe sepsis or systemic inflammatory response syndrome. A critical illness myopathy affecting the diaphragms and other muscles of respiration can be encountered under the same circumstances. Finally, diaphragmatic dysfunction can arise as a component of a myopathy induced by the concurrent use of high-dose systemic corticosteroids and neuromuscular blocking agents.

Patients with diaphragmatic dysfunction are generally well-suited for noninvasive positive pressure ventilatory support if they are awake and able to effectively handle respiratory secretions. Tracheostomy is indicated for patients with ineffective cough and those who cannot be weaned from conventional mechanical ventilation. The prognosis for patients with thermal or traction injury of the phrenic nerve is favorable; recovery is typically complete, but often protracted. In symptomatic patients with unilateral diaphragmatic paralysis due to transection of the phrenic nerve, surgical plication of the flaccid hemidiaphragm usually results in improved pulmonary function and can lead to successful liberation from mechanical ventilation.

Pulmonary Embolism An increased risk of pulmonary embolism (PE) accompanies a number of surgical procedures, including upper abdominal, neurosurgical, cardiac, major urological, and lower extremity orthopedic procedures. Other, nonsurgical risk factors that predispose the patient to PE may also be present, including obesity, immobility, and underlying malignancy.

While alterations in gas exchange typify pulmonary embolism, frank hypoxemic respiratory failure is relatively uncommon and suggests massive clot burden. Lesser degrees of clot burden may produce equally devastating physiological impairment in patients with underlying pulmonary disease.

In the presence of severe hypoxemia, there is little remaining cardiopulmonary reserve. Failure to establish a correct diagnosis and to swiftly and appropriately intervene can prove lethal.

Acute Respiratory Failure in the Surgical Patient

Unfortunately, little information pointing specifically to a diagnosis of PE is easily gleaned at the bedside. The patient is often dyspneic, and tachypnea and tachycardia are observed on physical examination. However, these features are common in many postoperative patients because of pain and atelectasis. More informative, but infrequently detected, is evidence of acute cor pulmonale (e.g., distended neck veins, a parasternal heave, right-sided third heart sound, and accentuation of the pulmonic component of the second heart sound).

An electrocardiogram may also demonstrate evidence of right heart strain, with an “S1Q3T3” pattern or new right bundle branch block. The chest radiograph is most suggestive of PE when it is normal in the face of severe hypoxemia.

When abnormal, the greatest use of the chest radiograph is in identifying other causes of hypoxemia, such as pneumonia, pneumothorax, or ARDS. Echocardiography is commonly performed in the setting of hypotension; evidence of a dilated right ventricle in the face of a normal or underfilled left ventricle should raise suspicion for massive PE. The choice of diagnostic studies is dictated by the urgency of the situation. In the setting of life-threatening hypoxemia or hemodynamic instability, pulmonary angiography provides the most definitive and expeditious means of establishing the diagnosis. Pulmonary angiography also permits the immediate placement of an inferior vena cava filter or performance of catheter embolectomy or thrombus fragmentation, as needed. In more stable patients, CT angiography is emerging as the imaging procedure of choice. Until its performance characteristics in the ICU patient population are better defined, however, a negative CT angiogram in the setting of high clinical suspicion should not necessarily be viewed as definitively excluding PE. While anticoagulation with heparin forms the mainstay of therapy for the otherwise stable patient, the presence of life-threatening hypoxemia and/or hemodynamic instability should prompt consideration of alternative or additional interventions. Since additional clot burden could be fatal, insertion of an inferior vena cava filter is generally advised in this setting. Certainly this intervention is mandatory when anticoagulation is contraindicated. Thrombolytic therapy should also be considered in the critically ill patient, but its use in the postoperative period is limited by the risk of precipitating bleeding at the site of recent surgery. This risk appears to fall to an acceptable level beyond the seventh postoperative day; the exception is intracranial surgery, which contraindicates use of lytic agents for at least 2 months. Several interventional radiologic techniques—thrombus fragmentation, suction embolectomy, and intraembolic infusion of low-dose thrombolytics—as well as surgical embolectomy are alternative considerations in the deteriorating patient for whom systemic thrombolytics are either contraindicated or unsuccessful.

Obstructive Sleep Apnea Obstructive sleep apnea (OSA) is a common disorder affecting 2 to 4 percent of the adult population. It is characterized by

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repetitive upper-airway obstruction during sleep, resulting in periodic arterial desaturation, hypercapnia, and arrhythmias.

Because of alterations in oropharyngeal anatomy that commonly accompany obesity and OSA, orotracheal intubation at the time of induction may be difficult. The immediate postoperative period is a particularly precarious time for patients with this disorder, as the use of volatile anesthetics, opioids, and sedatives diminish the activity of the upper-airway musculature and increase the frequency and duration of obstructive apneas. Failure to recognize and appropriately support patients with OSA in the perioperative period can lead to serious complications, including respiratory arrest, hypoxemia, confusion, and ventricular arrhythmias. Institution of nasal continuous positive airway pressure immediately after extubation permits safe administration of analgesic and sedative agents, without undue risk of precipitating life-threatening airway obstruction. It is estimated that as many as 80 percent of patients with OSA are undiagnosed; a high index of suspicion, therefore, is required in the surgical patient to intervene appropriately when upper-airway obstruction is anticipated or observed.

USE OF NONINVASIVE POSITIVE PRESSURE VENTILATION For patients with respiratory failure refractory to conservative measures, endotracheal intubation is the standard means to facilitate mechanical ventilatory support. However, in recent years, a greater appreciation for the untoward effects of endotracheal intubation has emerged. In addition to airway trauma, these include an increased risk of nosocomial pneumonia and sinusitis and the frequent need for heavy sedation that, while addressing patient discomfort, often prolongs the process of weaning and extubation. The desire to avoid endotracheal intubation has prompted interest in the use of noninvasive positive pressure ventilation (NIPPV), employing a tight-fitting nasal or full-face mask as the interface between patient and ventilator.

There is ample evidence supporting the benefits of NIPPV in the treatment of a variety of causes of respiratory failure in the medical patient, but only recently have data emerged confirming its safety and efficacy in the postoperative setting. The most compelling study randomized patients with hypoxic respiratory failure following lung resection surgery to standard therapy (supplemental oxygen, bronchodilators, chest physiotherapy) with or without NIPPV. Compared to the control group, the use of NIPPV was associated with a marked reduction in the need for endotracheal intubation (20.8 percent versus 50 percent) and in mortality at 3 months (12.5 percent versus 37.5 percent). While there has been concern about using NIPPV following esophageal or gastric surgery, recent experience suggests that this can be accomplished safely. In this setting, care must be taken to avoid gastric distention, using a nasogastric tube for decompression

if necessary, and the magnitude of positive pressure ventilation employed should be limited to less than 12 cm H2 O. Since NIPPV often requires a period of acclimation, it should not be used in unstable patients. Other contraindications to its use include depressed or agitated mental status, inability to protect the airway, and compromised airway clearance due to copious secretions or weak cough.

SUGGESTED READING Al-Ruzzeh S, Ambler G, Asimakopoulos G, et al: Off-pump coronary artery bypass surgery reduces risk-stratified morbidity and mortality: A United Kingdom multi-center comparative analysis of early clinical outcome. Circulation 108(Suppl II):II-1–II-8, 2003.

Arozullah AM, Daley J, Henderson WG, et al: Multifactorial risk index for predicting postoperative respiratory failure in men after major noncardiac surgery. Ann Surg 232:242– 253, 2000.

Asimakopoulos G, Smith PLC, Ratnatunga CP, et al: Lung injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 68:1107–1115, 1999.

Auriant I, Jallot A, Herve P, et al: Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection. Am J Respir Crit Care Med 164:1231–1235, 2001.

Bolliger CT, Jordan P, Soler M, et al: Exercise capacity as a predictor of postoperative complications in lung resection candidates. Am J Respir Crit Care Med 151:1472–1480, 1995.

Canver CC, Chanda J: Intraoperative and postoperative risk factors for respiratory failure after coronary bypass. Ann Thorac Surg 75:853–858, 2003.

Cashman JN, Dolin SJ: Respiratory and haemodynamic effects of acute postoperative pain management: Evidence from published data. Br J Anaesth 93:212–23, 2004.

Cohen AJ, Katz MG, Katz R, et al: Phrenic nerve injury after coronary artery grafting: Is it always benign? Ann Thorac Surg 64:148–53, 1997.

Dureuil B, Cantineau JP, Desmonts JM: Effects of upper or lower abdominal surgery on diaphragmatic function. Br J Anaesth 59:1230–1235, 1987.

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.

Jaber S, Delay JM, Chanques G, et al: Outcomes of patients with acute respiratory failure after abdominal surgery treated with noninvasive positive pressure ventilation.

Chest 128:2688–2695, 2005.

Jayr C, Matthay MA, Goldstone J, et al: Preoperative and intraoperative factors associated with prolonged mechanical ventilation: A study in patients following major abdominal vascular surgery. Chest 103:1231–1236, 1993.

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Jordan S, Mitchell JA, Quinlan GJ, et al: The pathogenesis of lung injury following pulmonary resection. Eur Respir J 15:790–799, 2000.

Linden PA, Bueno R, Colson YL, et al: Lung resection in patients with preoperative FEV1 <35% predicted. Chest 127:1984–1990, 2005.

Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665–671, 2001.

Marini JJ, Pierson DJ, Hudson LD: Acute lobar atelectasis: A prospective comparison of fiberoptic bronchoscopy and respiratory therapy. Am Rev Respir Dis 119:971–978, 1979.

Markos J, Mullan BP, Hillman DR, et al: Preoperative assessment as a predictor of mortality and morbidity after lung resection. Am Rev Respir Dis 139:902–910, 1989.

Money SR, Rice K, Crockett D, et al: Risk of respiratory failure after repair of thoracoabdominal aortic aneurysms. Am J Surg 168:152–155, 1994.

Nakahara K, Ohno K, Hashimoto J, et al: Prediction of postoperative respiratory failure in patients undergoing lung

Acute Respiratory Failure in the Surgical Patient

resection for lung cancer. Ann Thorac Surg 46:549–552, 1988.

Pedersen T, Eliasen K, Henriksen E: A prospective study of risk factors and cardiopulmonary complications associated with anaesthesia and surgery: Risk indicators of cardiopulmonary morbidity. Acta Anaesthesiol Scand 34:144– 155, 1990.

Strandberg A, Tokics L, Brismar B, et al: Atelectasis during anaesthesia and in the postoperative period. Acta Anaesthesiol Scand 30:154–158, 1986.

Van Mieghem W, Coolen L, Malysse I, et al: Amiodarone and the development of ARDS after lung surgery. Chest 105:1642–1645, 1994.

Ware LB, Matthay MA: The acute respiratory distress syndrome. N Engl J Med 342:1334–1349, 2000.

Warner MA, Warner ME, Weber JG: Clinical significance of pulmonary aspiration during the perioperative period.

Anesthesiology 78:56–62, 1993.

Wilcox P, Baile EM, Hards J, et al: Phrenic nerve function and its relationship to atelectasis after coronary artery bypass surgery. Chest 93:693–698, 1988.

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SECTION TWENTY-THREE

Respiratory Pump Failure

148 CHAPTER

Pump Failure: The Pathogenesis of Hypercapnic Respiratory Failure in Patients with Lung and Chest Wall Disease Steven G. Kelsen

Nathaniel Marchetti

I. COMPENSATORY/ADAPTIVE MECHANISMS Respiratory Chemosensitivity Responses to Heightened Respiratory Load Integrated Motor Responses Changes in Respiratory Structure II. DECOMPENSATING/MALADAPTIVE RESPONSES Respiratory Muscle Fatigue Rapid, Shallow Breathing Undernutrition III. SPECIFIC DISEASES Chronic Obstructive Pulmonary Disease Asthma Neuromuscular Diseases

The ventilatory pump accomplishes bulk transfer of air to and from the alveoli. Accordingly, diseases that perturb the mechanical properties of any component of the ventilatory pump (i.e., the bony rib cage, the extra- and intrathoracic

Obesity Kyph oscoliosis Obesity IV. ASSESSMENT OF PATIENTS WITH ABNORMALITIES OF THE VENTILATORY PUMP Symptoms Physical Findings Maximum Static Inspiratory Pressure V. TREATMENT Abnormalities in Chemosensitivity Respiratory Muscle Weakness or Fatigue Chronic Ventilatory Support/Nasal Positive-Pressure Ventilation

conducting airways, and the respiratory muscles) may interfere with CO2 elimination and O2 uptake. If disturbances in the function of the ventilatory pump are sufficiently severe, alveolar hypoventilation and respiratory acidosis may ensue.

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Hypercapnic respiratory failure is defined as a steady-state Paco2 while awake at more than 45 mmHg, the upper limit of normal. This definition is somewhat arbitrary but has proved clinically useful.

Conceptually, diseases that cause hypercapnic respiratory failure do so by deranging respiratory mechanics and lung dead-space volume (e.g., chronic obstructive pulmonary disease [COPD], asthma, or kyphoscoliosis) or by impairing the contractile properties of the respiratory muscles (e.g., neuromuscular disease). Diseases that impair respiratory mechanics increase the elastic or resistive load against which the respiratory muscles must contract. On the other hand, neuromuscular diseases impair the strength or endurance properties of the respiratory muscles and impair their ability to generate swings in intrathoracic pressure sufficient to maintain ventilation.

A variety of compensatory neural mechanisms that sense alterations in blood gas tensions or ventilatory performance elicit increases in the neuromuscular drive to breathe—which, in turn, helps preserve alveolar ventilation.

In fact, in most patients, rather marked abnormalities in ventilatory pump performance are required before hypercapnic respiratory failure ensues. Conceptually, the susceptibility to develop CO2 retention in the setting of lung, chest wall, or respiratory muscle dysfunction, therefore, depends on the balance between the severity of the derangement in ventilatory pump function and the intensity of the respiratory neuromuscular drive to breathe.

This chapter deals with the pathogenic mechanisms at work in the development of CO2 retention in lung and chest wall diseases. The compensatory/adaptive mechanisms that help preserve ventilation (e.g., respiratory chemosensitivity, motor responses to alterations in the mechanics of breathing, and intrinsic changes in respiratory muscle strength and endurance) and the decompensating/maladaptive responses that predispose to CO2 retention (e.g., respiratory muscle wasting and fatigue and a rapid, shallow pattern of breathing) will be discussed.

COMPENSATORY/ADAPTIVE MECHANISMS Respiratory Chemosensitivity Overview---Regulation of Ventilation Hypoxia and hypercapnia stimulate chemoreceptors in the arterial circulation (peripheral chemoreceptors) and ventrolateral medulla (central chemoreceptors) that reflexively increase motor activity to the respiratory skeletal muscles of the chest wall and upper airway. Contraction of the muscles of the chest wall (e.g., diaphragm, intercostals, abdominals, and neck muscles) deforms the ventilatory pump and moves air. Contraction of the muscles of the upper airway (genioglossus, alae nasae, posterior arytenoids, pharyngeal dilators, sternohyoid, etc.) increases the caliber of the upper

airway and diminishes its susceptibility to collapse during inspiration.

Chemoreceptor-induced increases in inspiratory and expiratory muscle activity are proportional to the severity of abnormalities in blood gas tensions and represent a feedback control loop that restores blood gas tensions toward normal by enhancing alveolar ventilation. The magnitude of the swings in intrathoracic pressure and resistance and compliance of the upper airway are determined by these changes in respiratory motor activity. The maintenance of blood gas tensions within a relatively narrow, normal range from neonatal life to senescence attests to the power of this homeostatic mechanism.

Hypoxic and hypercapnic chemical drives to breathe exert the following stereotypic effects on the activity of chest wall and upper-airway muscles. Peak respiratory muscle electrical activity and its rate of rise are increased. For the inspiratory muscles, these changes in muscle electrical activity increase the rate of change and peak inspiratory intrathoracic pressure, inspiratory airflow, and tidal volume. For the expiratory muscles, increased electrical activity enhances the rate of expiratory airflow. For the upper-airway muscles, the resistance to inspiratory airflow decreases.

Chemosensitivity-induced increases in respiratory activity also affect the timing of respiratory motor activity as reflected in the duration of inspiration (Ti ) and expiration (Te ). Hypoxia and hypercapnia lead to decreased Ti and Te , allowing the frequency of breathing to increase. Reductions in Te are generally out of proportion to Ti , thereby increasing the fraction of the respiratory cycle spent in inspiration. This partitioning of the respiratory cycle is reflected in the Ti /Tt ratio, where Tt is the total breath cycle duration (i.e., the sum of Ti and Te ).

Hypoxia and hypercapnia differ in their effects on the activity of the inspiratory muscles after the cessation of inspiratory airflow, the so-called postinspiratory inspiratory activity (PIIA). Hypoxia increases PIIA in both chest wall inspiratory muscles and muscles that constrict the laryngeal aperture. Accordingly, hypoxia has a braking effect on the rate of expiratory airflow. As Te decreases with increasing hypoxic drive, end-expiratory lung volume increases. PIIAinduced increases in lung volume increase the caliber of the intrathoracic airways and the O2 content of the lung. Hypoxiainduced PIIA affects the load on the respiratory muscles in complex fashion; that is, PIIA reduces inspiratory resistive work of breathing but increases the inspiratory elastic and expiratory resistive work of breathing. It has been suggested, however, that the net effect of hypoxia-induced PIIA is a reduction in overall energy expenditure during breathing. In contrast, hypercapnia diminishes the duration of PIIA. Indices of Respiratory Motor Output

Ventilation is a well-accepted index of respiratory motor output. Traditionally, ventilation was viewed as the product of tidal volume (Vt ) and respiratory rate (which is equal to 60/Tt ). More recently, ventilation has been viewed as the product of separate “drive” and “timing” components. The

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average rate of inspiratory airflow, Vt /Ti —which reflects the rate of rise of inspiratory muscle activity and intrathoracic pressure—is increased when blood gas tensions are deranged. Accordingly, Vt /Ti has been taken as a reflection of the activity of mechanisms that regulate the drive to breathe.

Of note, Vt /Ti may also be increased by excitatory inputs arising from respiratory mechanoreceptor afferents (e.g., vagal irritant receptors) and higher central nervous system (CNS) structures engaged in thermoregulation and emotion (i.e., hypothalamic and limbic areas). Conversely, the Ti /Tt ratio has been taken as a reflection of the activity of mechanisms that regulate respiratory timing. The Ti /Tt ratio is strongly affected by afferent input from mechanoreceptors in the lungs, airways, and respiratory muscles, as well as increasing chemical drive. For example, Ti /Tt increases in anesthetized animals when vagal stretch receptors are stimulated by increases in lung volume and is decreased by bronchoconstrictioninduced activation of vagal irritant receptors.

In subjects with normal lung function, Vt /Ti and ventilation are accurate reflections of inspiratory muscle electrical activity and the rate of rise of intrathoracic pressure. On the other hand, diseases that adversely affect the mechanical properties of the ventilatory pump (e.g., obstructive lung disease, kyphoscoliosis) interfere with the translation of changes in intrathoracic pressure into ventilation and airflow. Conversely, conditions that impair respiratory muscle contractility (e.g., neuromuscular diseases, respiratory muscle fatigue) interfere with the translation of inspiratory muscle electrical activity into intrathoracic pressure changes. Accordingly, Vt /Ti reflects the intensity of motor outflow to the inspiratory muscles produced by increasing chemical drive only when the mechanical properties of the ventilatory pump and inspiratory muscle strength are normal. When the ventilatory pump function is abnormal, respiratory motor outflow is best assessed from respiratory muscle electrical activity (i.e., diaphragm electromyography [EMG] activity), a complicated measurement largely confined to the research laboratory.

A simpler, clinically useful measurement that reflects the neuromuscular drive to breathe and the driving pressure to inspiratory airflow is the airway occlusion pressure. The occlusion pressure is the pressure generated at the airway opening 100 ms after the onset of an occluded inspiratory effort (i.e., P100 or P0.1 ) initiated at end-expiratory lung volume.

Since the airway is occluded, the inspiratory muscles contract quasi-isometrically, a condition in which muscle force correlates closely with muscle electrical activity. Measurements are made early in inspiration (100 ms) to prevent behavioral responses elicited in response to airway occlusion from altering the shape/trajectory of the pressure waveform. The lack of flow or volume change during the measurement means that the occlusion pressure is unaffected by abnormalities in the flow-resistive or compliance properties of the ventilatory pump. The occlusion pressure, therefore, has been used to assess the drive to breathe in patients with lung diseases (e.g., COPD and asthma) and chest wall diseases (e.g., kyphoscoliosis) during resting and chemically stimulated breathing. On

the other hand, the occlusion pressure depends on the ability of the inspiratory muscles to convert neural activity into force and pressure. Accordingly, like ventilation, occlusion pressure may not reflect respiratory motor-neuron activity when the inspiratory muscles are weak (e.g., neuromuscular disease) or fatigued.

Hypoxic Response Under isocapnic conditions, ventilation (or occlusion pressure) increases in curvilinear fashion as Po2 falls. However, hypoxic responses depend importantly on the prevailing level of Paco2 (i.e., the O2 –CO2 interaction). When Paco2 is in the hypocapnic range, arterial Po2 must fall considerably (to approximately 55 to 60 mmHg or less) before respiratory activity increases. Hypercapnia profoundly increases the response to hypoxia by shifting the threshold of the response toward higher levels of Po2 and augmenting the change in ventilation elicited for a given reduction in Po2 .

Although the physiological stimulus for the hypoxic response is the Pao2 of the blood perfusing the peripheral chemoreceptors, for convenience the oxyhemoglobin saturation assessed with a pulse oximeter has been taken as a reflection of the stimulus. Use of the oxyhemoglobin saturation linearizes the relationship between the hypoxic stimulus, ventilation, and occlusion pressure. The intensity of the hypoxic response has been assessed from the slope of the change in ventilation (or occlusion pressure) relative to the change in O2 saturation (i.e., # Ve /# % O2 sat) and from the intercept of the relationship (e.g., ventilation at O2 saturation of 85 percent).

Hypercapnic Response In contrast to the response to hypoxia, the ventilatory and occlusion pressure responses to hypercapnia under iso-oxic conditions are linear over a relatively wide range of Paco2 above and below the resting level of 40 mmHg. The intensity of the ventilatory and occlusion pressure response to CO2 has been assessed from the slope of the relationship of Ve to Paco2 (i.e., # Ve/# Paco2 ) and from the intercept of the relationship (i.e., Ve at Paco2 50 mmHg).

The ventilatory response to hypercapnia is strongly affected by the prevailing level of Pao2 and is heightened as Pao2 decreases. In fact, hypoxemic and hypercapnic stimuli interact multiplicatively to enhance inspiratory and expiratory motor activity. Worsening hypoxemia enhances the ventilatory response to hypercapnia in accordance with the O2 –CO2 interaction. The strength of a subject’s chemosensitivity to O2 and CO2 and, in particular, to the O2 –CO2 interaction is a powerful feedback mechanism opposing the tendency to retain CO2 in patients with ventilatory pump dysfunction.

Consequently, treatment of the hypercapnic, hypoxemic patient with supplemental O2 may decrease Vt /Ti and Ti /Tt and, hence, worsen hypercapnia in accordance with O2 –CO2 interaction. Increases in Pao2 in hypoxic, hypercapnic subjects move the O2 response to the right (less stimulus)

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Figure 148-1 Theoretical effects of supplemental O2 on the ventilatory response to CO2 and steady-state arterial PCO 2 in subjects with COPD in hypercapnic respiratory failure. Increasing PaO 2 decreases alveolar ventilation and increases PaCO 2 as dictated by effects of O2 on the CO2 ventilatory response. The two straight lines represent hypercapnic ventilatory response curves at PaO 2 of 40 and 60 mmHg. As may be seen, increasing PaO 2 produces a downward, rightward shift of the ventilatory response. In contrast, the hyperbolic line intersecting the ventilatory response lines is the metabolic CO2 –ventilation curve, which represents the effect of increasing alveolar ventilation (independent variable) on PaCO 2 (the dependent variable) when CO2 production is normal (∼200 ml/min). Steady-state alveolar ventilation and PaCO 2 at rest are dictated by intersection of the ventilatory response curves with the metabolic curve (points 1 and 2). Note the increase in PaCO 2 as the ventilatory response with PaO 2 60 mmHg intersects at a lower alveolar ventilation and higher PaCO 2 (point 2) compared to the higher ventilatory response when PaO 2 was 40 mmHg (point 1).

and decrease the slope and shift the intercept of the ventilatory response to hypercapnia to the right (Fig. 148-1). Shifts in the CO2 response with increases in the prevailing Pao2 mean that a higher CO2 stimulus is required to maintain ventilation at the baseline level. Accordingly, ventilation falls and Paco2 rises. The magnitude of the rise in Paco2 in patients with COPD in acute respiratory failure produced by supplemental O2 varies widely among subjects as determined by their chemosensitivity.

Of note, hypercapnia induced by supplemental O2 in patients with COPD is multifactorial and reflects increases in lung dead-space volume as well as reductions in alveolar ventilation. Hypoxemia causes bronchoconstriction via increases in parasympathetic outflow to airway smooth muscle. Accordingly, relief of hypoxemia causes bronchodilation and increased dead-space volume.

Role of Blunted Chemosensitivity in Development of Respiratory Failure Chemosensitivities to hypoxemia and hypercapnia are hereditofamilial and ethnic traits that vary widely interindividually

Figure 148-2 Variability of the slopes of the ventilatory responses to progressive hypercapnia (i.e., VE /PCO 2 ) in a normal population. Shown is the frequency distribution histogram of the slopes in 126 normal South African medical students. Note the considerable interindividual variation in CO2 responsiveness. In some healthy subjects, the ventilatory response is blunted to less than 1 L/min/mmHg PCO 2 . (Based on data from Irsigler GB: Carbon dioxide response lines in young adults: The limits of the normal response. Am Rev Respir Dis 114:529–536, 1976, with permission.)

(Fig. 148-2). In a given subject, responses to hypoxemia and hypercapnia correlate weakly, so that subjects with strong responses to hypercapnia also tend to have strong responses to hypoxia. Respiratory chemosensitivity to both hypoxemia and hypercapnia declines with age. The decline in chemosensitivity with aging may explain why elderly subjects with lung disease (e.g., COPD) or chest wall disease (e.g., kyphoscoliosis) develop hypercapnic respiratory failure more frequently than young adults. When chemosensitivity is low, subjects with diseases of the ventilatory pump are predisposed to develop hypercapnic respiratory failure.

In patients with advanced COPD, the severity of airway obstruction required to cause CO2 retention varies widely from subject to subject (Fig. 148-3). Subjects with the greatest respiratory effort responses to changes in Paco2 —as measured by diaphragm EMG, respiratory work of breathing, or occlusion pressure—have arterial Paco2 values closer to normal than subjects with blunted responses to CO2 but the same severity of lung dysfunction. Accordingly, when chemosensitivity is low, subjects with diseases of the ventilatory pump are predisposed to develop hypercapnic respiratory failure.

However, since CO2 retention per se may blunt the response to acute hypercapnia, studies in patients in respiratory failure have not been able to determine whether blunted CO2 responses are a cause or consequence of respiratory failure.

The tendency for chemosensitivity to be inherited has been used in a number of subsequent studies to assess the role of hypoxic and hypercapnic responses in the pathogenesis of CO2 retention in the setting of obstructive lung disease. Study of relatives with normal lung function and blood gases has been employed to circumvent the effects of CO2 retention on respiratory chemosensitivity in patients with COPD. In general, normal relatives of hypercapnic patients with COPD have lower ventilatory responses to hypoxia and hypercapnia than relatives of eucapnic patients with COPD

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Figure 148-3 Results of repeated measurements of arterial PCO 2 and FEV1 (liters) in five patients with advanced COPD. Free-hand curves of the data are shown plotted together in the lower right graph. Note that cases 1, 11, and 13 show marked increases in PCO 2 , with relatively small changes in FEV1 , whereas cases 4 and 5 do not. (Based on data from Lane DJ, Howell JBL, Giblin B: Relation between airways obstruction and CO2 tension in obstructive airways disease.

Br Med J 3:707â&#x20AC;&#x201C;709, 1968, with permission.)

(Fig. 148-4). Among the offspring of patients with COPD with equally severe airway obstruction, the slopes of the ventilatory responses to isocapnic hypoxemia and hyperoxic hypercapnia are 30 to 40 percent lower in the offspring of hypercapnic patients than in offspring of eucapnic patients. Similarly, the slopes of the ventilatory and airway occlusion pressure responses to isocapnic hypoxia in the offspring of hypercapnic patients are approximately 40 percent of the values obtained in the offspring of normocapnic patients. In one study, the Pao2 of COPD patients while in a stable state and the Pao2 and Paco2 during COPD exacerbations correlated with the

hypoxic ventilatory response of their sons. It appears that blunted chemosensitivities to hypoxia and hypercapnia are likely to be premorbid characteristics of hypercapnic patients with COPD, which contribute to the development of respiratory failure.

A number of reports describe patients with asthma and respiratory failure who had blunted ventilatory responses to hypoxia and hypercapnia and whose healthy immediate family members also showed blunted hypoxic and hypercapnic responses. Respiratory responses to hypoxia and hypercapnia in patients with asthma who have near-fatal attacks differ from those of asthmatics who did not have near-fatal attacks and age-matched, normal subjects. The slopes of the ventilatory and occlusion pressure responses to hypoxia in the patients with a history of near-fatal asthma are approximately 33 percent of the responses of the asthmatics without nearfatal attacks or normals, which are similar. Hypercapnic responses tend to be lower in the near-fatal asthmatic groups than in the other two groups, but the differences are smaller in magnitude.

Responses to Heightened Respiratory Load

Figure 148-4 Mean isocapnic hypoxia and hyperoxic hypercapnic ventilatory response curves of 12 offspring of hypoventilating patients with COPD (solid line) and 10 offspring of eucapnic COPD patients (dashed line). Ventilatory responses to hypoxia and hypercapnia are significantly lower in the offspring of hypercapnic COPD than in the offspring of eucapnic COPD patients. (Based on data from Mountain R, Zwillich CW, Weil JV: Hypoventilation in obstructive lung disease: The role of familial factors. N Engl J Med 297:521â&#x20AC;&#x201C;525, 1978, with permission.)

A complex array of mechano- and proprioceptors whose afferents project to respiratory neurons in the brain stem and higher CNS structures provides the respiratory controller with information about the mechanics of breathing and performance of the ventilatory pump. The sensory receptors providing this afferent feedback and the CNS structures that integrate this feedback into a coordinated respiratory response (see below) are not perfectly understood. However, mechanoreceptors in the intercostal muscles that sense muscle tension and length (Golgi tendon receptors and spindle

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organs, respectively) and pressure and flow sensors in the lower (vagal irritant receptors) and upper airway (larynx and mouth) clearly play a role in shaping the neuromuscular response to alterations in the mechanics of breathing.

Diseases of the airways (COPD and asthma) or chest wall (kyphoscoliosis) change the resistance and compliance properties of the ventilatory pump and, hence, stimulate mechanoreceptors in the ventilatory pump. In normal subjects and those with COPD, mechanoreceptor afferent inputs increase inspiratory neuromuscular output as reflected in airway occlusion pressure in response to bronchoconstriction or external resistances or elastance. Changes in ventilation during acute increases in airway resistance are inversely related to changes in occlusion pressure. Thus, the magnitude of the motor response to increases in respiratory load determines the ventilatory response.

External ventilatory loads that can be consciously detected and alter the intensity of the sensations associated with breathing elicit increases in respiratory effort as reflected by the diaphragm EMG and occlusion pressure. Increases in effort occur abruptly within the first loaded breath and in feedforward fashion; that is, the experience of the previous breath elicits a response in anticipation that the load will still be present. These responses are eliminated by general anesthesia and dulled if not absent in stages III and IV and REM sleep.

The afferent input to the CNS elicited by external ventilatory loads probably arises from spindle and tendon organs in the respiratory muscles that project to the sensorimotor cortex and medullary respiratory neurons. The motor response to external ventilatory loads is thought to be behavioral.

The magnitude of the respiratory motor response to external loads varies widely from subject to subject and may be a hereditofamilial trait. Of considerable importance, some subjects with COPD demonstrate lesser occlusion pressure responses to acutely applied external resistive loads than agematched normal subjects. It has been suggested that the blunted respiratory motor response to external loads may be a form of sensory adaptation to chronic increases in respiratory resistance. The fact that occlusion pressure responses of patients with COPD to external elastic loads and patients with asthma to external resistive loads are normal supports this concept. Of interest, the blunted motor response to external loads in some patients with COPD may reflect an increase in endogenous opiates within the CNS, since naloxone administration immediately enhances the response.

In subjects with COPD, bronchoconstriction increases airway occlusion pressure in proportion to increases in airway resistance and to a greater extent than with external flowresistive loads. Bronchoconstriction increases the activity of vagal â&#x20AC;&#x153;irritantâ&#x20AC;? receptors in the airway, which exert an inspiratory augmenting effect on breathing. Irritant receptors may also be excited chemically by inflammatory mediators (e.g., histamine, prostaglandin F2Îą) and, in contrast to external loads, elicit simple monosynaptic reflexes not abolished by sleep or anesthesia.

Mechanoreceptor inputs modify the respiratory motor responses to chemical stimuli to breathing. Increases in the elastic or resistive load to inspiration augment inspira-

tory muscle electrical activity and the airway occlusion pressures to hypoxia and hypercapnia. Subjects with asthma show heightened occlusion pressure responses to hypoxia and hypercapnia for this reason. Increases in the inspiratory neuromuscular drive to breathe allow ventilation to be maintained in the face of abnormalities in respiratory mechanics. Respiratory motor activity (i.e., occlusion pressure) also tends to be increased when the respiratory muscles are weak. In all likelihood, this reflects the fact that the maintenance of force output by a weakened muscle requires an increase in activation by the CNS. Increased ventilatory loads also alter the pattern of breathing in load-dependent fashion. Subjects breathing against resistive loads breathe slowly and deeply, with an increase in tidal volume and prolongation of Ti and Te . In contrast, subjects breathing against elastic loads tend to breathe with smaller tidal volumes and a reduced Ti and Te ; that is, they demonstrate a rapid and shallow pattern of breathing. Slow, deep breathing during resistive loading and rapid, shallow breathing during elastic loading diminish the resistive and elastic work of breathing, respectively. Alterations in breathing pattern when the mechanics of breathing are deranged are believed to be attempts to minimize the work of breathing, muscle tension, or energy expended.

Integrated Motor Responses Respiratory motor responses to heightened chemical or mechanoreceptor drives to breathe elicit highly coordinated patterns of muscle activity that optimize the mechanical output of the respiratory musculature contracting in concert.

These responses may take the following forms: (1) simple reflex-mediated recruitment of additional agonists, which exert similar mechanical effects on the chest wall; (2) sequential activation of inspiratory and expiratory muscles, which exert opposing effects on chest wall structures; and (3) complex behavioral acts that use nonrespiratory muscles to effect changes in body posture and expiratory airflow, minimizing dyspnea.

For example, hypercapnia and hypoxia recruit the external intercostal and parasternal muscles during inspiration in a stereotypic rostral-to-caudal direction, and the internal intercostals and triangularis sterni during expiration in the opposite direction. Preferential activation of the inspiratory external intercostal and parasternal muscles in the rostralmost interspaces decreases the impedance of the rib cage to rostral movement and, hence, facilitates thoracic expansion. Conversely, recruitment of the expiratory internal intercostals and triangularis sterni in the most caudal interspaces decreases the impedance to caudal movement and facilitates thoracic deflation. In addition, recruitment of the parasternal intercostal muscles facilitates inspiratory pressure as tidal volume increases. The parasternal intercostal muscle fiber length, which is optimum for tension development, is shorter than that of the diaphragm and occurs at higher lung volume.

Accordingly, the parasternal muscles become mechanically more effective than the diaphragm as lung volume increases above functional residual capacity (FRC).

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Moreover, hypercapnia and hypoxia increase phasic and tonic inspiratory activity in the dilator muscles of the upper airway (e.g., posterior arytenoid, alae nasae, genioglossus). Increases in activity of the dilator muscles of the upper airway decrease the load on the chest wall pumping muscles by decreasing the resistance to inspiratory airflow through the upper airway. Increased activity of these muscles also diminishes the susceptibility of the upper airway to collapse as inspiratory efforts become greater and subpharyngeal pressure becomes more subatmospheric.

In addition, phasic increases in abdominal expiratory muscle electrical activity during expiratory airflow accelerate lung emptying, thereby allowing the time of expiration to decrease. When sufficiently intense, activation of the abdominal muscles reduces end-expiratory lung volume and improves the ability of the diaphragm to generate pressure by favorably affecting its precontraction length, radius of curvature, and alignment with the rib cage. Reductions in end-expiratory lung volume achieved by the expiratory muscles also allow elastic work to be stored in the passive recoil of the chest wall and released suddenly at the onset of inspiration. Sudden release of the recoil pressure of the chest wall thereby “assists” the inspiratory muscles by contributing to the driving pressure to inspiratory airflow. A portion of the inspiratory load is thus assumed by the expiratory muscles.

Finally, hyperinflated, dyspneic patients with COPD often assume a stereotypic body posture that improves diaphragm, neck accessory, and pectoral girdle muscle mechanical advantage. This posture is forward flexion of the trunk, extension of the head and neck, bracing of the pectoral girdle by rounding of the shoulders, and grasping of the thighs with the arms. The effect of this posture is to increase abdominal pressure (thus increasing diaphragm precontraction length and radius of curvature); provide more favorable alignment of the scalenes and sternomastoid with the upper rib cage; and anchor the pectoral girdle muscles, allowing them to apply an inspiratory action on the rib cage. In this posture, transdiaphragmatic pressure is increased and diaphragm and sternomastoid muscle EMG activity is decreased. Patients with advanced COPD also spontaneously adopt pursed-lip breathing to slow expiratory airflow, thus minimizing dynamic airway compression.

Effects of Sleep Responses to chemical stimuli to breathing are powerfully influenced by CNS state (e.g., sleep vs. waking). Slow-wave and REM sleep depress O2 and CO2 chemosensitivity, with greatest depression occurring in REM sleep. While the subject is awake, apnea does not occur in the presence of even marked hypocapnia, and ventilation is largely independent of changes in Pco2 . Rather, ventilation persists even when Paco2 is less than about 30 to 35 mmHg. Persistence of ventilation in the setting of hypocapnia (the so-called wakefulness drive to breathe) probably represents the effects on medullary neurons of inputs activated by auditory, visual, and tactile stimuli. In contrast, in the sleeping or anesthetized state, the ventilatory response to CO2 extrapolates to zero ventilation

in the hypocapnic range. In fact, apnea occurs when Pco2 falls only 4 to 6 mmHg below waking eucapnic levels. Sleeprelated changes in chemosensitivity, therefore, underlie the recurrent periods of apnea and hyperpnea and exaggerated hypercapnia that occur in some patients with diseases of the lung and chest wall.

The increase in respiratory motor activity induced by derangements in respiratory mechanics is also statedependent; that is, heightened activity in awake subjects is absent in sleeping or anesthetized subjects. REM sleep, in particular, impairs the “load” response and causes collapse of the upper rib cage during inspiration, which adversely affects the level of ventilation as well as its distribution. Descending inhibitory drives to spinal α– and spindle γ– motor neurons in REM sleep cause atonia of all the respiratory muscles except the diaphragm. Muscle spindle γ-efferent activity determines spindle sensitivity by progressively contracting the intrafusal fiber. Accordingly, reductions in muscle spindle γ-efferent activity diminish spindle organ sensitivity and interfere with a mechanism for augmenting respiratory muscle spinal α– motor neuron activity. The diminished or absent load response during sleep and anesthesia probably explains the exaggerated increases in Paco2 that occur during these periods in patients with lung and chest wall disease. In fact, REM sleep is the period in which Paco2 is highest and Pao2 lowest in patients with stable COPD (Fig. 148-5).

Changes in Respiratory Structure Respiratory Muscles The respiratory muscles are highly plastic and undergo changes in structure, biochemistry, and contractile properties in response to chronic increases in load or changes in precontraction length. Chronic increases in inspiratory muscle activity enhance their strength and endurance. In animal models, chronic increases in inspiratory load produced by emphysema or inspiratory resistive loading increase diaphragm endurance and the content of oxidant enzymes (e.g., succinic dehydrogenase and citrate synthase) essential for high-energy phosphate synthesis. In patients with chronic asthma, inspiratory and expiratory muscle endurance assessed from the time course of the fall in maximum static pressure is about 40 percent greater than in normal controls. The effect of COPD per se on inspiratory muscle endurance has not been assessed. In subjects with COPD, however, daily training with inspiratory resistive ventilatory loads increases inspiratory muscle strength by about 40 percent as reflected by maximum static inspiratory pressure (Pimax ) over an 8- to 10-week period.

Hyperinflation impairs the force- and pressuregenerating ability of the inspiratory muscles by decreasing muscle precontraction length and unfavorably changing muscle alignment with the chest wall. In particular, severe hyperinflation alters diaphragm shape (i.e., flattening) and decreases the zone of apposition with the rib cage. Flattening of the diaphragm displaces the vector of contraction force from a rostral-caudal direction to a medial-lateral direction and diminishes the ability of the diaphragm to increase abdominal

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Figure 148-6 Active (upper trace) and passive (lower trace) length-tension (L-T) relationship of costal diaphragm of emphysematous (open circles) and normal hamsters (solid circles), assessed in vitro during electrical stimulation. Note that in emphysematous animals, the L-T curve is displaced toward shorter fiber lengths. This adaptive change in emphysematous animals allows the diaphragm to generate maximal tension (force) at shorter fiber lengths and helps preserve diaphragm contractile performance in the face of considerable hyperinflation. (From Supinski GS, Kelsen SG: Effect of elastase-induced emphysema on the forcegenerating ability of the diaphragm. J Clin Invest 70:978–988, 1982, with permission.)

Figure 148-5 Changes in steady-state arterial PCO 2 during sleep in eight patients with stable COPD. Note that arterial PCO 2 increases and arterial PO 2 decreases during sleep. Greatest changes occur during REM sleep. For PaCO 2 , average increase is 10 mmHg. (Based on data from Koo KW, Sax DS, Snider GL: Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am J Med 58:663–670, 1975, with permission.)

pressure. Reductions in the zone of apposition diminish the inflationary effects on the lower rib cage produced by increases in abdominal pressure induced by the diaphragm. In extreme cases of hyperinflation, the diaphragm may exert an expiratory action on the lower rib cage and retract the lower rib cage on inspiration (Hoover’s sign).

In part, hyperinflation-induced impairment in the action of the diaphragm is compensated for by adaptive changes in the intrinsic muscle length–tension characteristic. In emphysematous animals, the active and passive length–tension curve of the costal diaphragm is displaced toward shorter lengths, thereby allowing maximum tension to be developed at significantly shorter lengths and higher lung volumes (Fig. 148-6). The shift in the length–tension curve appears to be the reverse of normal growth, in which muscle length is increased by addition of sarcomeres in series. A similar adaptation in the diaphragm seems to occur in chronically hyperinflated, stable outpatients with COPD. Chest Wall Anatomy Chronic hyperinflation elicits adaptive changes in the pressure-volume (P-V) characteristic of the passive chest wall.

In animal models of emphysema, the static deflation, chest

wall P-V curve is shifted up and to the left, so there is a decrease in elastic recoil at any given lung volume. Shifts in the passive P-V curve are accomplished by a structural remodeling of the rigid structures in the chest wall. The length of the sternum and the lengths of the ribs in anteroposterior and transverse dimensions are increased. This displacement of the chest wall P-V curve diminishes the inspiratory elastic work of breathing during hyperinflation and preserves the zone of apposition of the diaphragm. An increase in the zone of apposition of the diaphragm in hyperinflation preserves the appositional force exerted by the diaphragm on the lower rib cage by virtue of changes in abdominal pressure. If present in patients with COPD, the process is reversible, since recent observations of the thorax after volume reduction surgery or lung transplantation for COPD indicate that the shape of the chest wall can quickly revert to normal.

DECOMPENSATING/MALADAPTIVE RESPONSES Respiratory Muscle Fatigue Overview/Definition Studies in the laboratory and in the clinic indicate that the respiratory skeletal muscles, like muscles in the limbs, fatigue under conditions of intense activity, leading to respiratory failure. Conditions that increase the level of phasic inspiratory muscle activity, or the duty cycle of breathing, or that decrease the maximal pressure-generating capacity of

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the muscle, make fatigue more likely. For example, derangements in the mechanical properties of the lung or chest wall or increases in ventilatory drive increase inspiratory muscle contractile activity. Of note, increases in ventilatory drive increase both the peak inspiratory pressure and Ti /Tt ratio, the latter by causing greater reductions in the duration of expiration than in that of inspiration.

Decreases in inspiratory muscle strength caused by aging, protein-calorie malnutrition, or electrolyte imbalances predispose to fatigue at any given level of inspiratory impedance or ventilation by decreasing Pimax . Finally, on the basis of data from animal models, reductions in diaphragm blood flow are likely to decrease the level of muscle activity that leads to fatigue.

Respiratory muscle fatigue has been defined as a loss in muscle capacity to develop force or shorten, resulting from muscle fiber activity under load; it is reversible by rest. In contrast, respiratory muscle weakness has been defined as impairment in the capacity of a fully rested muscle to generate force.

Fatigue is viewed as developing when the muscle is highly active and generating appreciable levels of force. Recovery from fatigue is generally observed over a short time (e.g., minutes to hours). On the other hand, muscle weakness is commonly caused by muscle fiber atrophy, metabolic derangements that impair the ability of actomyosin crossbridges to generate force (e.g., acidosis or electrolyte abnormalities that affect intracellular calcium flux), or chronic reductions in muscle precontraction length that impose a mechanical disadvantage (e.g., hyperinflation of the thorax and its effects on the inspiratory muscles). Implied in the definition of weakness is the idea that alterations in muscle function are secondary to alterations in muscle structure or lung volume and hence induce changes in muscle function that are more slowly reversible than fatigue (e.g., days to weeks). In the clinical setting, however, the distinction between muscle weakness and fatigue is difficult and not easily accomplished. Moreover, a close association exists between respiratory muscle weakness and respiratory muscle fatigue. In fact, weak muscles are predisposed to fatigue (see below).

Fatigue produces complex effects on muscle mechanical output. Fatigue prolongs contraction and relaxation time and depresses the force generated at a given stimulus frequency and fiber length, and reduces the velocity of shortening against a given load.

Depending on the cause of the fatigue, depression of force output can occur at primarily subtetanizing frequencies of muscle stimulation (e.g., less than 15 to 20 Hz), a condition called low-frequency fatigue, or at frequencies above 50 Hz, a condition called high-frequency fatigue (Table 148-1, Fig. 148-7). The biochemical and biophysical processes that underlie low-frequency and high-frequency fatigue differ. Muscle force responses to tetanizing frequencies of stimulation (i.e., above 50 Hz) are primarily determined by the processes of neuromuscular transmission and muscle excitation. In contrast, muscle mechanical output at subte-

Table 148-1 Classification of Respiratory Muscle Fatigue Central Refers to decreases in phrenic motor output mediated by spinal or supraspinal mechanisms Peripheral Refers to fatigue occurring at the level of the muscle itself Transmission Failure of mechanisms operative in muscle excitation (“high-frequency” fatigue) Contractile Failure of mechanisms involved in excitationcontraction coupling or contractile protein function (“low-frequency” fatigue)

tanizing frequencies is determined primarily by the processes of excitation-contraction coupling (e.g., calcium release from the sarcoplasmic reticulum, calcium-troponin interactions), perhaps caused, in part, by O2 free radical–induced injury.

Of interest, recovery from high-frequency fatigue is more rapid (minutes) than recovery from low-frequency fatigue (hours) (Fig. 148-8). Moreover, the two forms of fatigue have different physiological consequences. High-frequency fatigue impairs muscle force output under conditions in which the muscle is maximally driven by the CNS (i.e., when muscle strength is being evaluated). Low-frequency fatigue, on the other hand, impairs force generation during resting breathing, when phrenic motor unit discharge rates are typically about 15 Hz. Since low- and high-frequency fatigue reflect impairments occurring at the level of the muscle, they have been termed peripheral fatigue.

Performance of strenuous ventilatory tasks may also elicit an additional, qualitatively different response—i.e., a reduction in central motor output and failure of the CNS to fully activate the respiratory muscles. That is, the diaphragm EMG or phrenic neurogram may decrease late in the performance of strenuous respiratory efforts before the point of exhaustion. This reduction in motor activity may limit task performance. The failure of CNS mechanisms to fully activate the muscle near the point of exhaustion has been termed central fatigue. The mechanisms underlying central fatigue are poorly understood. It is not clear whether central fatigue represents a behavioral response elicited by the unpleasant sensations present during ventilatory loading or is mediated reflexively or by changes in brain neurotransmitter levels.

Detection of Respiratory Muscle Fatigue Diaphragm muscle fatigue has been diagnosed in humans from changes in the response of the muscle to electrical stimulation (i.e., the force-frequency relationship), the power

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Figure 148-7 Force-frequency relationship of the human diaphragm during electrophrenic stimulation showing rate of recovery from high- and low-frequency fatigue. Data obtained in four subjects before and after a period of inspiratory resistive loading to exhaustion. At the point of exhaustion, the subject was unable to generate targeted values of transdiaphragmatic pressure (Pdi). Note the decrease in Pdi in response to low (20 Hz) and high (50 Hz) electrical stimulation immediately after loading, indicating the presence of both high- and low-frequency fatigue. Note also that high-frequency fatigue disappears within 14 to 17 min. In contrast, low-frequency fatigue persists beyond the period of observation (>30 min). (Based on data from Aubier M, Farkas A, De Troyer RT, et al: Detection of diaphragmatic fatigue in man by phrenic stimulation. J Appl Physiol 50:538â&#x20AC;&#x201C;544, 1981, with permission.)

spectral content of the EMG, and Pimax . As will be seen, the force-frequency relationship and EMG power spectrum analyses are complex and require sophisticated electronics and instrumentation. Consequently, their use has been confined to the research laboratory. On the other hand, Pimax is convenient and easily performed at the bedside but suffers from relative nonspecificity.

Electrical Stimulation

The force-frequency relationship represents a way of assessing muscle mechanical output over a wide range of stimulus intensities. Since fatigue shifts the force-frequency curve downward (and possibly to the left), the magnitude of the shift in the force-frequency relationship can be used to assess the severity of low- and high-frequency fatigue and the time course of recovery.

Electrical stimulation of the muscle of interest has several advantages. It allows the muscle to be activated in response to a standard stimulus without the cooperation of the

subject. Hence, neurological deficits, decreased effort, and central fatigue, which may diminish muscle activation, are circumvented and peripheral fatigue can be detected.

EMG Power Spectrum

Fatigue alters the power-EMG spectral content of the raw EMG of the respiratory muscles analyzed by fast Fourier transform (Fig. 148-8). In the fresh diaphragm, the power (or voltage) contained in the EMG waveform reaches a maximum between approximately 85 and 105 Hz, and thereafter declines. (Maximum power in the EMG of the diaphragm, parasternal intercostal, and sternocleidomastoid occurs at somewhat different frequencies, however.) Fatigue-inducing contractions cause a leftward shift of the power spectral density, so that more of the power in the EMG is contained in a lower-frequency domain. The power-spectral density of the contracting diaphragm changes almost immediately with fatiguing contractions and considerably before the mechanical output of the muscle fails. The diaphragmatic EMG power

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under standard conditions as well as during volitional contractions.

Muscle Activity

Figure 148-8 Schematic representation of the power-spectral density of a respiratory muscle EMG determined by fast Fourier transform. Note the concave appearance of the relationship. Note that fatigue (dashed line) decreases and increases power in the high- and low-frequency domains, respectively, thereby shifting the relationship toward the left. (Based on data from Moxham J, Edwards RHT, Aubier M, et al: Changes in EMG power spectrum (highto-low ratio) with force fatigue in humans. J Appl Physiol 53:1094– 1099, 1982, with permission.)

spectrum can be obtained from the raw EMG of the muscle, recorded from surface electrodes on the chest wall or within the esophagus. It is, therefore, relatively noninvasive and well tolerated. Moreover, the EMG power spectrum, unlike maximal static pressure, can be measured continuously— i.e., breath by breath—and does not require subject cooperation. Accordingly, the EMG power spectrum has proved to be a useful tool to study the pathophysiological mechanisms of human respiratory muscle fatigue. A significant caveat in the use of the power spectrum is the suggestion that it may be unable to detect low-frequency fatigue.

Pathogenesis of Respiratory Muscle Fatigue Studies designed to examine the pathogenetic mechanisms that lead to respiratory muscle fatigue have largely focused on the diaphragm. The diaphragm has been the primary focus of attention for several reasons. First, it is the major respiratory muscle. Second, anatomic considerations allow the mechanical output of the diaphragm (i.e., transdiaphragmatic pressure) and its EMG, an index of phrenic motor outflow and fatigue state, to be assessed relatively easily. Finally, the cervical phrenic nerves can be electrically stimulated, thereby allowing the mechanical output of the muscle to be assessed

In seminal studies, Roussos and Macklem observed that the time of onset of diaphragm fatigue was not related to the magnitude of the phasic inspiratory swings in Pdi during loading alone or to Pdimax alone. Rather, the time of onset of mechanical failure of the diaphragm was a unique curvilinear function of the ratio of Pdi generated on each breath over Pdimax (Pdi/Pdimax ) (Fig. 148-9). Values of Pdi/Pdimax less than 40 to 50 percent could be maintained indefinitely; values greater than this threshold were associated with progressively more rapid exhaustion. These results made several important points. First, diaphragm fatigue depended on the relative intensity of contraction (i.e., muscle force output as a percentage of its strength). Second, contractions below some critical threshold could be sustained indefinitely and did not lead to fatigue.

Subsequent studies demonstrated that the timing as well as the intensity of diaphragmatic contractions determined the time of onset of mechanical failure of that muscle.

Increases in the ratio of the Ti over the Tt increased the rapidity of onset of fatigue at any given Pdi/Pdimax ratio. That is, increasing the duration of diaphragm contraction relative to the period during which the diaphragm is relaxed, the duty cycle of breathing, predisposes to fatigue. In fact, diaphragm fatigue appears to be largely a function of the product of Pdi/Pdimax × Ti /Tt , which has been termed the diaphragm tension–time index (TTI) (Fig. 148-10). The TTI is, in essence, the integrated area under the pressure waveform over time.

The TTI is usually expressed not in absolute terms of pressure per unit of time but, rather, in relative terms as a dimensionless value (i.e., as a percentage of the maximum) to reflect the importance of relative changes in pressure and timing of contraction. The TTI determines muscle energy use as reflected in the O2 consumption.

A threshold for the onset of fatigue occurs at a TTI of approximately 15 to 20 percent of maximum (Fig. 148-10).

The greater the TTI above this value, the more rapidly fatigue ensues.

Subsequent studies in normal subjects demonstrated that mechanical failure of the inspiratory muscles as pressure generators can be accelerated at a given TTI by increasing the Vt /Ti . Increases in Vt /Ti reflect an increase in the velocity of inspiratory muscle shortening. Since the greater the velocity of shortening and the more rapid actomyosin cross-bridge cycling, the greater the rate of adenosine triphosphate splitting, this is not surprising. Also of interest, respiratory maneuvers associated with high levels of ventilation appear to selectively fatigue the diaphragm, whereas maneuvers that produce high levels of pressure primarily fatigue the intercostal and neck muscles.

Muscle Blood Flow

Diaphragm fatigue may relate, in part, to a compromise of muscle blood flow during intense contractions. The

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Figure 148-9 Relationship between the intensity of diaphragm contractile activity reflected in the diaphragm tension-time index (TTdi)–-i.e., the product of Pdi/Pdimax × TI /TT and the time of onset of mechanical failure of the diaphragm, Tlim. The two scales are logarithmic. Data obtained in normal subjects during strenuous volitional contractions during inspiratory resistive ventilatory loading. Note that above approximately 15 percent TTdi, Tlim decreases progressively with increasing TTdi. These data indicate that a fatigue threshold exists for the human diaphragm above TTdi 15 to 20 percent and that above this threshold, diaphragm endurance is a unique function of the TTdi. (Based on data from Bellemare F, Grassino A: Evaluation of human diaphragm fatigue. J Appl Physiol 53:1196–1206, 1982, with permission.)

relationship of diaphragm blood flow to muscle contractile activity is complex and depends, like fatigue itself, on both the intensity and timing of contractions. The level and pattern of diaphragm activation, therefore, determine not only muscle energy use but also the availability of metabolic fuel (i.e., glucose, free fatty acids, and other nutrients).

Contractions of low intensity increase blood flow. In contrast, contractions in excess of 20 to 30 percent of Pdimax mechanically compromise blood flow and cause postcontraction hyperemia. When the diaphragm contracts rhythmically, the Ti /Tt also affects diaphragm blood flow. At Pdi/Pdimax values that compromise blood flow during contraction (i.e., above 20 to 30 percent), blood flow occurs solely during the phase of muscle relaxation. Consequently, increases in the Ti /Tt ratio decrease overall blood flow by encroaching on relaxation time. Diaphragm blood flow is, therefore, a function of the TTI rather than Pdi/Pdimax or the Ti /Tt alone. Blood flow increases up to a TTI of 20 to 30 percent and thereafter falls progressively with further increases in TTI. Compromise of diaphragm blood flow when TTI is greater than 20 to 30 percent of maximum may lead to a condition in which the metabolic needs of the muscle outstrip the availability of energy supply. Alternatively, the importance of blood flow may lie in washing out toxic metabolites (e.g., hydrogen and

phosphate ions) from the muscle. The diaphragmatic TTI associated with limitation of blood flow is also a complex function of the level of systemic arterial pressure. Reductions in arterial pressure produced in animal models by bleeding decrease blood flow at any given level of TTI and reduce the Pdi value at which blood flow is mechanically impeded.

Of considerable importance, diaphragm blood flow may also be a determinant of steady-state diaphragm contractile function in COPD patients in acute respiratory failure. In small numbers of COPD patients, 30 to 50 percent increases in diaphragm blood flow with intravenous dopamine (8 µg/kg/min) caused rapid, approximately 40 percent increases in Pdi during electrophrenic twitch contractions. These findings require confirmation before vasodilator therapy to improve diaphragm function can be advocated.

However, they suggest the possibility that diaphragm blood flow may be compromised by intense contractile activity in patients with severe lung disease.

Rapid, Shallow Breathing Patients with abnormalities in ventilatory pump function breathe rapidly and shallowly in respiratory failure. Respiratory rate is increased and tidal volume is decreased.

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Figure 148-10 Effect of increasing Pdi/Pdimax (i.e., the ratio of peak inspiratory Pdi) during resistance breathing over maximum static Pdi (ordinate) at the time of onset of mechanical failure of the diaphragm, Tlim (abscissa). Data from three normal subjects (shown as separate symbols). Note that progressive increases in Pdi/Pdimax are associated with more rapid onset of diaphragm fatigue. Note also the curvilinear nature of the relationship, with apparent asymptote between 40 and 50 percent Pdi/Pdimax , which represents a fatigue threshold. (Based on data from Roussos CS, Macklem PT: Inspiratory muscle fatigue, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 511â&#x20AC;&#x201C;527, with permission.)

Reductions in Ti are out of proportion to reductions in Te , so the duty cycle of breathing (Ti /Tt ) is reduced to less than normal values (below 40 percent). Average inspiratory airflow (Vt / Ti ) tends to be normal, despite abnormalities in mechanics, because of increases in the neuromuscular drive to breathe as reflected in the airway occlusion pressure. Reductions in Ti have the effect of increasing the dead-spaceto-tidal-volume ratio (Vd /Vt ) and predisposing to alveolar hypoventilation.

A rapid, shallow pattern of breathing with an abnormally low Ti /Tt ratio and reduced tidal volume is extremely common in patients with COPD during acute exacerbations and tends to get better with improvements in clinical condition. Rapid, shallow breathing appears to cause CO2 retention rather than result from it. It can be produced in patients with COPD by histamine-induced bronchoconstriction and reversed by topical airway anesthesia. Patients with neuromuscular disease in whom the ability to generate inspiratory pressure is impaired require more intense motor outflow to the respiratory muscles to maintain tidal volume. Patients with respiratory muscle weakness also tend to breathe rapidly and shallowly.

The pattern of breathing has been quantified in adults receiving ventilatory support for acute respiratory failure from the ratio of respiratory rate (breaths per minute) divided by tidal volume (liters). This useful parameter has been termed the rapid shallow breathing index (RSBI). It has proved to be an extremely powerful way of assessing weanability in

adults with a variety of medical and surgical conditions. The greater the value, the more rapid and shallow is the pattern of breathing. Values for the RSBI exceeding 100 are associated with a high probability of failure to wean from mechanical ventilation. The RSBI lends itself to a more general use in patients with disorders of the ventilatory pump not requiring mechanical ventilation.

Rapid, shallow breathing leading to CO2 retention exerts a number of deleterious effects. First, CO2 retention decreases Pao2 and arterial pH. Decreases in Pao2 result in accordance with the alveolar air equation. In general, a 1 mmHg increase in Pco2 causes a 1.25 mmHg reduction in Pao2 (assuming a respiratory quotient of 0.8; larger respiratory quotient values are associated with smaller changes in Pao2 ). Second, renal compensation for hypercapnia-induced respiratory acidosis stimulates bicarbonate resorption. Increases in body fluid bicarbonate restore pH toward normal values but blunt the ventilatory response to further increases in CO2 . Third, hypercapnia depresses diaphragm contractility; that is, Pdi is decreased at a given level of diaphragm electrical activity in proportion to the increase in Pco2 .

However, rapid, shallow breathing may also confer beneficial effects to subjects with severe ventilatory pump dysfunction. First, CO2 retention increases the CO2 partial-pressure gradient between the alveolus and atmosphere. Accordingly, during hypercapnia the same volume of metabolically produced CO2 can be excreted at a lower level

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of alveolar and minute ventilation and O2 cost of breathing than during eucapnia. As such, CO2 retention affords a mechanism to diminish the activity level of the inspiratory muscles and their propensity to fatigue. Normal humans and animal models fatigued by inspiratory resistive loads in the laboratory spontaneously minimize the diaphragm TTI after fatigue by adopting a shallow, rapid pattern of breathing. In fact, a large study of stable outpatients with advanced COPD indicates that the inspiratory muscle TTI is below the fatigue threshold even in markedly hypercapnic (above 60 mmHg) subjects (see below). Second, rapid, shallow breathing minimizes the magnitude of dynamic hyperinflation in patients with severe COPD who breathe on the envelope of the maximum expiratory flow-volume loop; that is, reductions in tidal volume and decreases in the Ti /Tt ratio diminish the volume to be exhaled and prolong the expiratory time available to reach FRC. The balance between the beneficial and deleterious effects of CO2 retention is difficult to define with precision; however, the balance probably is determined by the magnitude and rapidity of the changes in Paco2 and pH and their effect on the cardiovascular and central nervous systems. Relatively small (5 to 15 mmHg) changes in Paco2 , produced gradually over days to weeks and leaving pH at levels of 7.25 to 7.30, are likely to be well tolerated and, on balance, beneficial. On the other hand, Paco2 changes that occur rapidly and reduce pH to less than 7.25 are likely to exert net negative effects. In fact, respiratory acidosis to pH values under 7.25 is life-threatening and generally considered an indication for intubation and mechanical ventilation. Cardiac function and sympathetic regulation of peripheral vascular resistance are impaired at this level of pH. Patients become encephalopathic (i.e., somnolent and unable to care for themselves and control their airway secretions). Obviously, hypercapnia of such magnitude is to be avoided.

Pathogenesis of Rapid, Shallow Breathing The neurophysiological mechanisms driving the altered pattern of breathing are obscure. Moreover, whether changes in breathing pattern in animal models and humans are reflexively induced or behaviorally mediated, or reflect changes in brain neurotransmitter levels (e.g., endorphins), is unclear.

However, chemosensitivity-induced alterations in respiratory activity do not appear to be the explanation. Hypoxia- and hypercapnia-induced reductions in Te are disproportionately greater than reductions in Ti , so the Ti /Tt ratio increases.

Moreover, Vt / Ti and the tidal volume increase rather than decrease.

Reflexes originating from mechanoreceptors in the contracting rib cage muscles and diaphragm (i.e., Golgi tendon organs, spindle organs, and type III and type IV endings) probably play a role in shaping the rapid, shallow pattern of breathing. In deeply anesthetized animals, stretch of the intercostal muscles or an increase in diaphragm tension may abruptly terminate inspiration. Activation of vagal irritant receptors in the airway may also produce rapid, shallow breath-

ing. In animal models, rapid, shallow breathing produced acutely by inhalation of allergen or inflammatory mediators (e.g., histamine, bradykinin) can be prevented by vagal blockade. These observations suggest that rapid, shallow breathing in bronchoconstriction may be mediated by vagal sensory endings in the airways.

Finally, changes in the pattern of breathing may represent a behavioral response to minimize the sense of dyspnea.

The sense of dyspnea is a complex perceptual construct that is not fully understood but is probably multifactorial. In fact, an important determinant of the sense of dyspnea is the magnitude of the CNS motor command to the inspiratory muscles as reflected in the peak inspiratory intrathoracic pressure.

Studies indicate that the sense of breathlessness increases for any set of respiratory mechanical conditions with increases in peak inspiratory pressure, the duration of inspiration, or respiratory rate. In particular, the magnitude of the sense of dyspnea depends on inspiratory pressure (P) swings as a percent of maximum (P/Pmax ), the duration of inspiration relative to the total breath cycle (Ti /Tt ), and the respiratory rate (freq). However, the relative importance of these three terms is quite different. The peak inspiratory pressure has a far greater effect than the duration of inspiration, which in turn has a greater effect than breathing frequency. The sensation of dyspnea can be expressed quantitatively by each of these parameters raised to a power: Dyspnea = P1.3 × Ti /Tt 1.14 × freq–0.97 Increases in intrathoracic pressure required to maintain airflow and tidal volume in patients with abnormalities in ventilatory pump function increase the sense of dyspnea. Given the greater exponential value for P than for the timing variables, it can be seen that the magnitude of the swing in inspiratory pressure is the predominant determinant of dyspnea.

Thus, at a given level of minute ventilation and set of respiratory mechanics, the pattern of breathing determines the intensity of breathlessness. When the mechanics of breathing are deranged by COPD or kyphoscoliosis, diminishing peak inspiratory intrathoracic pressure (i.e., tidal volume) and increasing respiratory rate (i.e., a rapid, shallow pattern of breathing) tend to minimize the sense of breathlessness.

At equivalent levels of airway resistance and inspiratory effort, the sense of dyspnea is greater during bronchoconstriction than during external resistive loading, probably because of the activation of vagal irritant receptors. Differences in the intensity of dyspnea at any given level of airway obstruction, therefore, may depend on the site of airway obstruction (i.e., intra- vs. extrathoracic). Also, the sense of dyspnea at a given level of peak intrathoracic pressure, Ti /Tt ratio, and frequency of breathing are increased in the setting of inspiratory muscle fatigue, probably because a greater motor command is required to generate a given level of intrathoracic pressure. Finally, it should be apparent from the above equation that the sense of dyspnea depends on the same variables that determine respiratory muscle fatigability. However, respiratory muscle fatigue, in contrast to dyspnea, does not

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Figure 148-11 Severity of dyspnea experienced during breathing against external resistive ventilatory loads in normal subjects, patients with asthma but no near-fatal attacks, and patients with near-fatal asthma. Y axis indicates the intensity of dyspnea (i.e., Borg score). Increasing numerical values on the Borg score indicate increasing dyspnea. Note that at any given level of external resistance, dyspnea was significantly less in patients with near-fatal asthma than in the normal group. (Based on data from Kikuchi Y, Okabe S, Tamura G, et al: Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N Engl J Med 330:1229–1234, 1994, with permission.)

appear to depend on the pattern in which TTI is developed; that is, whether a given TTI is arrived at by a higher P/Pmax or a higher Ti /Tt is irrelevant in the development of fatigue, but it is important in the generation of respiratory sensations.

Perceptual acuity of the respiratory sensations elicited when the mechanical properties of the ventilatory pump are deranged is a major determinant of the pattern of breathing and tendency to develop CO2 retention in subjects with COPD. For example, when airway resistance is increased experimentally, patients with COPD who retain CO2 are those with the greatest perceptual acuity for changes in intrathoracic pressure. That is, spontaneous tidal volume and Ti are smallest in patients with COPD who have the highest perceptual acuity for changes in intrathoracic pressure.

On the other hand, when airway resistance was increased experimentally by external resistive loads, asthmatics with near-fatal attacks experienced less dyspnea at any level of resistance than normal subjects (Fig. 148-11). Accordingly, in patients with COPD the acuity of respiratory perception plays an important role in the pathogenesis of respiratory failure.

The mechanism by which respiratory perception contributes to respiratory failure awaits clarification.

Undernutrition Undernutrition, defined as a body weight less than 90 percent of the ideal, is extremely common in patients with COPD, occurring in about 25 percent of stable outpatients and about 40 percent of hospitalized patients. Undernutrition is an independent risk factor for mortality. For a given level of lung function, undernourished patients with COPD have a greater

5-year mortality than normally nourished subjects. The respiratory muscles, like skeletal muscles in other parts of the body, atrophy under conditions of chronic protein-calorie deficiency. In patients without lung disease, Pimax is significantly smaller in those who are undernourished than in those who are well-nourished. In those with COPD at autopsy, the mass (i.e., weight and thickness) of the diaphragm is diminished in undernourished compared to well-nourished subjects. Both slow and fast fibers in respiratory muscles (e.g., the diaphragm and intercostals) atrophy in subjects with advanced COPD. In patients with COPD, resting Paco2 is inversely related to Pimax .

The weaker the subject, the greater the Paco2 . Reductions in Pimax predispose to inspiratory muscle fatigue by increasing the Pdi/Pdimax ratio and, hence, the TTI during breathing against a given set of lung mechanics. Of practical importance, aggressive nutritional repletion, which increases body weight, augments Pimax and Pdimax . Thus, respiratory muscle wasting and atrophy are reversible in undernourished patients with COPD. The pathogenesis of body wasting in subjects with chronic diseases like COPD is unclear. However, increases in the work of breathing and respiratory muscle activity increase resting energy expenditure by as much as 50 to 100 percent above normal. In normal subjects in whom basal energy requirements are similarly increased by heavy physical labor (e.g., lumberjacks), caloric intake is increased appropriately to meet metabolic demands and body weight is preserved.

Accordingly, the root of the problem in undernourished patients with COPD may be “relative anorexia,” so that increases in basal caloric requirements are not accompanied by adequate caloric intake. Undernourished patients with COPD have higher blood levels of the cachexia factor tumor necrosis factor-α than well-nourished COPD subjects.

SPECIFIC DISEASES Chronic Obstructive Pulmonary Disease Patients with advanced COPD develop CO2 retention because of abnormalities in the gas exchange and mechanical properties of the lung. The relationship between the severity of COPD as reflected by the forced expiratory volume in 1 s (FEV1 ) and steady-state resting Pco2 is curvilinear (Fig. 148-12). In general, Paco2 does not increase above normal until the FEV1 decreases to about 20 to 25 percent of predicted normal values.

The effects of COPD on lung gas exchange are complex.

Simply put, increases in lung dead space and abnormalities in ventilation/perfusion relationships impair CO2 elimination and O2 uptake. Increases in physiological dead space require greater than normal levels of ventilation and tidal volume to maintain eucapnia. Maintenance of “normal tidal volume” in the setting of increased dead space predisposes to CO2 retention because of an unfavorable Vd /Vt . Normally, during resting breathing, ventilation is 4 to 5 L/min, of which alveolar ventilation is approximately 70 to 80 percent.

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Figure 148-12 Relationship between the severity of airway obstruction reflected in the FEV1 and steady-state arterial PCO 2 in COPD and asthma. Shaded area represents normal range of arterial PCO 2 . The relationship is curvilinear, so CO2 retention occurs only after FEV1 is considerably reduced. The asthmatic curve (dashed line) lies below and to the left of the curve for COPD, indicating that much greater levels of obstruction are necessary before arterial PCO 2 rises. (From Fishman AP: Pulmonary Diseases and Disorders. New York, McGraw-Hill, 1980, vol 1, p 426, with permission.)

In COPD, abnormalities in lung gas exchange for O2 and CO2 (i.e., increased dead-space volume and alveolar-arterial O2 gradient) require greater than normal levels of ventilation to maintain eucapnia and euoxia. Consequently, in subjects with advanced COPD, minute ventilation is typically two to three times the normal value (i.e., 10 to 15 L/min). Minute ventilation is increased still further in hypoxemia. Increases in ventilation require increases in airflow, tidal volume, and the duty cycle of breathing.

Hyperinflation and heightened airway resistance are common in patients with advanced COPD. Hyperinflation and increases in FRC in patients with COPD are multifactorial. First, emphysema decreases lung (and possibly chest wall) elastic recoil pressure. Second, tonic activation of chest wall inspiratory muscles throughout the respiratory cycle enhances transpulmonary pressure. Third, activation of laryngeal constrictor muscles and pursed-lip breathing during expiration slow the rate of expiratory airflow. Fourth, severely obstructed patients breathing on the envelope of the maximum expiratory flow-volume curve may have insufficient time during expiration to exhale to passively determined FRC. In advanced COPD, increases in airway resistance and hyperinflation require greater than normal swings in intrathoracic pressure to generate normal levels of airflow and tidal volume. In consequence, the respiratory neuromuscular drive to breathe, peak inspiratory intrathoracic pressure, and the TTI of the inspiratory muscles are increased considerably. Normally, at rest, respiratory muscle O2 consumption is less than 2 percent of total body O2 consumption (i.e., about 5 ml/min or less). In contrast, patients with advanced cardiopulmonary disease may have levels of respiratory muscle O2 uptake greater than 50 percent of total body O2 uptake (i.e., in excess of 125 ml/min).

Figure 148-13 Inspiratory muscle strength as reflected in the maximum static inspiratory pressure (PImax ) at functional residual capacity (FRC) in subjects with advanced COPD and agematched normal subjects. Each symbol represents a single subject. Note that in COPD subjects, because of hyperinflation and muscle wasting, PImax is reduced to approximately 40 percent of the value in normal subjects. Note the tendency for hypercapnic subjects to have even lower values of PImax than eucapnic COPD subjects. (Based on data from Sharp JT, van Lith P, Nuchprayoon C, et al: The thorax in chronic obstructive lung disease. Am J Med 44:39â&#x20AC;&#x201C; 46, 1968, with permission.)

In subjects with severe COPD, hyperinflation reduces inspiratory muscle mechanical advantage, which decreases the capacity of the inspiratory muscles to generate pressure (Pmax ). Pmax values in patients with COPD may be as low as one-third to one-half that of age-matched normal subjects (Fig. 148-13). Moreover, aging- and malnutrition-associated changes in the diaphragm may further impair Pdimax in subjects with COPD. COPD typically becomes disabling in the sixth and seventh decades of life, a period of life at which Pdi normally falls. For example, Pdimax is about 25 percent less in healthy men over 65 years of age than in healthy men under 35 years of age.

Respiratory Muscle Fatigue in COPD Severe COPD is arguably the clinical condition most likely to cause inspiratory muscle fatigue. The combined effects of increases in inspiratory muscle activity and decreases in

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Pump Failure: The Pathogenesis of Hypercapnic Respiratory Failure in Patients with Lung and Chest Wall Disease

Figure 148-14 Diaphragmatic tension-time index (TTdi) in 20 stable outpatients with COPD breathing room air at rest. Each symbol represents a separate COPD subject. Shaded area represents the fatigue threshold in normal subjects. Most COPD subjects breathe well below the fatigue threshold and cluster around 0.05 TTdi. (Based on data from Bellemare F, BiglandRitchie B: Central components of diaphragmatic fatigue assessed by phrenic nerve stimulation. J Appl Physiol 62:1307â&#x20AC;&#x201C;1316, 1987, with permission.)

muscle strength in severe COPD increase the diaphragm TTI during resting breathing in elderly COPD patients considerably above the normal value of 1 to 2 percent. The TTI may, in fact, approach the fatigue threshold (i.e., 15 to 20 percent) in patients with COPD (Fig. 148-14). These and similar data indicate that diaphragm activity is increased in patients with advanced COPD, and that the diaphragm is highly susceptible to fatigue when breathing is increased above spontaneous levels by minor increases in tidal volume or Ti /Tt .

The diaphragm TTI is higher in hypercapnic than in eucapnic COPD subjects, but even in hypercapnic subjects it does not exceed the fatigue threshold. Mean TTI, even for hypercapnic subjects, is approximately 10 percent. Therefore, hypercapnia per se does not indicate the presence of diaphragm fatigue even in patients with severe COPD. Rather, hypercapnia may be a manifestation of a breathing strategy (i.e., rapid, shallow breathing) that minimizes inspiratory muscle activity and, hence, prevents fatigue.

On the other hand, inspiratory muscle fatigue may be a relatively common occurrence during the hyperpnea of exercise and could contribute to exercise limitation in COPD subjects. A high percentage (about 50 percent) of subjects with moderate to severe COPD demonstrate EMG evidence of scalene or diaphragm (or both) fatigue during exercise. Of interest, improvement in exercise performance and elimination of the EMG signs of fatigue can be achieved following inspiratory resistance training.

Subjects with COPD in acute respiratory failure requiring mechanical ventilation are more likely to show evidence of inspiratory muscle fatigue. During weaning from mechanical ventilation, diaphragm EMG changes indicative of fatigue precede the increases in Paco2 . These findings suggest that diaphragm fatigue contributes to ventilator dependence after the onset of hypercapnic respiratory failure in at least some critically ill subjects.

In COPD patients being weaned from mechanical ventilation during a bout of acute respiratory failure, the tracheal occlusion pressure is usually greater than 6 cm H2 O and EMG evidence of diaphragm fatigue is present during spontaneous breathing. Patients with persistently elevated tracheal occlusion pressure values (above 6 cm H2 O) and EMG evidence of diaphragm fatigue generally cannot be successfully weaned from mechanical ventilation. In contrast, sternomastoid muscle fatigue is evident in fewer than 10 percent of COPD patients hospitalized for worsening respiratory distress.

In summary, most subjects with stable COPD adopt a pattern of breathing that minimizes the diaphragm TTI and prevents inspiratory muscle fatigue. Behavioral mechanisms may be operative in an attempt to minimize the sensation of dyspnea. On the other hand, inspiratory muscle fatigue contributes to the morbidity of a subgroup of patients with COPD by preventing weaning from mechanical ventilation, and possibly by impairing exercise performance. The reported number of COPD subjects with respiratory muscle fatigue is small, however, and may represent a highly select population. Further studies are needed to define the extent of this problem.

Asthma The pathophysiology of CO2 retention appears to be generally similar in patients with asthma and COPD, but the likelihood of developing CO2 retention is less in asthma than in COPD. That is, the level of expiratory airway obstruction required to produce CO2 retention in subjects with acute asthma is greater than that required in subjects with COPD (Fig. 148-14). Several possibilities may explain this tendency.

First, it appears that inspiratory drive is higher in patients with asthma than in those with COPD. The airway occlusion pressure is considerably higher at any given level of Paco2 in patients with asthma than in normal subjects or patients with COPD. The heightened inspiratory drive in patients with asthma may in part arise from irritant receptors within the airway, which have an augmenting effect on inspiratory motor neuron activity. Furthermore, the inspiratory muscles are stronger, and ventilatory responses to CO2 and hypoxia are greater, in the younger asthmatic than in COPD subjects.

These differences are not simply due to age, as the endurance of the inspiratory and expiratory muscles is greater in asthmatic than in age-matched normal subjects. The increased respiratory muscle endurance in subjects with asthma may be a response to chronic increases in inspiratory muscle load.

Finally, greater lung elastic recoil in asthma than in COPD tends to preserve maximal expiratory airflow.

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Neuromuscular Disease Subjects with neuromuscular disease and weak inspiratory muscles tend to breathe rapidly and shallowly. Despite this breathing pattern, these subjects tend to have hypocapnia at rest, and hyperventilate at any given level of CO2 during progressive hypercapnia. Increases in ventilation are associated with increases in airway occlusion pressure. Heightened occlusion pressure in the setting of weak inspiratory muscles suggests that the drive to the inspiratory muscles early in inspiration is greater than normal.

The pathogenesis of hypercapnic respiratory failure is very different in patients with neuromuscular disease than in patients with COPD. Patients with neuromuscular disease demonstrate an impaired ability to sigh (i.e., a greater than twofold increase in the tidal volume) because of inspiratory muscle weakness. Inability to sigh decreases lung compliance by interfering with the redistribution of surfactant within the alveolar space. Progressive stiffening of the lung leads to microatelectasis and ultimately lobar atelectasis. Breathing high concentrations of O2 accelerates this process. In addition, expiratory muscle weakness impairs the cough mechanism and causes retention of secretions.

The best indicators of a tendency to develop CO2 retention in patients with neuromuscular disease are reductions in inspiratory muscle strength (Pimax ) and forced vital capacity (FVC). Reductions in Pimax and FVC to less than 30 and 25 percent of predicted, respectively, are associated with CO2 retention. Suffice it to say, hypercapnia is a late manifestation of neuromuscular disease and requires marked impairment in inspiratory and expiratory muscle function. With diaphragm dysfunction, hypercapnia may occur during sleep (especially REM sleep) even when the subject is eucapnic while awake.

Obesity Obesity imposes a stress on the respiratory system both by altering lung mechanics and the work of breathing (see Chapter 92). The mass loads applied to the thorax and abdomen by excess fatty tissue decrease chest wall compliance and endexpiratory lung volume resulting in increases in the elastic and resistive work of breathing. Furthermore, by diminishing airway caliber, obesity predisposes to premature airway closure and even atelectasis. The resultant low ventilation-perfusion ratios of these lung regions increase alveolar-arterial O2 gradient and cause arterial hypoxemia. In fact, hypoxemia is the most common respiratory abnormality in the morbidly obese.

In addition, the excessive body mass results in increased CO2 production and O2 consumption. Increases in metabolism may be two to three times normal in morbidly obese subjects. These metabolic changes require significant increases in minute and alveolar ventilation in order to maintain eucapnia and hence, increasing ventilatory demands. For example, a doubling in CO2 production requires a doubling in alveolar ventilation to maintain eucapnia. Finally, arterial hypoxemia, which is common, induces a further increase in ventilation.

Given these stresses, the maintenance of normal blood gas tensions requires a considerable increase in respiratory motor output and the work of breathing. Increased work of breathing appears to explain the common occurrence of dyspnea in the morbidly obese person.

Not all morbidly obese subjects develop hypercapnic respiratory failure, however. Although body weight alone does not predict the development of hypercapnia, approximately 30 percent of severely obese subjects with a body mass index (BMI) of more than 35 kg/m2 and almost 50 percent with a BMI of 50 kg/m2 or greater have unexplained daytime hypercapnia. Observations of eucapnic and hypercapnic obese subjects demonstrate that eucapnic subjects have greater increases in diaphragm electrical activity with increases in CO2 than hypercapnic subjects. Obese subjects with hypercapnic respiratory failure may have impaired chemosensitivity to hypercapnia and hypoxemia.

A subset of obese subjects with hypercapnia also have daytime hypersomnolence, polycythemia, pulmonary hypertension, and cor pulmonale. This constellation of signs and symptoms has been termed the obesity hypoventilation syndrome (see Chapter 92.) Of interest, leptin may be involved in the pathogenesis of hypercapnic respiratory failure in obese individuals. Leptin stimulates ventilation and a deficiency of leptin has been associated with hypoventilation. Clearly excessive body weight is the primary pathogenetic factor, since weight reduction into the normal range, however difficult this may be to accomplish, corrects the problem.

Kyphoscoliosis Kyphoscoliosis decreases chest wall and lung compliance, presumably as a result of atelectasis and deformation of the lungs (see Chapter 92). The elastic work of breathing is markedly increased. In addition, the mechanical action of the respiratory muscles may be impaired by changes in configuration of the bony structures on which the respiratory muscles insert.

Ventilation-perfusion mismatch and increase in the alveolararterial O2 gradient are common. As expected in patients with diminished respiratory compliance, subjects with kyphoscoliosis breathe rapidly and shallowly. The tendency to develop CO2 retention is a function of the severity of the restrictive process in kyphoscoliosis, as reflected in the Cobb angles, and is predicted separately for the magnitude of scoliosis and kyphosis.

Hypercapnic respiratory failure tends to develop late in life, even if the severity of the spinal deformity has not changed since childhood; that is, stability of the Cobb angles of kyphosis and scoliosis does not preclude development of hypercapnic respiratory failure. It is not clear why respiratory failure ensues late in life. However, several possibilities exist. Aging adversely affects compliance of the chest wall, leading to an increase in the elastic work of breathing. In addition, aging diminishes respiratory muscle strength. Finally, chemosensitivity to O2 and CO2 declines with advancing age, and it seems likely that the subjectâ&#x20AC;&#x2122;s ability to compensate

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for derangements in blood gas tensions is progressively impaired.

ASSESSMENT OF PATIENTS WITH ABNORMALITIES OF THE VENTILATORY PUMP Symptoms Dyspnea appears to be an early manifestation of respiratory muscle impairment in neuromuscular disease and typically occurs before the development of CO2 retention. Breathlessness in the supine position is characteristic of isolated diaphragm dysfunction. In the supine position, the increased hydrostatic pressure imposed by the abdominal viscera represents an increased inertial load on the diaphragm.

Physical Findings Physical signs of ventilatory pump dysfunction revolve around evidence of accessory respiratory muscle recruitment, abnormal thoracoabdominal movement, and rapid, shallow breathing.

Use of Accessory Muscles Inspection and palpation demonstrate accessory respiratory muscle use. Intense respiratory efforts are associated with visible activation of the neck accessory muscles, interosseous intercostals, and abdominal expiratory muscles and flaring of the alae nasae.

Abnormal Thoracoabdominal Movement Normally, in the supine position, the anterior abdominal wall displays a prominent outward movement during inspiration.

With impaired diaphragm function, as occurs in diaphragm weakness or fatigue, the abdominal wall may move inward on inspiration. This is called abdominal paradox. Abdominal paradox reflects cephalad movement of the contracting diaphragm in response to the negative intrathoracic pressure generated by the inspiratory action of the neck and intercostal muscles. Abdominal paradox may also be present in patients with marked derangements in lung mechanics, in whom inspiratory intrathoracic pressure swings exceed 30 percent of maximum. Abdominal paradox, therefore, is not specific for diaphragm weakness or fatigue.

Abdominal paradox, resulting from ineffectual contractions of the diaphragm, should be distinguished from pseudo-abdominal paradox, resulting from strong contractions of the expiratory muscles during expiration, with rapid relaxation during early inspiration. For example, intense contraction of the transverse abdominis muscles causes inward movement of the lateral abdominal wall and outward movement of the anterior abdominal wall during expiration. Subsequent relaxation of the abdominal muscles with the onset of inspiration causes outward movement of the lateral

abdominal wall and inward movement of the anterior abdominal wall. Tenseness of the lateral abdominal wall during expiration easily distinguishes pseudo- from true abdominal paradox.

Maximum Static Inspiratory Pressure Perhaps the most practical method of assessing the function of the inspiratory muscles contracting in aggregate is from the pressure generated during maximal volitional contractions against an occluded airway at FRC. This parameter is discussed in greater detail in Chapter 93. In brief, however, reductions in Pimax indicate inspiratory muscle weakness or high-frequency fatigue. Improvements in Pimax occurring over several hours to several days in a patient with COPD suggest that lung volume is improving toward normal and that the mechanical disadvantage imposed on the inspiratory muscles is disappearing. More rapid improvements (occurring over hours) may indicate resolution of high-frequency fatigue or elimination of the metabolic disturbances (e.g., hypercapnia or hypophosphatemia) that depress inspiratory muscle function. Of note, Pimax is not affected by low-frequency fatigue.

Pimax depends on patient cooperation and motivation.

With training, however, patients can provide reproducible values. Performance of the maneuver at FRC, where respiratory system recoil is zero, is preferred; that is, at FRC, changes in airway pressure during inspiratory efforts equal the pressure generated by the inspiratory muscles (Pmus ).

Maximum static expiratory pressure at FRC (Pemax ) has been used in the laboratory setting to assess the endurance properties of the expiratory muscles. The Pemax has not been used extensively in the clinical setting, however, because of the perception that it is more difficult to obtain consistent values than Pimax with breathless subjects.

TREATMENT Abnormalities in respiratory mechanics and gas exchange are the most important pathogenetic factors in the development of respiratory failure. Accordingly, therapy should be directed toward achieving maximum improvement in airway, lung, and respiratory muscle function. For example, in patients with COPD or asthma, an intensive regimen of bronchodilators (e.g., β2 -adrenergic agonists, anticholinergics, and theophylline) and anti-inflammatory therapy (e.g., corticosteroids) can correct respiratory failure by diminishing airway resistance, FRC, lung dead-space volume, the alveolar-arterial O2 partial-pressure gradient, and the work of breathing. Improvements in lung function in certain patients with advanced COPD and emphysema may also be accomplished by lung-volume reduction surgery (volumereduction pneumectomy) or lung transplantation. Lungvolume reduction surgery removes 20 to 30 percent of the most emphysematous regions of lung and appears to improve

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FRC, FEV1 , ventilatory capacity, inspiratory muscle function, and elastic recoil pressure of the lung. In patients with myasthenia gravis, cholinesterase inhibitors can improve inspiratory muscle strength and vital capacity and reverse atelectasis, which causes hypercapnia. Additionally, noninvasive positive-pressure ventilation (NIPPV) has become one of the most important modalities for treating hypercapnic respiratory failure (see below).

Abnormalities in Chemosensitivity Respiratory failure caused by impaired chemosensitivity is difficult to treat, since drug treatments to improve chemosensitivity to hypoxia or hypercapnia are not very effective. Since it was observed that women exhibit alveolar hypoventilation during pregnancy and the luteal phase of the menstrual cycle, progestational agents have been used for many years to treat idiopathic hypoventilation syndromes. In some subjects, medroxyprogesterone acetate, given orally in a dose of 20 mg three times a day, acts centrally to augment the ventilatory responses to hypercapnia and hypoxemia and can improve resting arterial blood gas tensions. Medroxyprogesterone is generally well tolerated in women but may produce feminizing side effects in men. The onset of action of the drug is slow. Several weeks may be required before a response is observed. Theophylline, in doses that produce blood levels in the therapeutic range (10 to 15 Âľg/ml), also has weak respiratory stimulatory effects, which may contribute to a reduction in Paco2 in patients with COPD. Theophylline also produces modest improvements (about 10 to 20 percent) in diaphragm contractile function in this population. Finally, in some patients with hypercapnia, elimination of medications having CNS respiratory depressant effects (e.g., opiate analgesics, benzodiazepine anxiolytics) can lead to improvements in Paco2 .

Hypoxemia leading to pulmonary artery hypertension and cor pulmonale may be the most serious complication of chronic hypercapnic respiratory failure. Supplemental O2 is usually indicated in patients with chronic hypercapnic respiratory failure. Supplemental O2 may produce exaggerated increases in Paco2 in patients with disorders of ventilatory control in whom the ventilatory response to CO2 is blunted but the O2 response is preserved. Accordingly, blood gas tensions should be monitored closely when O2 is applied initially. During sleep, patients with disorders of the control of breathing typically display exaggerated increases in Paco2 (e.g., 15 to greater than 30 mmHg) with hypoxemia and severe respiratory acidosis. In these subjects, mechanically assisted ventilation (typically with nasal positive-pressure ventilation), with or without O2 , may be required during the sleeping period. Nasal positive-pressure ventilation is an effective way of improving blood gas tensions during sleep. In fact, improvements in blood gas tensions achieved by nocturnal mechanical ventilation may carry over to the waking period in these patients, perhaps by preventing nocturnal increases in serum bicarbonate or hypoxic depression of CNS function.

Table 148-2 Principles of Therapy for Respiratory Muscle Fatigue Decrease inspiratory swings in transdiaphragmatic pressure (Pdi) Improve the mechanics of breathing (i.e., decrease airway resistance, improve thoracic compliance and static lung volume) Decrease ventilatory drive (i.e., relieve hypoxemia, hypercapnia, metabolic acidosis, fever, pulmonary congestion/inflammation, acute respiratory distress syndrome Increase Pdimax Correct hyperinflation Correct muscle atrophy induced by protein-calorie deficiency Correct electrolyte and blood gas abnormalities (i.e., hypoxemia, hypercapnia, hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia) Optimize muscle blood flow and substrate availability Correct low cardiac output state (e.g., cardiogenic shock, hypovolemic shock).

Correct hypoxemia, anemia, hypoglycemia

Respiratory Muscle Weakness or Fatigue The treatment of respiratory muscle weakness depends on pathogenic mechanisms. For example, inspiratory muscle weakness related to the hyperinflation of COPD is best treated by aggressive improvement of airway function. On the other hand, decreases in muscle strength caused by electrolyte abnormalities (e.g., hypophosphatemia) or proteincalorie malnutrition are best dealt with by repletion of the deficits.

The treatment of respiratory muscle fatigue has not been systematically studied. However, several approaches based on theoretical considerations appear to be applicable (Table 148-2). It is clear that diaphragm fatigue is a result of muscle overactivity (i.e., a TTI greater than 20 percent). Accordingly, attempts should be made to decrease the TTI of the inspiratory muscles to values below the fatigue threshold by improving lung mechanics or reducing ventilatory drive. In patients with abnormalities in airway resistance and hyperinflation secondary to severe COPD, this can best be accomplished with bronchodilators and corticosteroids. Reductions in ventilatory drive in hypoxic or febrile patients can be accomplished by administration of O2 or antipyretics.

Unloading the inspiratory muscles by reducing the TTI may be sufficient to prevent or reverse fatigue and allow the muscle to recover. In some cases, however, respiratory muscle fatigue may be sufficiently advanced so that the muscle must

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be placed at complete rest. Mechanical ventilation and ventilatory muscle rest are certainly indicated when the pH is less than 7.25 or the patient appears unable to maintain ventilation and stable blood gas tensions. The precise duration of mechanical ventilation to rest the inspiratory muscles in patients with respiratory muscle fatigue is unclear. However, no attempts at weaning should be made until the conditions that initiated fatigue are reversed. Since low-frequency fatigue persists for 24 h or more, it may not be advisable to wean patients with respiratory muscle fatigue from mechanical ventilation for at least 24 h, even if the factors that caused fatigue have been corrected.

Chronic Ventilatory Support/Nasal Positive-Pressure Ventilation Mechanically assisted ventilation, especially at night, may be helpful in reducing arterial Pco2 and increasing Po2 in the chronically hypercapnic subject. Nasal positive-pressure ventilation (NPPV) affords an effective, practical approach to treat selected subjects with chronic hypercapnia secondary to either impaired chemosensitivity or abnormalities in respiratory mechanics. In particular, selected subjects with the obesity hypoventilation syndrome, kyphoscoliosis, or neuromuscular disease have been successfully maintained on NPPV for prolonged periods.

NPPV is particularly effective in hypercapnic respiratory failure. NPPV obviates the need for airway intubation, provides considerable patient comfort, and is easy to use.

Many different types of masks exist. The most commonly used are oral or oronasal masks with a soft rubber seal. An oronasal mask may be more comfortable for mouth breathing patients. By setting the magnitude of the inspiratory positive airway (IPAP) and expiratory pressures (EPAP), tidal volume is determined. Small, portable, simple-to-operate bilevel ventilators (BiPAP) that deliver phasic pressure changes are available. Many bilevel machines allow manipulation of the pressure rise time during inhalation so that exhalation time and patient comfort can be maximized. No ideal pressure settings effective for all patients exist. Settings should be adjusted to maximize patient comfort and ventilation. The effectiveness of a given setting can be assessed by observing the degree of chest expansion and measuring the Paco2 . Disadvantages of NPPV include aerophagia and air leaks secondary to poorly fitting masks.

The use of NPPV during acute hypercapnic respiratory failure secondary to COPD has been demonstrated repeatedly to reduce mortality, reduce the need for airway intubation, and rapidly improve respiratory rate, Paco2 , and pH. Recently NPPV has been successfully used over a prolonged period for the treatment of the obesity hypoventilation syndrome.

In morbidly obese patients (mean BMI 44 kg/m2 ), NPPV decreased the Paco2 by an average of 17 mmHg and increased the Pao2 by 24 mmHg after an average of 50 months.

NPPV is also used in neuromuscular disease, particularly for nocturnal hypoventilation or progressive hypercapnic respiratory failure (see Chapters 93 and 94). NPPV

prolongs and improves the quality of life in amyotrophic lateral sclerosis. Its use in this disorder is discussed in detail in Chapter 94. Unfortunately, the majority of the neuromuscular disorders are progressive and many patients develop bulbar symptoms and thus have difficulty controlling their secretions.

SUGGESTED READING Altose MD, McCauley WC, Kelsen SG, et al: Effects of hypercapnia and inspiratory flow-resistive loading on respiratory activity in chronic airways obstruction. J Clin Invest 59:500–507, 1977.

Bark H, Supinski G, Kelsen SG: Relationship of changes in diaphragmatic muscle blood flow to muscle contractile activity. J Appl Physiol 62:291–299, 1987.

Bellemare F, Grassino A: Evaluation of human diaphragm fatigue. J Appl Physiol 53:1196–1206, 1982.

Cherniack NS, Altose, MD: Respiratory responses to ventilatory loading, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 905–987.

Coleridge HM, Coleridge JCG: Reflexes evoked from tracheobronchial tree and lungs, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 1. Bethesda, MD, American Physiological Society, 1986, pp 395– 429.

Cunningham DJC, Robbins PA, Wolff CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 2.

Bethesda, MD, American Physiological Society, 1986, pp 475–528.

De Troyer A, Loring SH: Action of the respiratory muscles, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 443–461.

Grassino AE, Goldman MD: Respiratory muscle coordination, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 463–509.

Hussain SNA, Roussos C, Magder S: Effects of tension, duty cycle, and arterial pressure on diaphragmatic blood flow in dogs. J Appl Physiol 66:968–976, 1989.

Irsigler GB: Carbon dioxide response lines in young adults: The limits of the normal response. Am Rev Respir Dis 114:529–536, 1976.

Kelsen SG, Cherniack NS, Jammes Y: Control of motor activity to the respiratory muscles, in Roussos C, Macklem PT (eds), The Thorax, Part A: Physiology. New York, Dekker, 1985, pp 493–529.

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Kikuchi Y, Okabe S, Tamura G, et al: Chemosensitivity and perception of dyspnea in patients with a history of nearfatal asthma. N Engl J Med 330:1229–1234, 1994.

Killian KJ, Summers E, Basalygo M, et al: Effect of frequency on perceived magnitude of added loads to breathing. J Appl Physiol 58:1616–1621, 1985.

Manning HL, Schwartzstein RM: Pathophysiology of dyspnea. N Engl J Med 333:1547–1553, 1995.

Mehta S, Hill N: Noninvsive ventilation. Am J Resp Crit Care Med 163:540–577, 2001.

Milic-Emili J, Whitelaw WA, Grassino AE: Measurement and testing of respiratory drive, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 675–743.

Moxham J, Edwards RHT, Aubier M, et al: Changes in EMG power spectrum (high-to-low ratio) with force fatigue in humans. J Appl Physiol 53:1094–1099, 1982.

Oliven A, Supinski GS, Kelsen SG: Functional adaptation of diaphragm to chronic hyperinflation in emphysematous hamsters. J Appl Physiol 60:225–231, 1986.

Olsen AL, Zwillich C: The obesity hypoventilation syndrome.

Am J Med 118:948–956, 2005.

Perrin C, Unterborn JN, D’Ambrosio C, et al: Pulmonary complications of chronic neuromuscular diseases and their management. Muscle Nerve 29:5–27, 2004.

Rebuck AS, Slutsky AS: Measurement of ventilatory response to hypercapnia and hypoxia, in Hornbein TF (ed), Lung Biology in Health and Disease, vol 17: Regulation of Breathing, part II. New York, Dekker, 1981, pp 745– 904.

Roussos CS, Macklem PT: Inspiratory muscle fatigue, in Macklem PT, Mead J (eds), Handbook of Physiology, section 3: The Respiratory System, vol III: Mechanics of Breathing, part 2. Bethesda, MD, American Physiological Society, 1986, pp 511–527.

Shannon R: Reflexes from respiratory muscle and costovertebral joints, in Cherniack NS, Widdicombe JG (eds), Handbook of Physiology, section 3: The Respiratory System, vol II: Control of Breathing, part 1. Bethesda, MD, American Physiological Society, 1986, pp 431–447.

Tolep K, Higgins N, Muza S, et al: Comparison of diaphragm strength between healthy adult elderly and young men. Am J Respir Crit Care Med 152:677–682, 1995.

SECTION TWENTY-FOUR

Management and Therapeutic Interventions

149 CHAPTER

Oxygen Therapy and Pulmonary Oxygen Toxicity Michael F. Beers

I. TISSUE OXYGENATION Oxygen Delivery and Utilization Mechanisms of Hypoxia II. RECOGNITION AND ASSESSMENT OF TISSUE HYPOXIA Clinical Manifestations Laboratory and Other Objective Assessments III. INDICATIONS FOR OXYGEN THERAPY Sh ort-Term Oxygen Therapy Long-Term Oxygen Therapy IV. TECHNIQUES OF OXYGEN ADMINISTRATION Oxygen Delivery Systems in the Acute Setting Long-Term Oxygen Delivery Systems

Mechanisms of Pulmonary Cellular Toxicity Cellular Antioxidant Defenses VI. PATHOPHYSIOLOGY OF OXYGEN TOXICITY Primary Morphologic and Cellular Changes Secondary Changes VII. CLINICAL SYNDROMES OF OXYGEN TOXICITY Acute Toxicity: Tracheobronchitis and Acute Respiratory Distress Syndrome (ARDS) Chronic Pulmonary Syndromes Potentiation of Oxygen Toxicity Prevention and Therapy VIII. SUMMARY

V. PULMONARY OXYGEN TOXICITY Molecular and Cellular Mechanisms of Oxygen Toxicity

Following Joseph Priestley’s discovery of molecular oxygen and Lavoisier’s subsequent demonstration of respiratory gas exchange, use of inhaled oxygen in treatment of a variety of clinical disorders accelerated rapidly during the late eighteenth century. However, a backlash of criticism developed as studies demonstrated that, under ambient conditions, the

oxygen-carrying capacity of arterial blood was nearly maximal, and that further increases in the fraction of inspired O2 produced no appreciable additional physiological benefit. Furthermore, in 1899, Lorrain-Smith confirmed the early suspicions of Priestley, Lavoisier, and others regarding the potential toxicity of inhaled oxygen, describing the pulmonary

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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pathological alterations associated with excessive oxygen exposure. As a result of these observations, by the start of the twentieth century, use of oxygen as a therapeutic modality fell into disrepute.

However, in the early 1920s supplemental oxygen breathing was rigorously reevaluated. Through pioneering efforts by Meakins, Baruch, and others, the concept of a therapeutic window for oxygen inhalation was established. Many investigators independently demonstrated that a reduction in oxygen availability had serious physiological consequences, and that in pathological states, the detrimental consequences of hypoxia could often be circumvented by administration of oxygen. Thus, use of inhaled oxygen again became mainstream therapy, but as adjuvant treatment for cardiac and pulmonary diseases specifically accompanied by hypoxemia and hypoxia.

Over the past 80 years, with the advent of improved oxygen delivery systems, mechanical ventilation, the modern intensive care unit, and long-term home oxygen administration, oxygen has become widely available and frequently prescribed. Nevertheless, despite a large clinical experience, many persistent uncertainties inhibit rational use of supplemental oxygen. As with any drug, indications for, and contraindications to, its use exist. Consensus conferences and numerous studies have resulted in establishment of guidelines defining clinical criteria for proper use of supplemental oxygen.

Unfortunately, in current practice, oxygen therapy is often prescribed without careful evaluation of its potential benefits and side effects and without adequate supervision. In a retrospective study of 90 consecutive hospitalized patients, oxygen therapy was prescribed inappropriately in 21 percent; monitoring was inadequate in 85 percent; and documentation of physiological criteria for termination of therapy was lacking in 88 percent of all patients. Prospective collected data have also indicated that less than 50 percent of hospitalized patients receiving supplemental oxygen do so at the prescribed dosage and flow.

This chapter provides the basis for the rational use of inhaled oxygen therapy. A review of the physiology of tissue oxygenation is followed by a discussion of the current indications and guidelines for acute oxygen therapy, the role of long-term oxygen therapy, and the pathophysiological basis for pulmonary oxygen toxicity. Because prescribed oxygen is administered typically under normobaric conditions, oxygen therapy and its toxic consequences are considered in this setting (i.e., at one atmosphere of pressure).

TISSUE OXYGENATION The physiological basis for oxygen therapy has been well documented for over 40 years. While treatment and prevention of arterial hypoxemia are the most common indications for oxygen therapy, the ultimate goal in its use is correction or avoidance of tissue hypoxia. In 1965, Chance first demon-

strated that a partial pressure of oxygen (Po2 ) in mitochondria of 18 mmHg or more is required to generate the high-energy phosphate bonds (as adenosine triphosphate) essential for all major cellular biochemical functions. At rest, the average adult man consumes about 225 to 250 ml of oxygen per min; this rate of consumption may increase as much as 10fold during exercise. Ongoing oxygen utilization in peripheral tissues dictates a very small oxygen reserve which is consumed quickly (within 4 to 6 min of cessation of spontaneous ventilation). A complete understanding of the concepts of oxygen delivery and utilization is required for careful assessment of the hypoxic patient and implementation of proper therapy.

Oxygen Delivery and Utilization Transport of oxygen from atmospheric air to tissue mitochondria (the ultimate sites of oxygen utilization) requires the integrated function of the pulmonary, cardiovascular, and hematologic systems. Under normal conditions, a pronounced drop in Po2 between ambient atmosphere and tissues is observed (Fig. 149-1). The measured basal tissue Po2 (i.e., mixed venous Po2 or v¯ o2 ) is only marginally greater than the threshold value for mitochondrial anaerobic metabolism measured in vitro (as illustrated in Fig. 149-1 by the dashed line at a Po2 of 20 mmHg). The consequence of such a steep oxygen concentration gradient and a marginal tissue reserve is that a variety of environmental and pathological factors can significantly impact on tissue oxygenation by altering Po2 at one of these intermediary stages. Hence, tissue hypoxia develops whenever oxygen delivery is inadequate to meet metabolic demands.

Oxygen delivery to the periphery is determined by two major factors: (1) oxygen content of arterial blood and (2) blood flow (i.e., cardiac output). Oxygen delivery is calculated as the product of cardiac output and arterial oxygen content. Total oxygen delivery is calculated as: Do2 = CO × Cao2 × 10

(1)

where Do2 = oxygen delivery, ml/min CO = cardiac output, L/min Cao2 = O2 content of arterial blood, ml/dl The oxygen content of arterial blood is determined by the hemoglobin concentration, its degree of saturation with molecular oxygen, and the fractional amount of oxygen physically dissolved in solution. The amounts of both bound and dissolved oxygen are related directly to the oxygen tension in arterial blood (Pao2 ), while the percentage of hemoglobin saturated with oxygen is a function of Pao2 , as described by the oxyhemoglobin dissociation curve (see Chapter 13). In turn, the amount of oxygen dissolved in solution is a function of the solubility coefficient of oxygen and the Pao2 . Hence, total arterial oxygen content is calculated as: Cao2 = ([Hgb] × 1.34 × Sao2 ) + (Pao2 × 0.0031) (2)

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Oxygen Therapy and Pulmonary Oxygen Toxicity

Figure 149-1 Graphical representation of sequential steps in the drop in oxygen tension (PO 2 ) at various stages of oxygen transport from atmosphere to peripheral tissues. Values depicted are calculated using the alveolar gas equation and data from Chance (J Gen Physiol 49:163–195, 1965). Dashed line represents the approximate intracellular anaerobic threshold.

where [Hgb] = hemoglobin concentration, g/dl 1.34 = O2 carrying capacity of hemoglobin at 37◦ C, ml/g hemoglobin Sao2 = measured %O2 saturation of hemoglobin 0.0031 = solubility coefficient for oxygen

Mechanisms of Hypoxia Aerobic metabolism requires a balance between oxygen deliv˙ 2 ). A biphasic relationery (Do2 ) and oxygen utilization (Vo ˙ 2 has been observed (Fig. 149-2). ship between Do2 and Vo During normal aerobic metabolism, oxygen transport and oxygen utilization are independent variables. Whereas the

amount of oxygen delivered to tissues per unit time defines the upper limit of oxygen availability for the body’s total metabolic needs, delivery of oxygen under normal circumstances always exceeds peripheral oxygen utilization. In this “supply-independent” region of the graph, oxygen consumption is commensurate with the rate of adenosine 5′ triphosphate (ATP) production and represents a measure of tissue cellular energy requirements. If oxygen delivery falls below a critical threshold (Do2 critical), or if utilization exceeds delivery (e.g., during strenuous exercise), tissues must shift from aerobic to anaerobic metabolism to supply adequate energy for total metabolic needs. When an imbalance arises, excessive lactic acid production ensues, resulting in progressive acidosis, disrupted cellular metabolism, and, potentially, cell death.

Figure 149-2 Relationship between oxygen consumption (V˙ O 2 ) and oxygen transport (DO 2 ). The critical DO 2 , indicative of the transition from supplydependent to supply-independent conditions, is denoted by the arrow. Anaerobic metabolism exists under supply-dependent conditions and ensues when oxygen consumption exceeds oxygen supply.

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Table 149-1 Causes of Tissue Hypoxia Categroy

Clinical Correlate

Pao2

Vo2

Cardiac Output

Hypoxemia

See Table 149-2

↓

↔ or ↓

↓ or ↑ or ↔

Hypovolemia; heart failure Sepsis; arterial insufficiency Inherited abnormal hemoglobins Acquired abnormal hemoglobin (Carbon monoxide poisoning) Anemia

↔ ↓ or ↔

↓ ↔ or ↓

↓ ↑ or ↔

↔

↔ or ↓

↑ or ↓

Impaired delivery Circulatory (forward flow) Distributive Defective Blood-O2 Transport

Table 149-1 lists the major causes of tissue hypoxia, which are mechanistically divided into three broad categories: (1) arterial hypoxemia, (2) reduced oxygen delivery, and (3) excessive or dysfunctional tissue utilization.

Maintenance of tissue oxygenation depends on the proper integration of three separate components: (1) the cardiovascular system, which determines cardiac output and blood flow distribution; (2) the blood, which determines hemoglobin concentration; and (3) the respiratory system, which determines Pao2 . Although causes of hypoxemia primarily reflect failure of proper oxygen loading of the blood (low Pao2 ) due to abnormal function of the respiratory system, defects in oxygen transport may result from either dysfunction of the cardiovascular system or hematologic issues. Finally, “misuse” of delivered oxygen, resulting from either defects in cellular metabolism or excessive demand, represents another class of disorders character-

ized by hypoxia. Each of these three categories is discussed below.

Arterial Hypoxemia Hypoxemia may be defined as a validated deficiency of oxygen tension in the arterial blood. A Po2 below the range of normal for age-matched subjects establishes the presence of arterial hypoxemia. Table 149-2 summarizes the major causes of hypoxemia. Since the driving force for oxygen transport across the alveolar barrier into the blood depends on both the concentration of oxygen in the alveolus (Pao2 ) and overall respiratory function, arterial hypoxemia results only from reduction of the inspired oxygen tension or respiratory dysfunction.

The most common pathophysiological causes of hypoxemia in lung disease include ventilation-perfusion mismatch, true shunt, or a diffusion barrier. In some

Table 149-2 Causes of Arterial Hypoxemia and Response to Oxygen Therapy Cause

Clinical Examples

Effect of Oxygen Therapy

Decreased oxygen intake

Altitude

Rapid increase in Pao2

Ventilation-perfusion imbalance

Chronic obstructive pulmonary disese

Moderately rapid increase in Pao2

Shunt

Atrial septal defect Pulmonary arteriovenous fistula

Rapid but variable increase in Pao2 depending on size of shunt

Diffusion defect

Interstitial pneumonitis

Moderately rapid increase in Pao2

Alveolar hypoventilation

Chronic obstructive pulmonary disease

Initial response: Increase in Pao2 Late response: Variable depending upon whether supplemental O2 depresses minute ventilation

2617 Chapter 149

nonpulmonary disorders, a low mixed-venous oxygen tension is responsible (Chapters 11 and 12). Alveolar hypoventilation, which also results in hypoxemia, acts indirectly through mechanisms that increase alveolar Pco2 and secondarily decrease alveolar Po2 . To a varying degree, most causes of arterial hypoxemia (with shunt physiology as the exception) can be improved by administration of supplemental oxygen. However, the magnitude of the response differs, based on the etiology.

Reduced Oxygen Delivery In the setting of a normal Pao2 , tissue hypoxia may result from abnormalities in any of the determinants of oxygen delivery, including circulatory causes, abnormal blood oxygen transport, or maldistribution of blood flow.

Circulatory hypoxia results when fully oxygenated blood is delivered to tissues in insufficient quantity or at an inadequate level to support tissue metabolic needs. Usual etiologies include low cardiac output states, systemic hypovolemia, and arterial insufficiency of peripheral tissues. Compensation is partially effected at the tissue level initially by increased oxygen extraction from blood, resulting in lowering of mixed-venous oxygen tension (vo2 ). Thus, a low vo2 is the hallmark of circulatory hypoxia. Because Pao2 may be normal and the hemoglobin normally saturated, oxygen administration is unlikely to be of great help in the majority of these disorders.

Tissue hypoxia may also result from abnormal bloodoxygen transport, in which the oxygen-carrying capacity of the blood is reduced, as manifested primarily by a decrease in the total hemoglobin content (i.e., anemia), or secondarily as a consequence of abnormal hemoglobin-O2 affinity.

States of abnormal hemoglobin-O2 affinity are characterized by an inability to bind oxygen (e.g., hemoglobinopathies) or to release oxygen to tissues (e.g., low levels of 2,3diphosphoglycerate). Acquired defects result typically from binding of a ligand with stronger affinity for hemoglobin than oxygen (e.g., carbon monoxide) or a toxic alteration in hemoglobin structure (e.g., methemoglobin). Under these circumstances, cardiac output is increased as an adaptive response, and vo2 is normal or decreased. Although not a primary therapy, oxygen administration may play an adjunctive role. In certain situations, including carbon monoxide poisoning, hyperbaric oxygen therapy (Chapter 62) may be helpful.

Finally, tissue hypoxia may result from maldistribution of a normal or supranormal cardiac output. Examples include microvascular perfusion defects observed in classical septic shock or in the more recently recognized systemic inflammatory response syndrome (SIRS) (Chapter 146). Maldistribution of perfusion leading to tissue hypoxia has also been described in other situations, such as experimental interleukin-2 therapy. The hallmark of a maldistributive hypoxia is the development of precapillary shunting in peripheral tissues. Thus, cardiac output is normal or increased, and vo2 is usually low. Because of the presence of peripheral shunt-

Oxygen Therapy and Pulmonary Oxygen Toxicity

ing, supplemental oxygen is usually not effective in increasing local cellular oxygen tension.

Cellular Causes of Hypoxia Hypoxia may also arise from misuse of oxygen at the tissue level. Cellular hypoxia results from inhibition of either intracellular enzymes or oxygen-carrying molecules involved in intermediary metabolism and energy generation. In hydrogen cyanide poisoning, Pao2 , hemoglobin concentration, percentage of hemoglobin saturation, and tissue perfusion are normal. However, peripheral utilization of oxygen is impaired as cyanide binds to cytochrome oxidase and inhibits intramitochondrial transport of electrons to molecular oxygen. This event blocks production of ATP via oxidative phosphorylation, resulting in lactic acidosis as anaerobic metabolism is triggered. In addition, oxygen extraction is often impaired, leading to a normal or increased vo2 . Although oxygen therapy is usually not effective, 100 percent oxygen is often administered while the patient is treated with specific antidotes.

“Demand hypoxia” results when tissue oxygen utilization is supernormal and exceeds the rate of oxygen delivery. Common causes include maximal exercise and hypermetabolic states, such as thyrotoxicosis. As in circulatory hypoxia, vo2 is decreased, but in contrast, cardiac output is normal or, more likely, increased. Because oxygen-carrying capacity is normal, oxygen administration is often ineffective, and definitive treatment requires control of the underlying disorder.

RECOGNITION AND ASSESSMENT OF TISSUE HYPOXIA The correct use of oxygen therapy requires clinical recognition of tissue hypoxia, careful evaluation of the pathophysiological basis for the hypoxia, understanding of factors that predict those hypoxic patients likely to receive benefit, and continued assessment of the optimal dosage. The benefit must be balanced against potential toxicity. In most circumstances, tissue hypoxia is not directly measurable, and detection is usually accomplished through a combination of clinical and laboratory parameters. In cases of isolated arterial hypoxemia, awareness of tissue hypoxia is enhanced through inference of abnormal measurements of arterial oxygen saturation.

Clinical Manifestations Clinical manifestations of hypoxia are highly variable and nonspecific and depend on both duration of the hypoxia (acute or chronic) and the individual’s fitness. Symptoms and signs associated with acute hypoxia, outlined in Table 149-3, include changes in mental status, dyspnea, tachypnea, respiratory distress, and cardiac arrhythmias. Alterations in mental status range from impaired judgment to confusion or coma. Cyanosis, often considered a hallmark of hypoxia, occurs only when the concentration of reduced hemoglobin

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Table 149-3 Signs and Symptoms of Acute Hypoxia System

Signs and Symptoms

Respiratory

Tachypnea, breathlessness, dyspnea, cyanosis

Cardiovascular

Increased cardiac output, palpitations, tachycardia, arrhythmias, hypotension, angina, vasodilatation, diaphoresis, and shock

Central nervous

Headache, impaired judgment, inappropriate behavior, confusion, euphoria, delierium, restlessness, papilledema, seizures, obtundation, coma

Neuromuscular

Weakness, tremor, asterixis, hyper-reflexia, incoordination

Metabolic

Sodium and water retention, lactic acidosis

in the blood is 1.5 g/dl or greater. However, this is not a reliable sign, as it is absent in anemia and during periods of poor peripheral perfusion.

patients who are chronically hypoxemic and who have developed compensatory mechanisms. In addition, assumptions about the adequacy of tissue oxygenation may not be warranted in clinical settings in which factors other than arterial hypoxemia are responsible for the development of hypoxia (Table 149-1).

INDICATIONS FOR OXYGEN THERAPY In every sense, oxygen must be thought of as a drug having a therapeutic window based on the dose and duration of administration. In addition, the cost of both short-term oxygen therapy for hospitalized patients and long-term therapy for patients with chronic lung disease dictates a rational understanding regarding its administration. For example, in the United States, using data from the Health Care Financing Administration, total annual Medicare expenditures for therapy and equipment range from $1.3 to $1.8 billion. Thus, indications for use of supplemental oxygen must be clear.

Oxygen should be administered in precise amounts, and patients should be monitored for both efficacy and toxicity of treatment. Despite the facts that the scientific foundation underlying these principles is incomplete and that all-inclusive guidelines have been difficult to develop, the economic implications and requirements for laboratory monitoring have prompted development of recommendations for oxygen therapy. These recommendations allow the physician flexibility in exercising appropriate clinical judgment in prescribing oxygen in a cost-effective manner, in both acute and chronic settings.

Laboratory and Other Objective Assessments Because of the variability of presentation and nonspecificity of the symptoms and signs of hypoxia, the laboratory assessment of the state of tissue oxygenation is desirable. Unfortunately, the current state of the art remains imprecise. Quantification of the degree of oxygenation of individual tissues is difficult.

The vo2 represents an approximation of mean tissue Po2 , and a level of less than 30 mmHg indicates overall tissue hypoxia. However, measurements of vo2 require pulmonary artery catheterization and, therefore, are limited to intensive care settings.

In most clinical situations, direct determinations of Pao2 , arterial hemoglobin oxygen saturation, and serum lactate levels are surrogate markers for tissue hypoxia. Pao2 determinations are made invasively with blood samples obtained from arterial puncture or indwelling arterial catheters, while noninvasive assessment of percent saturation of blood hemoglobin is routinely available by infrared pulse oximetry.

Both are useful in excluding arterial hypoxemia; neither directly measures tissue Po2 . Inadequate tissue oxygen delivery is inferred from moderate decreases in Pao2 , and the inference is usually warranted in acutely ill patients whose Pao2 is less than 50 mmHg or in whom blood lactate levels are elevated. However, this judgment may be unsubstantiated in

Short-Term Oxygen Therapy Recommendations for administration of supplemental oxygen, based upon guidelines of the American College of Chest Physicians, the National Heart, Lung and Blood Institute, and other organizations, are summarized in Table 149-4.

Tissue Hypoxia Associated with Arterial Hypoxemia In the acute setting, the most common indication for supplemental oxygen, regardless of the underlying etiology, is arterial hypoxemia. For a normal, middle-aged adult, the usual level of hypoxemia at which oxygen therapy is instituted is a Pao2 of less than 60 mmHg. Based on the oxyhemoglobin dissociation curve, this value for Pao2 results in a hemoglobin saturation of about 90 percent. Because of the sigmoidal shape of the curve at this Pao2 , a further decrease in oxygen tension results in a considerable drop in oxygen saturation.

Ventilation-perfusion mismatch is the most common pathophysiological cause of arterial hypoxemia (see Chapter 11). The magnitude of the response to administration of supplemental oxygen depends upon the range and degree of ventilation-perfusion mismatch within individual lung regions. Therefore, repeated measurements of Pao2 or Sao2

2619 Chapter 149

Table 149-4 Guidelines for the Use of Acute Oxygen Therapy Accepted Indications Acute hypoxemia (Pao2 < 60 mmHg; Sao2 < 90%) Cardiac and respiratory arrest Hypotension (systolic blood pressure < 100 mmHg) Low cardiac output and metabolic acidosis (bicarbonate < 18 mmol/L) Respiratory distress (respiratory rate > 24/min) Questionable Indications Uncomplicated myocardial infarction Dyspnea without hypoxemia Sickle cell crisis Angina ∗ Data

from Fulmer JD, Snider GL: Chest 86:234–247, 1984.

should be performed to document an effective response to a particular Fio2 .

Hypoxemia secondary to right-to-left shunting is often less responsive to administration of supplemental oxygen. Mixing of shunted and unshunted blood results in a large fall in Pao2 . When the shunt fraction is greater than 20 to 25 percent, hypoxemia may persist, despite an Fio2 of 1.0.

Finally, alveolar hypoventilation is often easily corrected with supplemental oxygen. However, recognition and correction of the underlying cause and immediate restoration of ventilation are the primary aims of treatment.

Although a Pao2 of 60 mmHg is a reasonable goal in the initial treatment of arterial hypoxemia, in certain clinical situations the acceptable threshold level may be adjusted upward or downward. For example, in patients with low oxygen-carrying capacity (e.g., severe anemia), or in flowlimited states (e.g., acute angina pectoris), increases in Pao2 beyond 60 mmHg (yielding increases in Sao2 from 90 to 100 percent) may result in marginal, but potentially important, increases in tissue oxygen delivery. Conversely, the “acceptable” Pao2 may have to be set at a lower level in patients with abnormal control of respiration, such as those with an acquired reduced hypoxic ventilatory drive due to chronic carbon dioxide (CO2 ) retention.

Tissue Hypoxia with Normal PaO2 The efficacy of supplemental oxygen in diseases that cause arterial hypoxemia is well-established. However, in cases where tissue hypoxia may exist without concomitant arterial hypoxemia, treatment should be directed ultimately to correcting the underlying cause. In these cases, Pao2 is an inadequate index of the need for, or the potential to benefit from, oxygen therapy. When available, alternative indices of tissue oxygena-

Oxygen Therapy and Pulmonary Oxygen Toxicity

tion should be used; oxygen therapy should be initiated and modified, based on the indices. Nevertheless, in some disorders, oxygen therapy has often been used even if Pao2 is not at a substantially depressed level. There is not always a consensus about the proper uses of oxygen in these circumstances.

Acute Myocardial Infarction Hypoxemia is extremely common in acute myocardial infarction. In such patients, oxygen administration is of unquestioned benefit. Data supporting use of oxygen therapy in nonhypoxemic patients with acute myocardial infarction is controversial. Double-blinded studies of the value of oxygen in uncomplicated myocardial infarction demonstrate no significant effects on morbidity or mortality.

Inadequate Cardiac Output (Low-Flow States) Oxygen has been recommended for temporary treatment of inadequate systemic perfusion resulting from cardiac failure.

Although this practice seems reasonable, no clinical studies to date have proved the value of oxygen therapy in this setting. Oxygen therapy is used in conjunction with inotropic agents and other devices to assist cardiac output as definitive treatment is undertaken.

Trauma and Hypovolemic Shock Oxygen has been advocated as adjunctive therapy in the setting of acute trauma. The low-flow state induced by acute hemorrhage is best treated by increasing the supply of circulating hemoglobin. However, supplemental oxygen as supportive therapy seems warranted until red blood cells become available for transfusion.

Carbon Monoxide Intoxication In carbon monoxide poisoning, the Pao2 is a poor guide to the need for oxygen therapy. Despite a normal or “supranormal” Pao2 , a state of significant tissue hypoxia exists, as often indicated by a severe metabolic acidosis. Because of the high concentration of carbon monoxide–bound hemoglobin (carboxyhemoglobin), administration of supplemental oxygen does not increase tissue oxygen delivery. However, administration of pure oxygen markedly shortens the half-life of circulating carbon monoxide (80 min vs. 320 min on room air).

Thus, oxygen administration for carbon monoxide poisoning constitutes an accepted therapy. Hyperbaric oxygen administration represents the current standard of care for those patients with high carboxyhemoglobin levels and evidence of end-organ ischemia-reperfusion damage (Chapter 62).

Miscellaneous Disorders Use of supplemental oxygen as adjuvant therapy in sickle cell crisis, in accelerating resorption of air in pneumothorax, and for relief of dyspnea without hypoxemia remains controversial.

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Long-Term Oxygen Therapy In recent years, use of long-term oxygen therapy in the chronically ill patient has increased. In the United States, over 800,000 patients currently receive long-term oxygen therapy; most are patients with arterial hypoxemia. Patients with chronic obstructive pulmonary disease (COPD) represent the largest group of patients, and most of the data regarding clinical efficacy of supplemental oxygen come from studies of these patients.

Early studies of oxygen therapy in COPD showed that continuous supplemental oxygen administered for 4 to 8 weeks decreased the hematocrit, improved exercise tolerance, and lowered pulmonary vascular pressures. In the early 1980s, two well-controlled studies demonstrated the value of longterm oxygen administration in patients with chronic hypoxemia due to COPD. Both the Nocturnal Oxygen Therapy Trial (NOTT) and the British Medical Research Council Domiciliary (BMRCD) study documented a significant reduction in mortality in patients receiving supplemental oxygen compared with controls who received no supplemental oxygen.

Although the treatment groups in the two studies are not directly comparable (patients in NOTT received either continuous or nocturnal oxygen, whereas those in BMRCD received nocturnal oxygen or no supplementation), nocturnal oxygen (greater than 15 h/day) is better than no oxygen; continuous supplemental oxygen imparts the most benefit. The greatest efficacy is seen in patients with polycythemia, pulmonary hypertension, or hypercapnia. Although similar studies in other groups of patients with chronic hypoxemia are not available, extension of the concept of long-term oxygen therapy for patients with resting hypoxemia from a variety of cardiopulmonary diseases, including restrictive lung disease, cystic fibrosis, and chronic cardiac disease, has become widely accepted in clinical practice.

Table 149-5 lists the currently accepted indications for long-term oxygen therapy. In addition to chronic arterial hypoxemia at rest, continuous-flow oxygen therapy is indicated for patients with exercise-induced hypoxemia (i.e., exercisedinduced arterial desaturation). Current data suggest that supplemental oxygen improves exercise endurance, as measured by either treadmill walking or bicycle ergometry. However, since ventilatory, rather than circulatory, factors often limit exercise in patients with airflow obstruction, increasing oxygen saturation is not a reliable predictor of improved exercise performance in all patients.

A third group of patients who benefit from chronic oxygen administration are those who develop significant decreases in arterial oxygen during sleep. Included are patients with primary sleep-disordered breathing (e.g., obstructive sleep apnea and obesity hypoventilation syndrome) and patients with primary lung disease who exhibit nocturnal desaturation. For the first part of this group, oxygen therapy may need to be coupled with invasive or noninvasive ventilatory support for treatment of hypercarbia; the latter part of the group can often make use of low-flow oxygen to blunt arterial desaturation.

Table 149-5 Indications for Long-Term Oxygen Therapy Continuous Oxygen 1. Resting Pao2 < 55 mmHg or oxygen saturation < 88% 2. Resting Pao2 of 56–59 mmHg or oxygen saturation of 89% in the presence of any of the following indicative of cor pulmonale: a. Dependent edema suggesting congestive heart failure b. P pulmonale on the electrocardiogram (P wave > 3 min in standard leads II, III, or aVF) 3. Polycythemia (hematocrit > 56%) 4. Resting Pao2 > 59 mmHg or oxygen saturation > 89% reimbursable only with additional documentation justifying the oxygen prescription and a summary of more conservative therapy that has failed.

Noncontinuous Oxygen∗ 1. During exercise: Pao2 < 55 mmHg or oxygen saturation < 88% with a low level of exertion 2. During sleep Pao2 < 55 mmHg or oxygen saturation 88% with associated complications, such as pulmonary hypertension, daytime sommolence, and cardiac arrhythmias ∗ Oxygen

flow rate and number of h-day must be specified.

In all patients, the need for additional supplemental oxygen should be based on measurements of arterial saturation. Certificates of medical necessity can then be completed appropriately. Most data support the notion that strategies for delivery of long-term oxygen should include early followup for assessing efficacy, followed by routine reevaluation at fixed intervals.

TECHNIQUES OF OXYGEN ADMINISTRATION In either the acute or chronic setting, once the need for supplemental oxygen is established, one of several types of delivery devices can be used to supply the patient with O2 -enriched gas. The choice of delivery system is based upon a variety of criteria, including: (1) the degree of hypoxemia, (2) the requirement for precision of delivery, (3) patient comfort, and (4) cost. The devices discussed below are reserved primarily for conscious patients who are capable of protecting their airways. Not included in the discussion are details on the use of endotracheal intubation (Chapter 151) or mechanical ventilation (Chapter 153).

2621 Chapter 149

Oxygen Therapy and Pulmonary Oxygen Toxicity

Figure 149-3 Commonly used classes of oxygen delivery systems. See text for complete descriptions.

Oxygen Delivery Systems in the Acute Setting A variety of delivery systems are available for short-term oxygen administration. The systems vary in complexity, expense, efficiency, and precision of oxygen delivery. Other than anesthesia breathing circuits, virtually all oxygen delivery systems are non-rebreathing (full or partial). In non-rebreathing circuits, the inspiratory gas is not made up of any portion of the exhaled volume, and the only inhaled CO2 is that which is entrained from ambient room air. Rebreathing is avoided through use of one-way valves to sequester expired from inspired gases. In addition, in all these systems, inspired gas mixtures must be presented in sufficient volume and at flows to allow compensation for the high-flow demands often exhibited by critically ill patients.

The major types of oxygen delivery systems are outlined in Fig. 149-3. They can be divided into low-flow and highflow varieties, each of which can deliver humidified, inspired gases. Each has advantages and drawbacks.

Low-Flow Oxygen Devices Low-flow oxygen delivery systems provide a fraction of the patientâ&#x20AC;&#x2122;s minute ventilatory requirement as pure oxygen; the remainder of the ventilatory requirement is fulfilled by addition of another gas, usually entrained room air. Flows supplied through these devices are low (less than 6 L/min), and they cannot deliver constant inspired oxygen concentrations, since small fluctuations in each tidal volume lead to variations in the amount of entrained room air. Consequently, in patients with an abnormal or variable ventilation pattern, marked variation

in the fraction of inspired oxygen may exist. Patient-related factors that affect the fractional concentration of inspired oxygen include: (1) shallow breathing, which results in entraining less room air and, therefore, a higher concentration of inspired oxygen; (2) deep, hyperpneic breathing, which enhances entraining of more room air; and (3) changes in respiratory frequency, which affect exhalation time, thereby producing variable filling of the deviceâ&#x20AC;&#x2122;s inspiratory reservoir.

When the delivery of a constant Fio2 is required (e.g., in patients with chronic CO2 retention), low-flow systems should not be used.

Nasal Cannulae

Nasal catheters and cannulae are the most widely used devices for delivering low-flow oxygen. They are simple, inexpensive, easy to use, and well-tolerated. As for all low-flow systems, the Fio2 may vary greatly, depending on the oxygen flow, inspiratory flow, and minute ventilation. With low-flow nasal cannulae set to deliver oxygen to the nasopharynx at flows between 1 and 6 L/min, the Fio2 ranges between 0.24 and 0.44 (Table 149-6). Flows above 6 L/min do not significantly increase Fio2 above 44 percent; these higher flows may result in drying of mucous membranes.

Oxygen Masks

Simple plastic oxygen masks which cover the nose and mouth are capable of delivering concentrations of oxygen up to 50 to 60 percent. Depending on mask size, these devices provide a self-contained reservoir of 100 to 200 ml of additional gas,

2622 Part XVII

Acute Respiratory Failure Masks with Reservoir Bags

Table 149-6 Approximate Fraction of Inspired Oxygen with Low- and High-Flow Oxygen Devices 100% O2 Flow Rate (L/min) Low-Flow Systems Nasal cannula 1 2 3 4 5 6 Transtracheal catheter 0.5–4 Oxygen mask 5–6 6–7 7–8 Mask with reservoir bag 6 7 8 9 10 Non-rebreathing 4–10 High-Flow System Venturi mask∗ 3 (80) 6 (68) 9 (50) 12 (50) 15 (41)

FI o2 (%)

24 28 32 36 40 44 24–40 40 50 60 60 70 80 90 >99 0.60–1.00

0.24 0.28 0.35 0.40 0.50

To deliver an Fio2 of greater than 0.6 to patients who do not have artificial airways, a reservoir bag (600 to 1000 cc) can be attached to a simple face mask (Fig. 149-4). A source of continuous oxygen at flow rates of 5 to 8 L/min is needed to ensure adequate distention of the bag and to flush out CO2 from the mask. If there are no one-way valves on the reservoir bag, the apparatus is referred to as a partial non-rebreathing mask (Fig. 149-4A). Partial non-rebreathing masks can deliver oxygen in concentrations of 80 to 85 percent. The true non-rebreathing mask makes use of a one-way valve between the mask and the bag so that the patient can only inhale from the reservoir bag and exhale through separate valves on either side of the mask (Fig. 149-4B). A very high Fio2 can be achieved when these masks fit tightly against the patient’s face. However, tight-fitting molded masks, including those used to deliver continuous positive airway pressure (CPAP), are often uncomfortable and are not suitable for use for more than a few hours.

High-Flow Oxygen Delivery Devices High-flow oxygen delivery systems maintain the selected Fio2 by incorporating a reservoir whose volume exceeds the patient’s anatomic dead space or by delivering oxygen at a very high flow. In quantitative terms, the flow of all high-flow systems exceeds four times the patient’s actual minute volume; otherwise, entrainment of room air at peak inspiration arises.

Common clinical indications for use of a high-flow oxygen delivery system are: (1) treatment of hypoxic patients who depend on their hypoxic drive to breathe but who require controlled increments in Fio2 , and (2) young, vigorous patients with hypoxemia who have an abnormal ventilatory pattern and whose ventilatory requirements may exceed the delivery capabilities of low-flow systems. When a clinical indication exists for a tightly controlled, high Fio2 , or when high flows are necessary, a high-flow delivery system should be used.

Jet-Mixing Venturi Masks

∗ Numbers

in parentheses indicate total flow of entrained room air in the Venturi mixture.

thereby facilitating increases in the achievable fraction of inspired oxygen above 0.44. Simple face masks require a flow of inspired oxygen of 5 to 6 L/min to avoid accumulation of CO2 within the mask.

Conventional oxygen masks suffer from the limitations of all face masks. They interfere with drinking, eating, and expectorating, and they can become displaced, particularly at night as the patient sleeps. In addition, use of face masks increases the risk of aspiration by concealment of vomitus or containment of regurgitant materials. Therefore, when using these devices, the risk-benefit ratio should be considered. As with nasal cannulae, respiratory mucous membrane drying from the inspired gas mixture is possible. Humidification of inspired gas reduces the magnitude of the problem.

Another high-flow oxygen delivery device is the Venturi mask, the operation of which is based on the Venturi modification of the Bernoulli principle of fluid physics for gaseous jet-mixing (Fig. 149-5). As forward flow of inspired gas increases, the lateral pressure adjacent and perpendicular to the vector of flow decreases, resulting in entrainment of gas. In a Venturi mask, a jet of 100 percent oxygen flows through a fixed constrictive orifice, past open side ports, thereby entraining room air.

The flow of jetting gas passing through, and then out of, the central orifice of the mask increases in velocity, and the resultant pressure drop along the sides of the jet draws room air into the face mask via the side ports. The amount of air entrained and, therefore, the resultant Fio2 , depend on the size of the side ports and flow of oxygen. Since both of these parameters are fixed, the resultant oxygen-room air mixing ratio is held steady, resulting in a well-controlled, constant Fio2 . Exhalation occurs through valved exhalation ports. The range of Fio2 obtainable through adjustments in the amount

2623 Chapter 149

PARTIAL REBREATHING

Expired Gas

Expired Gas

Inspired Gas

Inspired Gas 100% Oxygen

Oxygen Therapy and Pulmonary Oxygen Toxicity

NONREBREATHING Expired Gas One Way Valve

Expired Gas One Way Valve

Inspired Gas One Way Valve

100% Oxygen

Mixed Inspired and Expired Gas

Reservoir Bag

A

B

Reservoir Bag

Figure 149-4 Mask-reservoir bag systems, illustrating airflows with partial rebreathing ( A) and nonrebreathing (B ) masks. Arrows indicate direction of airflow. See text for details.

of entrained room air and oxygen flow (i.e., the â&#x20AC;&#x153;entrainment ratioâ&#x20AC;?) is broad (Table 149-6). Masks currently in use deliver inspired gas with an Fio2 between 0.24 and 0.50.

Since the Venturi mask reliably provides an accurate Fio2 up to 0.50, it is an ideal device for use in treatment of hypoxemia in patients with COPD and chronic respiratory failure characterized by a blunted hypercarbic respiratory drive.

Although the Fio2 usually can be regulated precisely, technical factors can alter the value. For example, water drops may clog the oxygen injector device, resulting in changes in gas flow.

In addition, development of back pressure by occluded exhalation ports may lead to decreases in the volume of entrained room air and a resultant increase in Fio2 .

Expired Gas

Other High-Flow Systems

Reservoir nebulizers and humidifiers are used to provide supplemental oxygen or highly humidified gas (including room air). Provision of high humidification is often important as adjuvant management of increased airway secretions. Usually, this delivery system is combined with endotracheal tubes or tracheostomy collars, and, therefore, its use is limited to patients with artificial airways. However, such delivery systems have also been used in combination with aerosol masks, face tents, and CPAP masks. If high-flow rates (in excess of 40 L/min) are supplied, they can usually provide a constant and predictable Fio2 .

Air-oxygen blenders consist of precision metering devices that convert high-pressure wall sources of compressed air and oxygen (at 50 to 70 psi) to usable, predictable flows of up to 100 L/min at an Fio2 ranging from 0.21 to 1.0. These devices also require pressure-reduction valves and an inlet pressure monitor to ensure consistency of Fio2 against minor fluctuations in wall pressure. Although they provide a predictable Fio2 , the devices have some disadvantages. They are noisy and require specialized personnel to set up and monitor the instrumentation.

Long-Term Oxygen Delivery Systems Room Air

Room Air

100% Oxygen

Figure 149-5 Venturi mask. Arrows denote direction of airflow.

See text for details.

A variety of modes of oxygen delivery and oxygen administration devices are available for use in the home and other chronic care settings. Gas supplies for long-term oxygen therapy include oxygen concentrators and compressed gas or liquid oxygen sources. Most patients requiring a stationary source of supplemental oxygen use oxygen concentrators.

2624 Part XVII

Acute Respiratory Failure

Because the concentrators weigh about 35 lb and require wall current, their use is limited as a fixed source of oxygen. Unless patients are immobile or confined to bed, both stationary and mobile oxygen delivery systems should be employed. Both compressed gas and liquid oxygen portable systems are available, but the liquid system containers are easier to refill than high-pressure cylinders. The major disadvantages of liquid oxygen are higher cost and the requirement for pressure-relief venting.

The delivery devices for long-term oxygen therapy include most of the low-flow devices described previously. Most patients who receive chronic oxygen use nasal cannulae and oxygen flow rates of 2 to 4 L/min.

To improve the efficiency of oxygen delivery and to limit both the need for repetitive home delivery and cost, a number of devices have been designed to “conserve” home oxygen. These include reservoir nasal cannulae, electronic conserving devices, and transtracheal catheters.

The reservoir nasal cannulae have a pouch that stores 20 ml of extra oxygen during expiration and delivers the oxygen as a bolus at the onset of the next inspiration. Electronic demand devices, triggered by the onset of inspiration, deliver a pulse of oxygen early in the breath. Oxygen conservers include those that deliver a fixed volume per breath (pulse devices) and those that deliver a variable volume, which is commensurate with the length of inspiration (demand devices). Pulse-type devices deliver fixed volumes for each flow setting each time a pulse is triggered and do not deliver any more or less volume as the length of the patient’s inspiration time varies. Some pulse devices deliver with every breath, others with alternate breaths. By comparison, demand devices vary the amount of oxygen delivered during each and every breath, consistent with the duration of inhalation. Following the initial gas bolus, demand devices deliver (at an equivalent flow) a continuous flow for the remainder of the inspiration.

These devices provide a variable volume at each flow setting, depending on the length of inspiration, and they have lower levels of savings at low breath rates. In addition, demand devices tend to deliver volumes equal to or greater than those achieved using continuous flow therapy in most settings; in the event of conserver malfunction, they revert automatically to continuous flow without patient interaction.

Transtracheal catheters improve oxygen delivery by bypassing the anatomic dead space of the upper airway, effectively using the upper airway as an oxygen reservoir during inspiration and expiration. Transtracheal oxygen is delivered directly into the trachea via a hollow catheter implanted surgically under local anesthesia, or inserted percutaneously using the Seldinger technique. In numerous studies, transtracheal catheters have been shown to effect reductions in total oxygen usage of 50 to 75 percent. Other advantages of transtracheal oxygen systems include their inconspicuousness, lack of nasal or facial irritation due to oxygen flow, and infrequency of catheter displacement during sleep. Disadvantages include an increased incidence of infection, development of potentially fatal “mucus balls,” and catheter breakage which necessitates replacement.

PULMONARY OXYGEN TOXICITY Potential adverse effects of exposure to increased oxygen tensions at one atmosphere include alterations of normal physiological functions and oxygen-mediated tissue damage.

Physiological changes to high concentrations of oxygen involve perturbations of both pulmonary and extrapulmonary homeostasis; they are easily correctable, if recognized promptly. Extrapulmonary physiological effects of hyperoxia include suppression of erythropoiesis, systemic vasoconstriction, and depression of cardiac output. These effects are usually clinically insignificant. In contrast, pulmonary physiological effects of hyperoxia include depression of hypoxic ventilatory drive, pulmonary vasodilation, and absorption atelectasis. Each is clinically relevant.

In addition to producing adverse physiological effects, oxygen in high concentrations is cytotoxic. Whereas all respiring cells are potentially susceptible to the toxicity derived of hyperoxia, the major clinical adverse effects are related to lung damage.

Molecular and Cellular Mechanisms of Oxygen Toxicity The molecular and cellular bases for tissue injury in oxygen toxicity are thought to be mediated biochemically by reactive free radicals, the formation of which directly depends on the oxygen concentration. Since oxygen concentration is directly proportional to partial pressure, breathing 100 percent O2 at an altitude of 5000 feet (0.8 ata), 80 percent O2 at sea level (1 ata), or 40 percent O2 in a hyperbaric chamber (2 ata) for the same duration results in a similar toxicity profile.

Aerobic cells utilize oxygen both as a metabolic substrate for the generation of ATP via the electron transport chain, and as a cofactor in intermediary metabolism involving oxidation or hydroxylation of various substrates. Molecular oxygen (O2 ), per se, is relatively nonreactive and nontoxic.

However, modification of molecular oxygen by addition of electrons (e− ) can result in formation of highly reactive free radicals. The consequences of the sequential addition of single electrons to molecular oxygen are illustrated in the following reaction: e−

e− + 2H e− e− + H O2 → O2 ·− → H2 O2 → OH· → H2 O (3)

Superoxide anion (O.− 2 ), hydrogen peroxide (H2 O2 ), and hydroxyl radical (OH·) represent 1-, 2-, and 3-electron reduction products of oxygen, respectively. Singlet oxygen (O2 ·), a potent electrophile, is also generated as a by product of oxygen-dependent metabolism. During normal cellular metabolism, almost all molecular oxygen is converted completely to water, and the enzymes responsible for the reduction reactions (e.g., cytochrome oxidase, cytochrome P450, dopamine-β-hydroxylase) release few or no O2 intermediates. However, under certain conditions, these cellular

2625 Chapter 149

Figure 149-6 Generation of free radicals. Mechanisms for generation of toxic species of oxygen include: (1) superoxide anion (O− 2 ) generation by 1-electron reduction of molecular oxygen (O2 ) through a variety of electron donors (A2+ ); (2) hydrogen peroxide (H2 O2 ) generation by 2-electron reduction of O2 , usually via enzymatic catalysis; (3) interaction of superoxide and hydrogen peroxide in the presence of metals which generate hydroxyl radical; and (4) production of peroxynitrite by diffusion-limited reaction of superoxide and nitric oxide.

enzymes, as well as others, can be misused by serving as incomplete electron donors (i.e., fewer than four electrons) to molecular oxygen, generating and releasing the reactive O2 intermediates shown in Eq. (3) above.

Figure 149-6 depicts general mechanisms responsible for generation of toxic metabolites of oxygen reduction. O2 ·− (reaction 1) and H2 O2 (reaction 2) are each generated by both enzymatic and nonenzymatic processes. Although both molecular species may have direct toxic effects, their interaction via the Haber-Weiss cycle, in the presence of metal ions (typically, Fe3+ ), may generate hydroxyl radicals (reaction 3) which represent the most highly reactive and potentially dangerous of the O2 -derived products.

Superoxide has also clearly been shown to interact with other molecular species, such as nitric oxide (NO), which result in production of the free radical, peroxynitrite (ONOO), as illustrated in reaction 4 in Fig. 149-6. The second-order rate constant for the reaction of NO and O2 ·− to form peroxynitrite is 6.7 × 109 M−1 s−1 . This represents a reaction rate that is three times faster than the clearance of superoxide by superoxide dismutase.

Mechanisms of Pulmonary Cellular Toxicity The previously described generalized mechanisms of oxygen toxicity and metabolic intermediates are probably operative in the lung. Hyperoxia has been shown to stimulate increases in oxygen radical production in whole rat lungs, lung mitochondria, lung microsomes, lung nuclear membranes, and in cultured pulmonary endothelial cells, providing important support for the free radical hypothesis. Likewise, peroxynitrite formation has been detected in cultured cells in some animal models of acute lung injury, as well as in infants with bronchopulmonary dysplasia.

Mitochondria appear to be the major subcellular source of O2 ·− which is produced by the oxidation of ubisemiquinone as part of the normal mitochondrial electron transport chain and by autooxidation of NADH dehydroge-

Oxygen Therapy and Pulmonary Oxygen Toxicity

nase. Additional O2 ·− is generated by: (1) the endoplasmic reticulum (and microsomes), through the auto-oxidation of flavins (e.g., cytochrome P450) or other components, as well as during turnover of NADPH-cytochrome c reductase; and (2) plasma membranes, by auto-oxidation of cytochromes and during prostaglandin synthesis. H2 O2 is produced at most of the aforementioned sites by the dismutation of O2 ·− and via oxidase activity (e.g., urate oxidase) in peroxisomes.

HO· is generated where concentrations of O2 ·− and H2 O2 are greatest (i.e., near their production sites). Because peroxynitrite is generated by a diffusion-limited reaction, it may be formed as physiological pH at any cellular sites that contain significant amounts of NO and O2 ·− .

The biochemical alterations produced by modification of cellular components by oxygen radicals and peroxynitrite are depicted in Table 149-7. Lipid peroxidation and protein oxidation are thought to represent important mechanisms

Table 149-7 Biochemical Alterations and Cellular Dysfunction from Free Radical Damage Cell Component Oxygen Radicals Lipids Lipid peroxidation Surfactant Eicosanoids Proteins

Nucleic acids Pyridine nucleotides Complex carbohydrates Peroxynitrite Proteins Nitrotyrosine formation Sulfhydryl groups Nucleic acids 8-Nitroguanine formation Lipid peroxidation

Cellular Manifestation Damage to cell and organelle membranes Altered lung mechanics Changes in cellular metabolism and intracellular signaling Inactivation of enzymes and transport proteins; Altered cellular and intercellular permeability Inhibition of cell growth and division Altered intermediary metabolism Altered recognition of macromolecules

Inactivation of enzymes and transport proteins

Cell death Cell and organellar membrane damage

2626 Part XVII

Acute Respiratory Failure

of direct O2 radical toxicity. Lipids containing unsaturated fatty acids are particularly susceptible to injury. Lipid hydroperoxides produced as intermediates are extremely toxic and can propagate the peroxidation process in an autocatalytic manner. Proteins are inactivated by reaction of radicals with sulfhydryl groups, through cross-linkage of proteins, or oxidation of constituent amino acids. Destruction of lipid and protein results in damage to cellular and organellar membranes, inactivation of key enzymes, and disruption of cellular transport mechanisms. In addition, DNA, pyridine nucleotides, and complex carbohydrates are susceptible to oxidative processes, leading to mutagenesis, growth inhibition, and alteration of intermediary metabolism. Peroxynitrite is a powerful oxidant and, as such, has been shown to oxidize many cellular components. Of particular interest is its interaction with proteins, resulting in oxidation of sulfhydryl groups and formation of nitrotyrosine residues.

Cellular Antioxidant Defenses The half-life and tissue levels of most reactive oxygen species are low, in part due to an elaborate network of cellular antioxidant defenses. Antioxidant mechanisms include any cellular process which (1) prevents formation of free radicals, (2) converts oxidants to less reactive species, (3) “compartmentalizes” reactive species away from important cellular structures, or (4) initiates repair of molecular injury by free radicals.

Cellular oxygen radical defenses are classified into three basic categories: (1) enzymatic scavenging systems, which directly catalyze removal of free radicals; (2) enzyme-cofactor systems, which use a recyclable (renewable) intermediate to remove or prevent formation of O2 radicals; and (3) nonenzymatic free radical scavengers, which re-reduce O2 radicals or quench radical-producing reactions.

The major enzymatic O2 radical scavenger in the lungs is superoxide dismutase (SOD). SOD is a metalloprotein present in three distinct forms, each of which has a metallic cofactor. Copper-zinc SOD is a dimeric protein which is predominantly cytosolic; manganese SOD is found mainly in mitochondria. Copper SOD, a tetrameric peptide, has been isolated from plasma. All forms of SOD catalyze the dismutation of O2 ·− to H2 O2 at very high rates. Hydrogen peroxide is subsequently removed enzymatically by either the glutathione (GSH) redox cycle (see below) or by catalase.

The GSH redox cycle is the most important cellular scavenger of H2 O2 . It represents a unique system that uses multiple enzymes and a renewable, low-molecular-weight scavenger. GSH peroxidase removes both H2 O2 and lipid peroxides at the expense of GSH oxidation. GSH is regenerated

by GSH reductase, using NADPH as a cofactor.

Low-molecular-weight, nonenzymatic free radical scavengers include ascorbic acid (vitamin C), α-tocopherol (vitamin E), and β-carotene (vitamin A). These nonrecyclable compounds are derived from extrinsic (dietary) sources.

PATHOPHYSIOLOGY OF OXYGEN TOXICITY The toxic effects of oxygen on the lung occur when free radical production during hyperoxic exposure overwhelms intrinsic antioxidant defenses. Excess free radicals interact with cellular components, resulting in cytotoxic events which produce a characteristic cascade of biochemical, cellular, morphologic, and physiological changes. The biochemical reactions, in turn, result in a sequence of characteristic cellular and morphologic changes.

Primary Morphologic and Cellular Changes Based primarily on data from animal models and some limited human studies, four basic phases constitute the development of oxygen toxicity in lung tissue. The first three phases— initiation, inflammation, and destruction—occur during exposure to both lethal and sublethal doses of hyperoxia. The fourth phase—proliferation and fibrosis—occurs if there is re-exposure to sublethal oxygen levels. If lethal exposure persists, ongoing tissue destruction and death are observed.

Initiation Phase The initiation phase of oxygen toxicity comprises the first few hours and continues throughout the duration of exposure.

Initiation follows short-term exposure to lethal doses of O2 and occurs over longer periods, with sublethal hyperoxia. In each setting, the initiation phase is associated with enhanced rates of oxygen radical formation; however, there is no significant evidence of morphologic injury. Decreased rates of protein synthesis, alterations in tracheobronchial clearance of particulates, and changes in endothelial cell function have been described.

Inflammatory Phase The earliest morphologic changes in the lung in response to hyperoxia occur as a consequence of primary cellular damage. They involve subtle changes in endothelial cell structure, resulting in pericapillary accumulation of fluid. Increased leakage from the pulmonary microcirculation via disruptions in the endothelial lining follows, along with accumulation of proteinaceous fluid, formation of hyaline membranes, and an influx of inflammatory blood cell elements with release of mediators. This combination of events gives rise to a pathological picture resembling noncardiogenic pulmonary edema, including morphologic characteristics of diffuse alveolar damage—a process frequently associated with acute respiratory distress syndrome (ARDS) and other forms of lung injury (see Chapters 144 and 145).

Destruction Phase Overt cellular destruction begins shortly after the inflammatory phase. From a large body of in vitro and in vivo evidence it now appears that two major patterns of cell death, apoptosis and necrosis, occur in the lung in response

2627 Chapter 149

to hyperoxia. Apoptotic signaling pathways appear to involve both the cell death receptor (CD40-CD40 ligand) and mitochondria-dependent pathways with activation of caspase family members. The earliest evidence for impending cellular destruction appears at the ultrastructural level. Observed changes in lung epithelial and endothelial cells include membrane damage, vacuolarization of cytoplasm, mitochondrial swelling, and nuclear degeneration. Soon thereafter, frank cell death is seen, and exposure of the basement membrane occurs.

Proliferation and Fibrosis Phase If exposure to toxic levels of O2 is terminated, a subacute or chronic stage, termed the proliferative phase, develops. The cellular proliferative response blunts the destructive phase and may enhance survival. Proliferation of type II pneumocytes occurs as alveolar remodeling takes place. In addition, an influx and proliferation of interstitial cells (fibroblasts, monocytes, and macrophages) appears to be mediated by both cytokine and autocrine factors; collagen deposition is seen as well. In baboons, lung histology and function have been shown to return to normal within 6 months of recovery from severe oxygen toxicity. However, in other settings, the end result may be, instead, varying degrees of fibrosis or emphysema. The complete complement of regulating factors remains to be defined.

In the aggregate, the pathophysiological and morphologic changes associated with hyperoxic stress are similar to other forms of diffuse alveolar damage. An initial inflammatory response (exudative phase) is followed by fibrosis and repair (proliferative phase), a sequence not dissimilar from other forms of ARDS.

Oxygen Therapy and Pulmonary Oxygen Toxicity

Table 149-8 Sequence of Pulmonary Changes during Hyperoxic Exposure in Humans O2 at 1 atm

Exposure Duration

100%

>12 h

>24 h >36 h

>48 h

>60 h

Manifestions Decreased tracheobronchial clearance; decreased forced vital capacity; cough; chest pain Altered endothelial function Increased alveolar-arterial oxygen gradient; decreased carbon monoxide diffusing capacity Increasing alveolar permeability; pulmonary edema; surfactant inactivation Acute respiratory distress syndrome

60%

7 days

Mild chest discomfort without changes in lung mechanics; possible changes in morphometry

24â&#x20AC;&#x201C;28%

Months

Subclinical pathological changes; no clinical toxicity documented

Secondary Changes The cellular changes that occur in response to toxic oxygen exposure also produce secondary changes in lung function.

The increased capillary permeability that occurs with cellular damage results in decreased lung compliance, an increased alveolar-arterial oxygen gradient, and a decreased carbon monoxide diffusing capacity. Hyperoxia has also been reported to alter the pulmonary surfactant system. Alveolar surfactant material recovered from animals exposed to hyperoxic conditions exhibits markedly decreased surface tensionâ&#x20AC;&#x201C; lowering capabilities. One potential explanation appears to be inactivation of the biophysical activity of surfactant by serum proteins which leak into the alveolar space.

CLINICAL SYNDROMES OF OXYGEN TOXICITY The scenario of clinical events following exposure to hyperoxic environments is well-described as summarized in Table 149-8.

Acute Toxicity: Tracheobronchitis and Acute Respiratory Distress Syndrome (ARDS) Normal volunteers exposed to 100 percent O2 experience symptoms within 12 to 24 h. The earliest manifestations represent effects on the tracheobronchial mucosa and include substernal chest pain and nonproductive cough. Measurements of tracheobronchial function show decreased particle clearance as early as 6 h after the start of exposure to 100 percent O2 . Systemic symptoms, including malaise, nausea, anorexia, and headache may be seen.

The onset of acute pulmonary oxygen toxicity usually follows an asymptomatic period during which no physiological changes are seen. In normal volunteer subjects given 100 percent O2 for 6 to 12 h, no abnormalities were noted in the alveolar-arterial oxygen gradient, pulmonary artery pressure, vascular resistance, cardiac output, pulmonary extravascular lung water, or chest radiograph. By 24 h, significant decreases in their vital capacities were found, and at 48 h of exposure to 98 percent oxygen, decrements in static compliance and carbon monoxide diffusing capacity were seen. In patients with irreversible brain damage given 100 percent O2 , the

2628 Part XVII

Acute Respiratory Failure

alveolar-arterial gradient increased precipitously after 40 to 60 h. The longest voluntary exposure to 100 percent O2 reported is 110 h; the subject developed severe dyspnea, a marked decrease in pulmonary function, and acute respiratory failure.

Chronic Pulmonary Syndromes Although not well understood in humans, the subacute and chronic phases of oxygen toxicity are well documented in animals and appear to be related to dose and duration of exposure. The best-known clinical syndrome of chronic pulmonary oxygen toxicity occurs in newborns receiving oxygen for treatment of neonatal respiratory distress syndrome.

Persistent morphologic changes with healing may produce the chronic disorder bronchopulmonary dysplasia. The effects of long-term exposure of adults to inspired oxygen concentrations of 60 to 100 percent are less clear, although morphometric changes after 13 days of exposure in braindead patients have been described. Data on longer exposures, including exposure to lower levels of inspired oxygen, are unavailable.

Diagnosis Pulmonary oxygen toxicity develops insidiously after a variable lag period, during which the biochemical and cellular changes described previously occur. Early clinical detection of oxygen toxicity during this lag period is impossible; tests to identify biochemical changes (e.g., lipid peroxidation) would improve diagnostic accuracy. However, such tests are currently unavailable for clinical use. Although reversible (early) physiological, anatomic, and biochemical changes can be detected following short exposure to hyperoxia, humans can tolerate 100 percent oxygen at sea level for 24 h without serious pulmonary injury. Currently, the diagnosis of hyperoxic lung injury depends on a nonspecific symptom complex or abnormal pulmonary function in the proper clinical setting.

Symptoms and Signs Development of chest pain, tachypnea, or cough in a patient breathing elevated concentrations of oxygen should alert the clinician to the possibility of oxygen toxicity. The best index of oxygen toxicity may be the individualâ&#x20AC;&#x2122;s subjective symptom of retrosternal chest pain. Unfortunately, in a critically ill patient who requires mechanical ventilation or who has an altered mental status, detection of subjective complaints is difficult or impossible. On physical examination, the presence of crackles suggestive of interstitial or alveolar edema may be noted as a nonspecific finding.

Pulmonary Function Tests Decreases in vital capacity, pulmonary compliance, or carbon monoxide diffusing capacity, as well as a widening of the alveolar-arterial oxygen gradient, have been observed during

hyperoxic exposures. Monitoring serial changes in vital capacity has been proposed as a means of detecting and following injury from oxygen exposure. However, the practicality and cost-effectiveness of such testing remains unsubstantiated.

Radiographic Changes The chest radiographic findings of increased interstitial markings or alveolar filling are similar to those found in other causes of diffuse alveolar damage; the findings are nonspecific and are insensitive as early markers.

Potentiation of Oxygen Toxicity Susceptibility of cells or organisms to oxygen toxicity can be modified by factors other than intrinsic cellular antioxidant mechanisms. Many therapeutic drugs act synergistically with hyperoxia, accelerating free radical production and worsening oxygen toxicity. Bleomycin has been shown to increase lung injury and fibrosis through enhanced production of O2 .â&#x2C6;&#x2019; .

Potentiation of oxygen toxicity by disulfiram occurs through inhibition of cytosolic superoxide dismutase by diethyldithiocarbamate, which is produced in vivo from the conversion (reduction) of disulfiram. The metabolism of nitrofurantoin and paraquat results in production of superoxide or hydroxyl radicals, and O2 has been shown to increase their cytotoxicity. Variability of dietary intake can also modify oxygen tolerance. Protein malnutrition, as well as dietary deficiency of any of the antioxidant quenchers, may alter the response to hyperoxia. Protein deficiency is thought to potentiate toxicity from hyperoxia due to a lack of sulfur-containing amino acids which are crucial for GSH synthesis. The adverse effects of vitamin A and vitamin E deficiencies are also well described.

Prevention and Therapy As with other drugs, oxygen should be administered judiciously, in doses designed to achieve therapeutic efficacy with limited toxicity. Because early detection of oxygen toxicity has remained elusive and specific therapy is lacking, avoidance of pulmonary toxicity during oxygen therapy remains the cornerstone of management. The best approach is to monitor the efficacy of the inspired oxygen concentration and to adhere to guidelines to use doses that have not been found to be associated with major side effects.

The primary therapeutic goal associated with use of supplemental oxygen is assurance of adequate tissue oxygenation without use of toxic levels of Fio2 . A significant obstacle in achieving this goal centers around monitoring the efficacy of oxygen therapy and assessing the adequacy of tissue oxygenation. As noted previously, the clinical approach entails correction of arterial hypoxemia as the cause of tissue hypoxia and assessment of the response to supplemental oxygen administration through measurement of Pao2 or use of continuous, cutaneous, infrared pulse oximetry.

2629 Chapter 149

Extrapolations about the state of tissue oxygenation from measurement of vo2 using an indwelling pulmonary artery catheter can be used in the critical care setting. Transcutaneous estimations of tissue Po2 and, hence, intracellular oxygen sufficiency, remain experimental. Based upon general consensus, the following guidelines can be offered regarding oxygen administration at 1 atmosphere.

Oxygen in concentrations up to 100 percent can be administered in the transport and initial management of critically ill patients. In patients who are not on mechanical ventilation, evidence of respiratory depression should be monitored. If needed, an Fio2 of 1.0 can be used for up to 24 h without significant lung injury. During this period, management should be directed toward improving pulmonary gas exchange, optimizing oxygen delivery, and limiting tissue metabolic demands so that inspired O2 concentration can be decreased to the lowest possible levels.

Oxygen at an Fio2 of 0.5 or less can be administered safely to most patients for weeks, although factors specific to individual patients (e.g., prior bleomycin use) may dictate a lower tolerance. The maximal safe duration for oxygen exposures between an Fio2 of 0.5 and 1.0 is less certain, although these concentrations probably can be tolerated longer than 24 h. The safe upper limit of Fio2 for chronic oxygen therapy in the ambulatory setting is largely undefined.

SUMMARY Use of supplemental oxygen is a powerful tool in the management of critically ill patients as well as those with chronic cardiopulmonary disease, but it represents a double-edged sword. Concomitant with initiation of its use in management of hypoxemia, careful assessment for the underlying etiology of the hypoxemia and implementation of therapeutic measures aimed at its reversal should be undertaken. The proper prescription of oxygen is based upon general principles that are applied to the administration of any other drug. Knowledge of the various techniques of oxygen administration, establishment of clear therapeutic end points, monitoring of the efficacy of treatment, and awareness of the potential toxicity of oxygen are required.

SUGGESTED READING Barber RE, Lee J, Hamilton WK: Oxygen toxicity in man. A prospective study in patients with irreversible brain damage. N Engl J Med 283:1478–1484, 1970.

Beckman JS, Koppenol WH: Nitric oxide, superoxide, and peroxynitrite: The good, the bad, and the ugly. Am J Physiol (Cell Physiol ) 40:C1424–C1437, 1996.

Oxygen Therapy and Pulmonary Oxygen Toxicity

Caldwell PR, Lee WL Jr, Schildkraut HS, et al: Changes in lung volume, diffusing capacity, and blood gases in men breathing oxygen. J Appl Physiol 21:1477–1483, 1966.

Celli BR, MacNee W: Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 23:932–946, 2004.

Chance B: Reaction of oxygen with the respiratory chain in cells and tissues. J Gen Physiol 49:163–195, 1965.

Christopher KL, Spofford BT, Petrun MD, et al: A program for transtracheal oxygen delivery. Assessment of safety and efficacy. Ann Intern Med 107:802–808, 1987.

Cottrell JJ, Openbrier D, Lave JR, et al: Home oxygen therapy.

A comparison of 2- vs 6-month patient reevaluation. Chest 107:358–361, 1995.

Crapo JD: Morphologic changes in pulmonary oxygen toxicity. Annu Rev Physiol 48:721–731, 1986.

DesRosiers A, Russo R: Long-term oxygen therapy. Respir Care Clin N Am 6:625–644, 2000.

Freeman BA, Crapo JD: Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J Biol Chem 256:10986–10992, 1981.

Fulmer JD, Snider GL: American College of Chest Physicians (ACCP)—National Heart, Lung, and Blood Institute (NHLBI) Conference on Oxygen Therapy. Arch Intern Med 144:1645–1655, 1984.

Harabin AL, Homer LD, Weathersby PK, et al: An analysis of decrements in vital capacity as an index of pulmonary oxygen toxicity. J Appl Physiol 63:1130–1135, 1987.

Hoffman LA, Dauber JH, Ferson PF, et al: Patient response to transtracheal oxygen delivery. Am Rev Respir Dis 135:153– 156, 1987.

Jeffrey AA, Ray S, Douglas NJ: Accuracy of inpatient oxygen administration. Thorax 44:1036–1037, 1989.

Kacmarek RM, Dimas S (eds): Essentials of Respiratory Care.

St. Louis, Mosby, 2005.

Levi-Valensi P, Weitzenblum E, Pedinielli JL, et al: Threemonth follow-up of arterial blood gas determinations in candidates for long-term oxygen therapy. A multicentric study. Am Rev Respir Dis 133:547–551, 1986.

Lodato RF: Oxygen-toxicity. Crit Care Clin 6:749–765, 1990.

Lorrain-Smith J: The pathological effects due to increase of oxygen tension in the air breathed. J Physiol 24:19–35, 1899.

Meakins J: Observations on the gases in human arterial blood in certain pathological pulmonary conditions, and their treatment with oxygen. J Pathol Bacteriol 24:79–90, 1921.

Medical Research Council Working Party: Long-term domiciliary oxygen therapy in chronic hypoxia cor pulmonale complicating chronic bronchitis and emphysema. Lancet 1:681–686, 1981.

Nocturnal Oxygen Therapy Trial Group: Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. A clinical trial. Ann Intern Med 93:391–398, 1980.

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Odonohue WJ, Plummer AL: Magnitude of usage and cost of home oxygen-therapy in the United States. Chest 107:301– 302, 1995.

Sackner MA, Landa J, Hirsch J, et al: Pulmonary effects of oxygen breathing. A 6-hour study in normal men. Ann Intern Med 82:40–43, 1975.

Tarpey S: Long-term oxygen therapy. N Engl J Med 333:710– 714, 1995.

Van De Water JM, Kagey KS, Miller IT, et al:. Response of the lung to six to 12 hours of 100 per cent oxygen inhalation in normal man. N Engl J Med 283:621–626, 1970.

150 Pulmonary Pharmacotherapy Karen J. Tietze

Scott Manaker

I. BRONCHODILATORS β-Adrenergic Agonists Anticholinergics Methylxanthines Magnesium Sulfate Inhaled Diuretics II. ANTI-INFLAMMATORY AGENTS Corticosteroids Corticosteroid-Sparing Agents Mast Cell Stabilizers Leukotriene Antagonists and Inhibitors Immunoglobulin E Antibody III. MUCOKINETIC AGENTS Dornase Alpha N-Acetylcysteine

A wide spectrum of therapeutic agents are currently employed in the treatment of respiratory disorders, including obstructive lung diseases. This chapter reviews the rationale for, and clinical use of, these agents in current clinical practice. A brief discussion of potentially useful therapeutic drug strategies for the future is also provided.

BRONCHODILATORS Pharmacologic management of obstructive airway diseases is based heavily upon bronchodilation produced by βadrenergic agonists, muscarinic antagonists, and methylxanthines. In addition, magnesium and inhaled diuretics may ultimately prove to be effective bronchodilators suitable for clinical use.

β-Adrenergic Agonists The β-adrenergic agonists mimic the actions of norepinephrine at neuroeffector and synaptic junctions. Norepi-

Iodinated Agents Sodium Bicarbonate Guaifenesin IV. PHYSIOLOGICAL REPLACEMENTS α1 -Antitrypsin Pulmonary Surfactant V. RESPIRATORY STIMULANTS Acetazolamide Almitrine Methylxanthines Doxapram Medroxyprogesterone Protriptyline

nephrine is the major neurotransmitter in the sympathetic nervous system; therefore, this class of drugs is referred to as adrenergic agonists or sympathomimetics. Adrenergic receptor stimulation catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′ 5′ -adenosine monophosphate (cAMP) by activating adenyl cyclase, a cofactor in the production of cAMP. The increase in cAMP triggers the intracellular events that mediate pulmonary and extrapulmonary responses. The two major types of adrenergic receptors are the alpha and beta receptors; at least two alpha and two beta receptor subtypes have been identified. The β-adrenergic agonists (Table 150-1) are indicated in the treatment of bronchospasm associated with acute and chronic asthma, bronchitis, emphysema, exercise, and other obstructive pulmonary diseases. Selection of a specific agent and route of administration depends on underlying patient risk factors and the receptor specificity of the drug.

Pharmacology Adrenergic receptor stimulation produces a wide range of responses, depending on the effector organ and the specific

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 150-1 Adrenergic Agonists Receptor Activity

Dosage Forms

Alpha

Beta1

Beta2

Duration

MDI

+

+ + +

+ + +

Very Short Short Short

X∗,†

Resorcinols Metaproterenol Terbutaline

± ±

++ +++

Short Short

X

Saligenins Albuterol Levalbuterol Salmeterol

± ± ±

+++ +++ +++

Short Short Long

X‡ X§

Other Pirbuterol Formoterol

± ±

+++ +++

Short Long

X†

DPI

Neb

Inj

X

X X

Oral

Agent Catecholamines Epinephrine Isoproterenol Isoetharine

X

X X

X X

X#,∗∗ X# X#,¶,∗∗

X

X

Duration: short = 2 to 6 h; long = 8 to 12 h Note: Abbreviation: MDI = metered dose inhaler; Neb = solution for nebulization; Inj = injectable dosage form; X = marketed dosage formulation; ± = present but minimal effect; + = mild effect; ++ = considerable effect; + + + = major effect. ∗ Nonprescription product. † Contains chlorofluorocarbons. ‡ Some products contain chlorofluorocarbon and some products contain hydrofluoroalkane. § Contains hydrofluoroalkane. # Immediate-release dosage formulation. ¶ Sustained-release dosage formulation. ∗∗ Syrup.

receptor. Although bronchial smooth-muscle relaxation results from β2 -adrenergic receptor stimulation, none of the currently marketed agonists are completely specific for β2 -adrenergic receptors.

The α-adrenergic receptor is generally associated with constrictor/contractor responses, including constriction of arteries and veins and contraction of the uterus, radial and sphincter muscles of the iris, urinary bladder, and stomach sphincters. β1 -Adrenergic receptor stimulation increases heart rate, atrial and ventricular contractility, and cardiac conduction velocity. Effects from β2 -adrenergic receptor stimulation include relaxation of bronchial and uterine smooth muscle, dilatation of arteries and veins, and several metabolic effects, including glycogenolysis, gluconeogenesis, and induction of hepatic pancreatic beta cell secretion.

Structure-Activity Relationships The parent compound for the adrenergic agonists, phenylethylamine (Fig. 150-1), consists of a benzene ring and

an ethylamine side chain. Substituents can be added to the alpha or beta carbons of the ethylamine side chain, the terminal amine group, or one or more of the carbons in the aromatic ring.

The basic chemical structures of the adrenergic agonists include the catecholamines, resorcinols, and saligenins (Fig. 150-1). The catecholamines were the first adrenergic agonists to be marketed. The resorcinols (metaproterenol and terbutaline) have hydroxyls at positions 3 and 5 of the aromatic ring. This promotes oral bioavailablity and prolongs the duration of effect by protecting the molecules from catechol-o-methyl transferase degradation. Terbutaline, with a large substituent on the terminal amine, is selective for β2 -adrenergic receptors. The saligenins (albuterol and salmeterol) have a hydroxyl at position 4, various carbon moieties on position 3 of the aromatic ring, and large substituents on the terminal amine. These large substituents confer a longer duration of action and β2 -adrenergic receptor specificity, particularly for salmeterol. Salmeterol’s long side chain results in increased lipophilicity, protecting the structure from

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CPC β α D5 6 G 1 C O CH 2 O CH 2 O NH 2 C4 M 3 2 J COC Phenylethylamine

CPC D G C O CH 2 O CH 2 O NH 2 HO O C M J COC D HO Catecholamine HO G CPC D G C C O CH 2 O CH 2 O NH O R M J COC D Resorcinol HO CPC D G C O CH 2 O CH 2 O NH O R HO O C M J COC D Saligenin R

OH CPC A D G HO O C C O CH O CH 2 O NH 2 M J COC D HO Epinephrine HO G OH CH 3 CPC A A D G C C O CH O CH 2 O NH O C O CH 3 M J A COC CH 3 D Terbutaline HO OH CPC CPC A D G D G C O CH O CH 2 O NH O (CH2 )6 O O O(CH2 )4 O C C HO O C M J M J COC COC D Salmeterol CH 2 D HO

Figure 150-1 Structures of adrenergic agonists.

metabolism by catechol-o-methyl transferase and allowing the compound to bind both to the beta receptor and to an adjacent exoreceptor site. In theory, the exoreceptor binding site anchors the drug close to the beta receptor, further prolonging its action. Albuterol is a 1:1 mixture of the Rand S-enantiomers. The R-albuterol enantiomer is the active moiety; the S-albuterol enantiomer is inactive. Although early animal and clinical studies suggested that the S-albuterol enantiomer might antagonize the effects of the R-albuterol enantiomer, a clear clinical advantage of levalbuterol, the first pure enantiomer (R-albuterol) has not been demonstrated. Formoterol is a phenylethanolamine derivative with a phenyl-isopropyl group attached to the terminal amine.

Physicochemical properties account for formoterol’s long duration of action. Pirbuterol differs from all other adrenergic agonists in that the aromatic ring is a pyridine, instead of a benzene.

Drug Delivery The β-adrenergic agonists may be administered systemically or by inhalation; however, not all drugs are marketed in every dosage form. Systemic dosage forms include oral, subcutaneous, and intravenous preparations. Systemic administration decreases the β2 -adrenergic receptor selectivity of the drug due to exposure to various metabolic enzymes, including catechol-o-methyl transferase, monoamine oxidase, and sulfatase. These enzymes change the chemical structure of the drug, decreasing the β2 -adrenergic receptor selectivity. The oral route of administration is generally reserved for patients who cannot successfully use metered-dose inhalers (e.g., children or the elderly). Sustained-release, oral dosage

forms may be useful in controlling nocturnal symptoms of asthma, although not as effectively as the long-acting, inhaled adrenergic agonists. The subcutaneous route is generally reserved for patients too dyspneic to inhale the drug, and parenteral drug administration is generally employed for pediatric patients.

The preferred route of β-adrenergic agonist administration is by inhalation. Local application of small amounts of drug directly to the airways decreases the amount available for systemic absorption, minimizing systemic side effects. Inhaled β-adrenergic agonists are available in several dosage forms, including wet aerosols, aerosols from metered-dose inhalers, and dry powder forms. Most commonly, wet aerosols are delivered by jet or ultrasonic nebulizer, whereas metereddose inhalers are primarily marketed as “press and breathe” devices. Historically, nebulized drug delivery was standard practice for children, emergency treatment of asthma exacerbations, hospitalized patients, and severely obstructed patients. However, nebulized drug delivery is labor intensive; significant cost savings can be realized, without sacrificing efficacy, by using metered-dose inhalers coupled with spacer devices.

Drug delivery by metered-dose inhaler is highly dependent on administration technique. Less than 10 percent of the dose is delivered to the lung using optimal inhalation technique; the rest of the drug is deposited in the mouth.

Spacer devices eliminate the split-second timing necessary with proper metered-dose inhaler technique and decrease the amount of drug deposited in the oropharynx (an important factor with inhaled corticosteroids); however, they do not provide a therapeutic advantage over correct use of a metered-dose inhaler alone.

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Metered-dose inhalers initially contained chlorofluorocarbon (CFC) propellants. In 1978, international concerns regarding the ozone-depeleting properties of CFCs led to a generalized ban on CFC-containing products. In 2005, the Food and Drug Administration (FDA) announced that CFCcontaining MDIs, previously exempt from the ban on CFC production and importation, will not be produced, marketed, or sold in the United States after December 31, 2008. CFCcontaining MDIs are being replaced by hydrofluoroalkane (HFA)-containing MDIs and a variety of dry powder inhalers (DPIs).

Clinical Use The β2 -adrenergic agonists are considered first-line drugs in the treatment of both asthma and chronic obstructive pulmonary disease (COPD). In asthma, the short-acting inhaled β2 -adrenergic agonists are preferred for treating acute symptoms and for preventing exercise-induced bronchospasm.

The subcutaneous route of administration is generally reserved for patients unresponsive to frequent, high-dose, inhaled β2 -adrenergic agonists; uncooperative patients; or patients too severely dyspneic to inhale the dose. Subcutaneous or parenteral administration should not be used in patients with angina or a recent history of myocardial infarction.

Oral adrenergic agonists may be appropriate for children too young to cooperate with inhaled drug administration; sustained-release, oral adrenergic agonists decrease nocturnal symptoms, but they are less effective than long-acting β2 -adrenergic agonists.

In COPD, β2 -adrenergic agonists provide modest symptomatic relief and improvement in pulmonary function. Long-acting inhaled β2 -adrenergic agonists are standard bronchodilator therapy for patients with moderate and severe COPD. Standard doses of inhaled β2 -adrenergic agonists appear as effective as inhaled anticholinergic drugs for relief of acute exacerbations of COPD. The value of subcutaneous drugs and high-dose short-acting bronchodilators in the management of COPD has not been determined.

The intensity and duration of response to β2 adrenergic agonists is dose- and frequency dependent. For patients with asthma, higher doses result in incrementally greater bronchodilation. The dose-response relationships are less well defined for COPD. The dose-response curve in asthma led to the development of intensive inhaled β2 -adrenergic agonist drug regimens for the treatment of severe, acute exacerbations. Typically, the nebulized drug is administered every 20 min for three to six doses; some patients respond better to continuous nebulized drug delivery.

These regimens are generally well tolerated, although cardiac stimulation is common.

The long-acting β2 -adrenergic agonists are add-on agents for patients with moderate or severe asthma when usual doses of inhaled corticosteroids are inadequate and for patients with moderate to severe COPD. The long-acting β2 -adrenergic agonists are also alternate add-on agents for patients with symptoms of nocturnal asthma. The long-acting

β2 -adrenergic agonists have no role in the treatment of acute asthma or an acute exacerbation of COPD; all patients should have a short-acting inhaler and should be instructed on how and when to use each type of β2 -adrenergic agonist.

Tolerance Tolerance, or receptor subsensitivity, is defined as a decreased response to receptor stimulation. Although tolerance to the nonbronchodilator effects of β-adrenergic agonists, including tremor, tachycardia, prolongation of the QTc interval on the electrocardiogram, hypoglycemia, hypokalemia, and vasodilator response, has been demonstrated, data on tolerance to the bronchodilator effects of β-adrenergic agonists are limited and conflicting.

Tolerance to the long-acting drugs may make patients less responsive to short-acting β2 -adrenergic agonists during an acute attack or may mask inadequate control of inflammation. Although the mechanism for tolerance to the long-acting drugs has not been precisely identified, one hypothesis is that prolonged drug-receptor interaction may induce receptor down-regulation. Concomitant diseasemodifying drug therapy (e.g., corticosteroids) may also modify the development of tolerance by modulating adrenoceptor function.

Safety The β2 -selective adrenergic agonists produce less cardiovascular toxicity than do the nonselective agents, but β2 selectivity does not protect from all adverse events. Biochemical abnormalities associated with the β2 -adrenergic agonists include hyperglycemia, hyperinsulinemia, lipolysis, hypokalemia, hypomagnesemia, and lactic acidosis. These side effects are most pronounced with parenteral and oral drug administration; they are minimal with usual doses of inhaled agents. Furthermore, the biochemical abnormalities are more pronounced in drug-na¨ıve normal volunteers than in asthmatic patients, suggesting that tolerance develops following chronic drug administration. β2 -adrenergic agonists cause dose- and routedependent hyperglycemia by stimulating glycogenolysis and gluconeogenesis. This effect may be clinically most important in asthmatic patients with diabetes mellitus or during pregnancy. β2 -adrenergic agonists increase plasma insulin by directly stimulating pancreatic islet cells; indirect increases occur secondary to the hyperglycemic response. β2 adrenergic agonists induce the release of free fatty acids from adipose tissue. Although hyperinsulinemia and high concentrations of free fatty acids have been linked with cardiovascular morbidity and mortality, tolerance minimizes these effects. β2 -adrenergic receptor stimulation also induces muscle glycogenolysis, increasing lactate production.

The β2 -adrenergic agonists induce hypokalemia by directly stimulating the uptake of potassium into skeletal muscle cells. β2 -adrenergic receptor stimulation induces the cellular uptake of magnesium; hypomagnesemia may induce arrhythmias or worsen symptoms of coronary artery disease. Other

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adverse β2 -adrenergic agonist effects include: (a) an increased baseline tremor by creating an imbalance in fast- and slowtwitch muscle groups; (b) tachycardia by direct chronotropy and through reflex peripheral vasodilatation and decreased venous return; and (c) central nervous symptoms, such as appetite suppression, headache, nausea, and sleep disturbances.

The nervousness reported by many patients is probably a response to the peripheral tremors rather than a result of direct stimulation of the central nervous system. β-adrenergic agonist use has increased coincident with the increase in asthma morbidity and mortality in the United States and other countries. This observation has promoted interest in the possible relationship between asthma mortality and use of these agents. The first link was made during the 1960s when the newly marketed nonselective βadrenergic agonist isoproterenol was associated with an increase in asthma morbidity and mortality in the United Kingdom. Although never conclusively proved, the increase in asthma morbidity and mortality was blamed partly on the lipolytic effect of the drug, which increases the potential for myocardial ischemia, and partly on the high-dose formulation. In the 1970s, when fenoterol was linked to an increased death rate in New Zealand, part of the increased mortality was attributed to the hypokalemic effect of fenoterol.

Interest in the association between regular use of shortand long-acting β-adrenergic agonists and asthma morbidity and mortality was heightened by several reports that use of multiple fenoterol or albuterol inhalers per month was associated with an increased risk of death. A subsequent metaanalysis of case-control studies reported only a very weak, although statistically significant, relationship between the use of nebulized β agonists and death from asthma. Although this weak relationship was more likely in adults than adolescents, data from large, well-designed trials are needed to assess accurately the risk of death associated with long-acting β-adrenergic agonists.

Anticholinergics Atropine and other anticholinergic alkaloids from plant extracts have been used for thousands of years to relieve respiratory symptoms in humans with airway diseases. Historically, clinical use of atropine and atropinelike agents has been limited by anticholinergic side effects, including dry mouth and skin, tachycardia, and meiosis; higher doses produce difficulties in speaking, swallowing, urinating, and mentating, as well as other neurologic side effects.

Pharmacology Muscarinic receptors control airway smooth muscle function.

Activation of airway M1 and M3 muscarinic receptors results in bronchial smooth muscle contraction and mucus secretion. M2 “autoreceptor” activation results in decreased acetylcholine (Ach) release; blockade of M2 receptors increases airway Ach. The ideal anticholinergic drug would selectively

Pulmonary Pharmacotherapy

block M1 and M3 receptors and have no effect on M2 receptors.

Quaternary ammonium atropine derivatives were developed to avoid the systemic side effects associated with tertiary derivatives, such as atropine. The quaternary ammonium compounds do not penetrate the blood-brain barrier, are minimally absorbed systemically, and have longer durations of action than atropine. Ipratropium bromide (FDA approved in 1998) and tiotropium bromide (FDA approved in 2004) are closely related quaternary ammonium drugs that differ in terms of muscarinic receptor binding affinities and receptor-drug complex half-lives. Ipratropium bromide nonselectively blocks M1 , M2 , and M3 receptors. Tiotropium bromide has a greater affinity for muscarinic receptors than ipratropium bromide, but it dissociates rapidly from M2 receptors, resulting in prolonged M1 - and M3 -drug complex half-lives compared to ipratropium bromide. Inhalation of ipratropium bromide produces bronchodilation in seconds to minutes, with a peak effect after 1 to 2 h. Inhalation of a single dose of tiotropium bromide produces a peak FEV1 in 1 to 3 h; the duration of effect is about 32 h. The trough FEV1 increases after multiple doses, reflecting carryover bronchodilation from the prolonged half-life.

Clinical Use Ipratropium bromide and tiotropium bromide are most efficacious in patients with COPD, including emphysema and chronic bronchitis. In such patients, ipratropium bromide and tiotropium bromide are equally or more effective than β-adrenergic agonists in increasing FEV1 and reducing airway resistance. Limited data suggest that tiotropium bromide may be superior to ipratropium bromide and the long-acting β2 -adrenergic agonist, salmeterol, in long-term management of moderate to severe COPD. The increased cost of tiotropium bromide may be offset by reduced overall health care expenditures. Chronic inhalation of ipratropium bromide or tiotropium bromide does not lead to development of tolerance or tachyphylaxis.

The combination of inhaled anticholinergic and βadrenergic agonist produces greater improvement in FEV1 and specific conductance than does administration of either agent alone. Most large-scale studies of patients with COPD demonstrate that the addition of oral corticosteroids does not increase maximal flow over that achieved by the administration of a β-adrenergic agonist with inhaled ipratropium bromide.

In contrast, ipratropium bromide is less effective than β-adrenergic agonists in the treatment of chronic asthma, and the role of tiotropium is not established. Some asthmatics may gain more relief of bronchospasm from inhalation of ipratropium bromide than β-adrenergic agonists. However, this unusual response requires initial evaluation with an empiric trial of ipratropium bromide and should be reserved only for patients whose moderate to severe asthma is difficult to control. A recent meta-analysis of 32 randomized controlled trials of anticholinergics in treatment of children

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and adults with acute asthma found that compared with use of inhaled β2 -adrenergic agonists alone, addition of inhaled anticholinergics significantly reduced hospitalizations and increased spirometric parameters 1 to 2 h after treatment.

Safety Consistent with their very low systemic bioavailability, both ipratropium bromide and tiotropium bromide are remarkably free of side effects. Transient dry mouth of mild intensity has been reported in 16 percent of patients inhaling tiotropium bromide and in up to 10 percent of patients inhaling ipratropium bromide. Side effects of tiotropium bromide typically appear after 3 to 5 wk of continued use, reflecting the slow linear tissue accumulation of the drug. Neither ipratropium bromide nor tiotropium bromide change pulmonary hemodynamics, ventilation-perfusion matching, oxyhemoglobin saturation, heart rate, or urinary flow; however, blurred vision and pupillary dilation may occur if either drug inadvertently contacts the eye. Both drugs should be used with caution in patients with myasthenia gravis, narrowangle glaucoma, prostatic hyperplasia, or bladder neck obstruction. Tiotropium bromide should be used with caution in patients with moderate to severe renal insufficiency (Clcr less than 30 to 50 ml/min).

Although systemic administration of muscarinic anticholinergics decreases mucus formation, neither ipratropium bromide nor tiotropium bromide have much effect on respiratory secretions. Ipratropium bromide inhalation produces a clinically insignificant decrease in mucus viscosity and does not change mucus transport or ciliary beat frequency. Tiotropium bromide does not appear to adversely affect mucus transport.

Concomitant use of drugs with anticholinergic properties may increase the risk of side effects with either ipratropium bromide and tiotropium bromide.

Methylxanthines Theophylline and aminophylline, the ethylenediamine salt of theophylline, are used to treat asthma and the obstructive component of COPD. Other pulmonary diseases for which theophylline may have a role include obstructive sleep apnea, apnea of prematurity, and airway obstruction secondary to pulmonary edema.

Potentially beneficial therapeutic effects of theophylline include bronchial smooth-muscle relaxation, enhanced mucociliary transport, inhibition of mediator release, suppression of permeability edema, decreased pulmonary hypertension, increased right ventricular ejection fraction, improved diaphragmatic contractility, and central stimulation of ventilation. Although bronchial smooth-muscle relaxation is most likely responsible for the majority of theophylline’s beneficial therapeutic effects in the treatment of obstructive lung disease, the anti-inflammatory and diaphragmatic effects may contribute to the overall efficacy of the drug.

Pharmacology Despite having been marketed and studied for several decades, the precise cellular mechanism of theophylline’s bronchodilating action is unknown. It is unlikely that theophylline bronchodilates via adenosine antagonism. However, many of the extrapulmonary effects associated with theophylline, including cardiac stimulation, anxiety, tremors, seizures, diuresis, gastric secretion, and free fatty acid release have been attributed to adenosine antagonism.

Anti-inflammatory Effects

Anti-inflammatory actions attributed to theophylline include inhibition of neutrophil and mononuclear cell migration, leukotriene B4 generation, T-cell proliferation, and lymphokine production; increased activity and number of suppressor T cells; and stabilization or inactivation of macrophages and platelets. The anti-inflammatory effect of theophylline appears to be qualitatively different than that of corticosteroids, resulting from the selective inhibition of phosphodiesterase IV at low serum theophylline concentrations. Although there has been a great deal of interest in the immunomodulatory effect of the methylxanthines, the clinical relevance of this effect remains unknown.

Diaphragmatic Effects

Theophylline increases diaphragmatic strength and contractility, actions potentially mediated by transmembrane calcium movement. Most data are from in vitro studies or from normal volunteers; results from controlled clinical trials in patients with COPD are limited and conflicting. Theophylline may be potentially most beneficial in patients with hypoxic and hypercapnic COPD when dosed to midtherapeutic plasma concentrations.

Structure-Activity Relationships Theophylline and aminophylline are 1,3-dimethylxanthines.

Other methylxanthines, including theobromine (3,7dimethylxanthine) and caffeine (1,3,7-trimethylxanthine), differ in the positions of the methyl substituents on the xanthine molecule. N-1 substituents are important for adenosine antagonism, whereas N-3 substituents augment bronchodilator activity. Substituents at N-7 decrease bronchodilator potency; substituents at N-9 decrease the potency of the xanthine.

Clinical Use For bronchodilation, the target theophylline serum concentration is generally accepted as 10 to 20 mg/L. The therapeutic range for other effects (e.g., anti-inflammatory properties, enhanced diaphragm capability, respiratory stimulation) may be different, prompting interest in a lower (5 to 15 mg/L) target range. Approximately 50 percent of maximal bronchodilation is achieved at a serum level of 10 mg/L; only an additional 17 percent increase is observed at 20 mg/L. The precise clinical role of theophylline is unclear. Relatively noncontroversial indications include severe

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bronchodilator-dependent COPD; severe, systemic, corticosteroid-dependent asthma; nocturnal asthma uncontrolled with adrenergic agonists; and acute, severe asthma progressing to respiratory failure.

Safety Adverse effects associated with theophylline include nausea, vomiting, diarrhea, irritability, insomnia, supraventricular tachycardia, ventricular arrhythmias, and seizures. Although the risk of adverse effects increases at serum concentrations greater than 20 mg/L, patients also may experience serious adverse effects within the usual therapeutic range. Because of this narrow therapeutic index, emphasis should be placed on achieving the midtherapeutic range for serum theophylline levels (10 to 15 mg/L), while accepting a broader range (5 to 20 mg/L) as appropriate.

Magnesium Sulfate Magnesium blocks calcium entry into smooth-muscle cells, thereby relaxing muscle fibers. Several small trials randomized patients upon presentation to the emergency room to receive either 2 g of magnesium sulfate intravenously over 20 min or placebo, in addition to standard therapy. Intravenous magnesium administration demonstrated no overall beneficial effect, although in retrospective analysis, the degree of airflow obstruction and rate of hospital admission were reduced for patients with severe asthma.

Subsequent case reports and small series suggested similar results could be obtained with inhalation of various doses of inhaled magnesium. The few randomized clinical trials reported to date seem to demonstrate similar small reductions in the degree of airflow obstruction and rate of hospital admission following magnesium sulfate inhalation in patients with severe asthma presenting to the emergency room setting.

Despite these limited clinical data demonstrating efficacy of magnesium sulfate, the recommendation from the Global Initiative for Asthma is that intravenous magnesium sulfate be considered in therapy of acute severe asthma. Recent survey data reveal that 21 percent of children receiving intensive care for asthma in the United States between 2000 and 2003 received parenteral or inhaled magnesium sulfate therapy during their hospitalization.

Inhaled Diuretics While inhaled magnesium may act as a direct bronchodilator, inhaled diuretics may act upon the airways through a variety of mechanisms to achieve bronchodilation, reduce mucosal inflammation, or interrupt sensory nerve reflex responses to irritiants. Inhaled furosemide has no role in the treatment of exacerbations of acute asthma, and additional information is needed before use of inhaled diuretics can be recommended for prevention of exercise- or irritant-induced asthma.

Pulmonary Pharmacotherapy

ANTI-INFLAMMATORY AGENTS Corticosteroids are the mainstay of current antiinflammatory regimens; other agents in clinical use include mast cell stabilizers, leukotriene receptor antagonists, and synthetic inhibitors of leukotrienes.

Corticosteroids Corticosteroids are cortisollike drugs that influence metabolic pathways and have an anti-inflammatory effect. By reducing airway inflammation, corticosteroids are clearly useful in the management of asthma, but they have a more limited and targeted role in the management of COPD. Pharmacology Glucocorticoids (i.e., cortisol) are produced by the adrenal cortex via the hypothalamic-pituitary axis in response to physical and emotional distress. Although the usual daily secretion of cortisol is approximately 10 to 20 mg, as much as 400 to 500 mg per day can be secreted during periods of severe stress. Although the cellular mechanisms are incompletely understood, corticosteroids stimulate the transcription and creation of certain proteins, such as lipocortin-1, and inhibit DNA transcription, resulting in decreased cytokine production. The clinical effects of corticosteroids are delayed for several hours following administration, reflecting the time needed to create new proteins or inhibit cytokine production. Leukocytes, mucous glands, and blood vessels are glucocorticoid targets.

The inhaled glucocorticoids differ in potency, lipophilicity, relative receptor binding affinity, and pharmacokinetics. Since glucocorticoid preparations are marketed and prescribed in relatively equipotent doses, potency may be the least important differentiating characteristic. However, lipophilicity and relative glucocorticoid receptor binding and dissociation affinities are important discriminants among the inhaled corticosteroids. These characteristics determine the rate of receptor association and dissociation and the amount of drug absorbed systemically following inhalation. All corticosteroids undergo hepatic metabolism. Orally administered drugs, including drug swallowed after inhalation, undergo significant first-pass metabolism.

Mometasone furoate and fluticasone propionate, with an esterified lipophilic group at the 17-Îą positon, are the most lipophilic of the marketed inhaled corticosteroids; beclomethasone dipropionate, budesonide, triamcinolone acetonide, and flunisolide follow in descending order of lipophilicity. The relative receptor binding affinity and receptor association follow the same order as lipophilicity.

Mometasone furoate differs from other inhaled corticosteroids in that it is less specific for glucocorticoid receptors; in addition, the drug demonstrates agonist activity at progesterone receptors and partial agonist activity at mineralocorticoid receptors.

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Clinical Use Corticosteroids are the cornerstone of therapy in the treatment of asthma; the role of glucocorticoid therapy in COPD is more limited.

inhaled corticosteroids. Twice-daily dosage regimens may be more effective for patients with severe or difficult-to-control asthma.

Chronic Obstructive Pulmonary Disease

Asthma

The role of airway inflammation in asthma is well established, and high-dose systemic (parenteral or oral) corticosteroids are standard therapy for patients experiencing severe acute exacerbations of asthma. Parenteral administration of corticosteroids is often used preferentially due to the inability of some patients to swallow medications while in respiratory distress or because of lack of oral access after intubation.

Dose-ranging studies of intravenous corticosteroids have not established a minimum effective dose, although as little as 120 mg/d of methylprednisolone (in divided doses administered every 6 h) is effective in asthmatic adults having an acute exacerbation. The time to initial response, as evidenced by augmentation of FEV1 with bronchodilator administration, begins as early as 1 h after corticosteroid administration; maximal response is achieved in 8 to 12 h. Parenteral corticosteroid therapy is usually maintained for 24 to 72 h, with subsequent conversion to oral prednisone at 60 mg daily when the FEV1 reaches a threshold of 50 percent of predicted normal. This dose may be maintained for 2 to 7 d, followed by gradual tapering of the dose over 1 to 3 wk. Parenteral methylprednisolone is emerging as the corticosteroid of choice, due to its lower mineralocorticoid and greater glucocorticoid effects than hydrocortisone.

Oral corticosteroid therapy is seldom indicated for chronic stable asthma. Oral therapy is maintained at the lowest dose possible to sustain control of symptoms and optimize peak expiratory flow in conjunction with inhaled β2 -adrenergic agonists. Hydrocortisone, methylprednisolone, or prednisone are most commonly used. Unlike prednisone, the first two agents do not require hepatic metabolism for therapeutic activity and are preferred in patients with significant liver disease.

Inhaled corticosteroids offer direct delivery to the lung and reduced risk of systemic effects. To achieve the same effect as higher potency agents, the lower potency agents are given in higher doses; adverse effects are more likely to occur.

The combination of an inhaled corticosteroid and a long-acting bronchodilator is better than either agent alone in terms of improving lung function and preventing asthma exacerbations; in patients with moderate-to-severe asthma, the combination of low-dose inhaled corticosteroid appears to be as effective as high-dose inhaled corticosteroid alone.

Poor adherence with inhaled corticosteroid regimens is an ongoing issue. Inhaled corticosteroids initially required four-times-a-day dosing schedules, but they are now usually prescribed twice daily. Mometasone furoate, the newest inhaled corticosteroid, is FDA approved for once daily administration. Although data are limited, patients with stable mild to moderate asthma might benefit from a trial of once-daily

The mechanism underlying the beneficial effects of corticosteroids in COPD is not fully known, but changes in inflammatory gene transcription and modulation of β2 -adrenergic receptor function appear to play a role.

No evidence exists that systemic corticosteroids prevent exacerbations in patients with stable COPD or that steroid responsiveness can be predicted. A common clinical practice has been to test steroid response by measuring the change in FEV1 following a trial of systemic corticosteroids and then limiting subsequent corticosteroid therapy to steroid responders.

However, in a 3-y, large, randomized, double-blind, placebocontrolled prospective trial, no significant relationship between initial steroid response and subsequent FEV1 decline was found.

Short courses (10 to 15 d) of moderate doses (40 mg/d of prednisone) of systemic corticosteroids in combination with standard bronchodilator therapies are effective for treating acute exacerbations of COPD in outpatients, inpatients, and patients in the emergency room who have moderate or severe COPD. However, the role of systemic corticosteroids in the treatment of patients with COPD who are receiving mechanical ventilation is unknown. Chronic maintenance therapy with inhaled corticosteroids reduces the incidence of acute exacerbations by 20 to 30 percent and improves health status in patients with stage III or IV COPD and a history of frequent exacerbations.

Definitive data regarding the clinical usefulness of combining inhaled corticosteroids and long-acting bronchodilators are lacking. Guidelines published in 2004 recommend the combination of inhaled corticosteroid and long-acting bronchodilator for patients with severe or very severe disease and frequent exacerbations.

Safety Short-term use (less than 14 d) of systemic corticosteroids is associated with mild glucose intolerance, fluid retention that may progress to edema and hypertension, proximal muscle weakness (especially with large parenteral doses), and mood alteration. Long-term systemic corticosteroids prolong the short-term effects; in addition, peptic ulcer disease, cataracts, increased risk of infection, and impaired wound healing occur. Truncal obesity, hirsutism, acne, moon-shaped facies, striae, and ecchymoses contribute to a cushingoid appearance. Disruption of bone metabolism predisposes patients to osteoporosis and resultant vertebral and long-bone fractures; inhibition of long-bone growth is the major complication in children who receive systemic corticosteroids.

Suppression of the hypothalamic-pituitary-adrenal axis diminishes body cortisol stores, which, in turn, reduces the capacity of the body to confront stress, such as trauma, surgery, or infection.

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Inhaled corticosteroids are less systemically bioavailable due to poor absorption from the tracheobronchial tree.

The most common adverse effect is local irritation of the oropharynx, cough, and bronchospasm. Dysphonia may arise from vocal cord myopathy induced by the presence of corticosteroid in the oropharynx. Thrush is easily avoided by rinsing the mouth after each use of a corticosteroid inhaler, using a spacer device to decrease deposition of drug particles in the mouth, and keeping the inhaler mouthpiece clean. Newer inhaled corticosteroids, such as fluticasone, undergo extensive first-pass metabolism to inactive substances, thereby decreasing concentrations of active drug and the potential for systemic adverse effects. Long-term studies of inhaled corticosteroids have not documented significant adrenal suppression.

Steroid Resistance Patients with asthma who are unresponsive to usually sufficient doses of corticosteroids are described as steroid resistant.

Steroid resistance has been formally defined by a smaller than 15 percent increase in FEV1 after 7 d of oral prednisolone administered at a dose of 20 mg daily in bronchodilatorresponsive asthmatics. Steroid resistance must be distinguished from steroid dependency, which is usually defined as the need for systemic corticosteroids for maintaining control of asthma.

Steroid resistance may involve reduced metabolism of oral corticosteroids to the active compound or accelerated drug clearance. An impaired cellular response to corticosteroids has been observed in steroid-resistant asthmatics, and altered receptor binding or the presence of antilipocortin antibodies may contribute to the phenomenon.

Corticosteroid-Sparing Agents Chronic systemic corticosteroid therapy required for the treatment of severe airflow obstruction often results in numerous side effects. Therefore, many anti-inflammatory agents have been evaluated in an effort to identify alternatives to systemic corticosteroid therapy.

Troleandomycin Since the 1960s, anecdotal clinical observations suggested that the macrolide antibiotic, troleandomycin, might reduce corticosteroid requirements in patients with severe asthma by decreasing steroid metabolism. However, results from doubleblind, randomized trials are mixed. To date, the weight of evidence suggests that troleandomycin has little or no clinical effect at relieving airway obstruction or inflammation independent of its effects on corticosteroid metabolism. Troleandomycin has little role in the current therapy of severe, steroid-dependent asthma.

Methotrexate From initial observations in patients with rheumatoid arthritis and coexistent asthma, methotrexate therapy appeared

Pulmonary Pharmacotherapy

to ameliorate both asthmatic and arthritic symptoms. Currently, no clear documentation exists of the clinical efficacy of methotrexate administration in severe, steroid-dependent asthma. Due to significant side effects, potentially fatal complications and long-term toxicity concerns, prudency argues for limiting methotrexate administration in severe, steroiddependent asthmatics to empiric trials in individual patients or investigations in large-scale, controlled clinical trials.

Cyclosporine Used widely in organ transplantation, cyclosporine inhibits lymphokine synthesis, thereby blocking the activation of T cells. The absence of significant drug interactions with β-adrenergic agonists, corticosteroids, or theophylline makes cyclosporine particularly attractive as an anti-inflammatory agent for use in asthma. However, only one of three small, double-blind, placebo-controlled studies suggested that cyclosporine increased peak expiratory flow and FEV1 , reduced exacerbations of airway obstruction, or reduced oral prednisolone dosage by over 60 percent. Hypertrichosis, hypertension, reversible nephrotoxicity, and a large number of nonspecific side effects limit widespread use of cyclosporine in the management of asthma.

Other Agents The search continues for anti-inflammatory agents with potential efficacy in asthma. A broad spectrum of agents have been touted, including gold salts, pooled immunoglobulins, azathioprine, colchicine, dapsone, hydroxychloroquine, ketotifen, nonsteroidal anti-inflammatory agents, and inhaled heparin. The original studies purporting the efficacy of these various agents comprise mainly anecdotal reports or small case series. Use of these drugs in obstructive airway disease should be restricted to well-designed, controlled clinical trials.

Mast Cell Stabilizers Cromolyn sodium and nedocromil exert anti-inflammatory actions by stabilizing mast cells. This blockade of mast cell degranulation prevents inflammatory mediator release, which is partially responsible for the bronchoconstriction and epithelial injury that are characteristic of asthma.

Cromolyn Sodium Cromolyn sodium was the first mast cell stabilizer to be approved for clinical use in asthma and is widely employed in pediatric asthmatics.

Pharmacology

Cromolyn sodium is a potent inhibitor of inflammatory responses. Cromolyn sodium diminishes early phase reactions in asthma by blocking the release of intracellular calcium and inhibiting enzymes responsible for mast cell degranulation; cromolyn reduces late phase reactions in asthma by inhibiting production of the enzymes necessary for superoxide

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generation. Cromolyn sodium may also exhibit tachykinin antagonism, accounting for some of its anti-inflammatory properties. In vitro, cromolyn sodium potentially inhibits the activation of inflammatory cells, antibody-induced granulocyte cytotoxicity, IgE production by atopic cells, and monocyte IgG production.

Clinical Use

Cromolyn sodium is indicated for the management of asthma in children and atopic young adults. Cromolyn sodium, alone or in combination with β2 -adrenergic agonists, improves exercise tolerance, enhances sleep quality, reduces asthma exacerbations, and facilitates patient acceptance of therapy.

Patients diagnosed with asthma prior to the age of 4 years, patients less than 17 years of age, and patients with longterm asthma (more than 5 y) may experience maximal benefit from cromolyn sodium therapy. Cromolyn sodium significantly improves seasonal allergic asthma symptoms. Longterm use of cromolyn sodium (at least 12 wk) four times daily is recommended for effective control of chronic bronchial hyperresponsiveness, while a shorter treatment duration (up to 6 wk) usually suffices for control of seasonal allergic attacks.

Cromolyn sodium prophylaxes against exerciseinduced asthma in children as efficaciously as do beta2 agonists. Premedication with cromolyn sodium, inhaled β2 -adrenergic agonist, or both, 15 to 30 min prior to vigorous exercise is recommended for children and adults. Cromolyn sodium is a useful adjunct to bronchodilators in adults with atopic asthma; it may provide added benefit when administered in conjunction with inhaled corticosteroids.

Safety

Cromolyn sodium causes few adverse effects, even after longterm use. Its efficacy in preventing childhood asthma symptoms and safety record make cromolyn sodium a first-line agent, in conjunction with β2 -adrenergic agonists, in management of asthma in children.

Nedocromil Nedocromil also stabilizes mast cells in the bronchial mucosa, but it has a broader anti-inflammatory spectrum than cromolyn sodium. Nedocromil blocks activation of eosinophils and neutrophils, further reducing inflammation.

Dose-dependent inhibition of IL-4-induced IgE and IgG production has been demonstrated in vitro. Nedocromil is useful prophylactically against asthma exacerbations, but not therapeutically for acute bronchospasm.

The similar pharmacology of cromolyn sodium and nedocromil have prompted direct comparisons of the two agents in asthmatics. Nedocromil appears to be more effective as a bronchodilator-sparing agent than cromolyn sodium in adults, but it provides a similar level of protection against exercise-induced asthma in children. Lack of long-term experience with nedocromil relegates it to second-line status as an adjunct to bronchodilators in the management of asthma.

Leukotriene Antagonists and Inhibitors The leukotriene antagonists and inhibitors are the first new class of asthma drugs to be developed in several decades. Advances in our understanding of the inflammatory pathogenesis of asthma and the role of leukotrienes as inflammatory mediators have generated great interest in the development of and therapeutic potential for these drugs.

Leukotrienes are synthesized from arachidonic acid, a fatty acid stored in phospholipids of cell walls. Numerous stimuli, including IgE receptor activation, antigen-antibody interactions, and activation of phospholipase A2 induce release of arachidonic acid from phospholipids. Arachidonic acid is converted to a variety of products via several unrelated pathways; the 5-lipoxygenase pathway is the pathway of importance in asthma. Leukotriene A4 (LTA4 ) is metabolized by two different pathways to either the nonpeptide LTB4 or the cysteinyl leukotrienes (LTC4 , LTD4 , and LTE4 ). LTB4 recruits and activates inflammatory cells but has no effect on bronchial tone or reactivity. The cysteinyl leukotrienes stimulate smooth-muscle contraction, increase vascular permeability, and enhance bronchial hyperresponsiveness; thus, they have a major role in the pathogenesis of asthma.

Leukotriene action may be inhibited by either selective receptor blockade or interference with synthesis. Most clinical experience has been with the LTD4 receptor antagonists, since LTC4 , LTD4 , and LTE4 interact with a common LTD4 receptor.

Inhibition of 5-lipoxygenase (5-LO) reduces the generation of all leukotrienes.

Clinical Use Two LTD4 receptor antagonists (montelukast and zafirlukast) and one 5-LO inhibitor are FDA-approved and marketed in the United States. The leukotriene receptor antagonists are alternate anti-inflammatory medications for long-term use in children and adults with mild to moderate asthma, including aspirin- or exercise-induced asthma and asthma associated with concomitant allergic rhinitis. To date, data are insufficient to assess the role of antileukotriene receptor antagonists in the management of acute exacerbations of asthma or COPD. Inhaled glucocorticosteroids in doses of 400 µg/d of beclomethasone equivalent are more effective than the leukotriene receptor antagonists in adults with mild or moderate asthma. However, addition of a leukotriene receptor antagonist to therapy that includes an inhaled corticosteroid results in some further improvement in lung function.

Safety Montelukast and zafirlukast are well tolerated. Montelukast chewable tablets contain phenylalanine and therefore are contraindicated in patients with phenylketonuria. Hepatotoxicity has been reported with zileuton. Zileuton is contraindicated in patients with active liver disease and in patients with serum transaminase levels exceeding three times the upper limit of normal. Baseline liver function tests should be obtained prior to initiating therapy with zileuton, and patients should be monitored closely for the duration of therapy. Zileuton must

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be discontinued if serum transaminase levels exceed five times the upper limit of normal.

The leukotriene receptor antagonists have numerous drug interactions.

Pulmonary Pharmacotherapy

Nonetheless, close observation, including frequent assessment of vital signs, is recommended for at least 2 h following initial drug administration; similar monitoring is warranted for at least 1 h following each subsequent administration.

Immunoglobulin E Antibody Pharmacology Omalizumab is a recombinant humanized antibody developed for therapy of allergic diseases that has significant efficacy in severe atopic asthmatics. By specifically binding with high affinity to immunoglobulin E (IgE), but not to other immunoglobulins, omalizumab does not activate mast cells or basophils. Clinical efficacy depends upon almost total elimination of circulating IgE; therefore, the role of omalizumab is limited to those asthmatics with elevated IgE levels. Parenteral administration of omalizumab produces rapid binding of circulating IgE, with serum levels slowly rebounding over the subsequent 4 to 6 wk.

Several randomized, double-blind placebo controlled studies of omalizumab have been completed in patients more than 12 years of age with moderate to severe atopic asthma refractory to high-dose inhaled corticosteroids; patients also received inhaled, long-acting β agonists and oral leukotriene antagonists. Use of omalizumab resulted in reproducible decreases in asthmatic flares, reduced inhaled and oral steroid dosage, and improved quality of life.

Clinical Use Omalizumab therapy is indicated for moderate to severe asthmatics who have serum IgE levels exceeding 30 IU/ml (75 ng/ml) and an allergic basis for their asthma, as demonstrated by positive skin testing or radioallergosorbent tests (RAST) to common antigens. As a chronic therapy, omalizumab treatment should not be initiated in the setting of an acute asthma flare. Subcutaneous administration of omalizumab every 2 to 4 wk is required to maintain reductions in circulating IgE, with required dose and frequency dependent upon body weight and initial serum IgE level. Up to three separate subcutaneous injections, each not exceeding 150 mg at a single site, may be required at each administration. Subsequent serum IgE measurements are unnecessary, as levels are expected to plummet to negligible levels and slowly rebound after each administration of the drug.

The total duration of necessary therapy is unclear, although a review every 6 to 12 mo is commonly employed to assess whether improved asthma control has been achieved (as indicated by reduced inhaled and oral steroid usage, fewer emergency medical encounters and hospitalizations, and decreased overall medical costs).

Safety Minor local skin reactions at the injection sites occur in almost one-half of patients. A diffuse urticarial rash has been reported, but it is extremely uncommon. Severe hypersensitivity reactions, including anaphylaxis, are rarely observed.

MUCOKINETIC AGENTS Chronic sputum production or inspissated airway secretions plague most patients with obstructive lung disease. Some mucokinetic agents are effective in promoting the clearance of obstructed airways.

Dornase Alpha Purulent, viscous secretions contribute to airway obstruction and chronic pulmonary infections in patients with cystic fibrosis, chronic bronchitis, and bronchiectasis. High concentrations of mucus contribute to the increased viscosity of bronchial secretions in these conditions. Polymorphonuclear leukocytes recruited to ward off chronic pulmonary infections eventually degenerate, releasing DNA into the extracellular environment. Although recombinant human deoxyribonuclease I (DNAse) metabolizes DNA liberated from airway leukocytes, the high concentration of DNA released in these chronic conditions overwhelms the endogenous ability of the lungs to clear the DNA. Exogenous administration of DNAse promots clearance of airway DNA by reducing mucus viscosity, increasing mucus clearance, diminishing airway obstruction, and preventing recurrent pulmonary infections.

Results of randomized clinical trials of nebulized DNAse as short-term adjunctive therapy in patients with cystic fibrosis demonstrate modest dose-dependent improvement in pulmonary function and reduction in symptoms.

Placebo-controlled investigations of DNAse in adults with chronic bronchitis or bronchiectasias not due to cystic fibrosis reveal prolonged antibiotic therapy requirements, no enhancement of pulmonary function, and no improvement in quality of life.

N-Acetylcysteine N-acetylcysteine (NAC) lyses disulfide bonds in mucus proteins, reducing airway mucus viscosity. Increased mobilization of mucus and decreased inspissation with use of inhaled NAC has been reported in patients with asthma or COPD. However, randomized placebo-controlled trials in COPD have demonstrated no objective benefit of treatment with NAC. Due to the in vivo conversion of NAC to the potent antioxidants, glutathione and cysteine, recent investigations have focused on NAC as an immunomodulator. Since antioxidant formation is distinct from the local mucolytic effect, oral NAC has been investigated in most studies. Unfortunately, intravenous NAC in patients with acute lung injury

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or the acute respiratory distress syndrome (ARDS) offers no significant reduction in mortality or disease progression.

Iodinated Agents Some iodinated compounds have mucolytic-expectorant properties. When ingested, iodide is liberated and stored in secretory glands of the tracheobronchial tree. Upon stimulation by coughing or inhalation of irritant substances, iodide promotes secretion of respiratory tract fluid and mucoproteins and augments ciliary activity. Increased mucus mobilization and decreased mucus viscosity result.

Adverse events appear to be infrequent, although thyroid dysfunction may be induced by the iodine load and has been reported after long-term use in elderly patients with COPD. Clinicians should use iodinated compounds with caution in elderly patients or those with preexisting thyroid dysfunction.

Sodium Bicarbonate Sodium bicarbonate solutions (2 to 7.5 percent) are frequently used as vehicles for bronchodilators and Nacetylcysteine. By raising the pH of the respiratory tract fluids, aerosolized sodium bicarbonate weakens the saccharide structure of airway mucus, increasing its susceptibility to proteases and promoting its removal through enhanced ciliary activity. These effects are additive when used with N-acetylcysteine and cause reduction in mucus viscosity. Local irritation from hypertonic sodium bicarbonate solutions may occur; cough and bronchospasm have been observed in some patients. Therefore, bronchodilators should be given prior to sodium bicarbonate aerosols.

Guaifenesin Guaifenesin remains the only agent approved by the FDA as an expectorant, based upon a single placebo-controlled trial in patients with chronic bronchitis in whom guaifenesin significantly reduced sputum volume and improved sputum quality.

These patients also experienced subjective relief of respiratory congestion, and no adverse effects were reported. However, the purported expectorant properties of guaifenesin have not been substantiated in well-controlled studies.

PHYSIOLOGICAL REPLACEMENTS Replacement therapy comprises a novel class of agents to replace deficient, or augment existing, endogenous substances.

To date, replacement therapy has been employed only in adults with α1 -antitrypsin deficiency or neonates with respiratory distress syndrome. However, clinical studies of replacement therapy are underway in patients with a wide spectrum of obstructive and other lung diseases.

α1 -Antitrypsin α1 -Antitrypsin is a glycoprotein synthesized and secreted by hepatocytes. A protease inhibitor, α1 -antitrypsin, blocks the actions of neutrophil-derived elastase in the lung. Inherited deficiency of α1 -antitrypsin promotes development of emphysema in adulthood; tobacco smoking rapidly accelerates the clinical presentation and severity of the emphysema. Since 1988, α1 -antitrypsin replacement therapy has been available for intravenous administration as a purified product derived from pooled human plasma.

Clinical Use Weekly or monthly intravenous infusion of α1 -antitrypsin to deficient patients increases α1 -antitrypsin levels in serum and bronchoalveolar lavage specimens and restores antielastase activity in serum and alveolar lining fluid. Numerous case reports and small series dispute whether α1 -antitrypsin replacement reduces the accelerated rate of decline in pulmonary function associated with α1 -antitrypsin deficiency. Currently, α1 -antitrypsin replacement therapy is recommended for patients with α1 -antitrypsin deficiency who are older than 18 years of age and have both abnormal pulmonary function tests and a serum α1 -antitrypsin level less than 11 mM. Replacement therapy for α1 -antitrypsin deficient patients is not recommended after lung transplantation.

Side Effects α1 -Antitrypsin replacement therapy is remarkably nontoxic, and current preparations have few side effects other than mild fever. Repeated administration of α1 -antitrypsin does not shorten the serum half-life, suggesting that α1 -antitrypsin antibodies do not develop, even in patients with complete deficiency.

Pulmonary Surfactant The administration of pulmonary surfactant to premature infants with, or at risk for, respiratory distress syndrome has become the standard of care. Surfactant administration decreases mortality from respiratory distress syndrome by 30 to 40 percent and reduces morbidity due to pneumothoraces, interstitial emphysema, bronchopulmonary dysplasia, and intraventricular hemorrhage.

Endogenous pulmonary surfactant is an emulsion of phospholipids, cholesterol, and apoproteins that reduces surface tension within alveoli. Natural surfactant is commercially available and is prepared from lung tissue or lavages from a variety of species. Synthetic surfactant is available from a number of commercial sources, although the optimal composition of the material remains to be determined.

Pulmonary surfactants reduce oxygen toxicity by scavenging free radicals, and the surfactants may be cytoprotective for alveolar cell surfaces. Pulmonary surfactants suppress mediator release by inflammatory cells and may deactivate inflammatory mediators upon release. In vitro studies indicate that surfactant suppresses lymphocyte mitogenic

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responses, leading to a decrease in inflammatory cell influx.

Pulmonary surfactant has both antibacterial and antiviral properties which are mediated by an increase in alveolar macrophage phagocytosis. Surfactant may promote airway clearance by changing the physical properties of mucus, as well as by increasing ciliary beat frequency. Finally, pulmonary surfactant may directly relax airway smooth muscle. This spectrum of putative biologic activities may directly interrupt the pathogensis of airway inflammation, chronic infection, and bronchoconstriction seen in most obstructive lung diseases.

Limited clinical data are available to document the effects of pulmonary surfactant in adults. In anecdotal case reports and small patient series, surfactant administration to patients with respiratory failure has produced occasional increases in Pao2 , although usually no change in radiographic, physiological, or respiratory findings were reported. However, in two large, double-blind, randomized, placebo-controlled trials, administration of synthetic surfactant for 5 days yielded no demonstrable physiological benefit and no significant decrease in mortality rate measured at 30 days.

Pulmonary Pharmacotherapy

patients with hypercapnic obstructive lung disease, acetazolamide produces modest reductions in Paco2 and pH, while improving Pao2 . Long-term safety and efficacy data are unavailable, and larger studies will be required before acetazolamide therapy can be recommended for hypoventilation associated with either sleep-disordered breathing or hypercapnic obstructive lung disease.

Almitrine Almitrine bismesylate stimulates peripheral chemoreceptors in the carotid body and has no central respiratory stimulant effect. Also a pulmonary vasoconstrictor, almitrine improves ventilation-perfusion matching and, therefore, has received attention in small case series as adjunctive therapy for hypoxemic respiratory failure from ARDS. Although marketed in Europe, almitrine bismesylate is not available in the United States. Toxicities and side effects include right ventricular strain from pulmonary arterial vasoconstriction, peripheral neuropathy, weight loss during long-term therapy, and diuretic activity.

Methylxanthines RESPIRATORY STIMULANTS Respiratory stimulants are a group of pharmacologically unrelated agents used to treat diverse pathophysiological conditions, including obstructive or central sleep apnea, COPD, postanesthesia respiratory depression, and acute mountain sickness.

Aminophylline and theophylline are methylxanthine bronchodilators that augment the central ventilatory response to hypoxia, likely through adenosine receptor activation in the carotid body and or brain stem ventilatory control centers.

Limited data suggest theophylline reduces periodic breathing at high altitude. Used to treat apnea of prematurity and infants with periodic breathing, methylxanthines are less useful in the treatment of obstructive sleep apnea or in stimulating adult respiration in normobaric environments.

Acetazolamide Acetazolamide is a noncompetitive inhibitor of carbonic anhydrase that induces a weak diuresis and mild metabolic acidosis. Currently, acetazolamide is approved for the prophylaxis of acute mountain sickness and has been proposed as an alternative therapy for chronic mountain sickness. Sometimes used to treat patients with chronic hypercapnia and druginduced or compensatory metabolic alkalosis, acetazolamide may have both indirect and direct respiratory stimulant properties. The increased hydrogen concentration indirectly stimulates respiration via peripheral and medullary chemoreceptor stimulation. Acetazolamide may also directly stimulate respiration by increasing cerebral blood flow through mechanisms unrelated to the metabolic acidosis.

Recently, a small, double-blind, placebo-controlled study demonstrated acetazolamide improves nocturnal oxyhemoglobin saturations and reduces hematocrit in patients with chronic mountain sickness. However, further large scale studies will be required before acetazolamide can be recommended over standard therapies, including phlebotomy or relocation to lower altitude.

Limited data from short-term trials of acetazolamide in hypercapnic patients are available. In small numbers of

Doxapram Doxapram is a short-acting, parenterally administered, peripheral chemoreceptor agonist and central respiratory stimulant. Doxapram has been approved for postanesthesia respiratory depression or apnea, drug-induced central nervous system respiratory depression, and short-term use as a respiratory stimulant in acute respiratory insufficiency superimposed on chronic pulmonary disease. Limited case reports and small studies describe doxapram as a respiratory stimulant in COPD complicated by acute respiratory failure.

Medroxyprogesterone Medroxyprogesterone is a gestational respiratory stimulant.

Although its mechanism of action is unclear, medroxyprogesterone increases minute ventilation and produces hypocapnia in normal subjects. However, it does not improve breathing disturbances during sleep in normocapnic patients with obstructive sleep apnea. Limited data reveal medroxyprogesterone stimulates minute ventilation in patients with hypercapnic obstructive lung disease, without improving nocturnal oxygenation.

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Protriptyline Protriptyline is a tricyclic antidepressant that is cited frequently as an effective respiratory stimulant in patients with obstructive sleep apnea. The mechanism of action may include suppression of rapid eye movement (REM) sleep and increased tone in the upper airway muscles. Protriptyline is contraindicated in patients with glaucoma or prostatic hypertrophy, and anticholinergic side effects limit its usefulness.

SUGGESTED READING Anzueto A, Baughman RP, Guntapalli KK, et al: Aerosolized surfactant in adults with sepsis-induced acute respiratory distress syndrome. N Engl J Med 334:1417–1421, 1996.

Blitz M, Blitz S, Hughes R, et al: Aerosolized magnesium sulfate for acute asthma. Chest 128:337–344, 2005.

Boulet L-P: Once-daily inhaled corticosteoirds for the treatment of asthma. Curr Opin Pulm Med 10:15–21, 2003.

Bowton DL, Goldsmith WM, Haponik EF: Substitution of metered-dose inhalers for hand-held nebulizers. Success and cost savings in a large, acute-care hospital. Chest 101:305–308, 1993.

Bratton SL, Odetola FO, McCollegan J, et al: Regional variation in ICU care for pediatric patients with asthma. J Pediatr 147:355–361, 2005.

Brusasco V, Hodder R, Miravitlles M, et al: Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58:399–404, 2003.

Burge PS, Calerley PMA, Jones PW, et al: Prednisolone response in patients with chronic obstructive pulmonary disease: results for the ISOLDE study. Thorax 58:654–658, 2003.

Ducharme FM: Inhaled glucocorticoids versus leukotriene receptor antagonists as single agent asthma treatment: Systematic review of current evidence. Br Med J 326:621–625, 2003.

Federal Register: Use of ozone-depleting substances: Removal of essential-use designations. Fed Reg 70:17168–17192, 2005.

Fischer R, Lang SM, Leitl M, et al: Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude.

Eur Respir J 23:47–52, 2004.

Greenstone M, Lasserson TJ: Doxapram for ventilatory failure due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database 2000:CD000223, 2003.

Gross NJ: Tiotropium bromide. Chest 126;1946–1953, 2004.

Irwin RS: Systemic corticosteorids for acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med 348:2679–2681, 2003.

Kattan M: Mirror images: Is levalbuterol the fairest of them all? J Pediatr 143:702–704, 2003.

Lock SH, Kay AB, Barnes NC: Double-blind, placebocontrolled study of cyclosporin A as a corticosteroidsparing agent in corticosteroid-dependent asthma. Am J Respir Crit Care Med 153:509–514, 1996.

Man SF, Sin DD: Inhaled corticosteroids in chronic obstructive pulmonary disease. Drugs 65:579–591, 2005.

Marcus PM: Incorporating anti-IgE (omalizumab) therapy into the pulmonary medicine practice: Practice management implications. Chest 129:466–474, 2006.

McDonald NJ, Bara AI: Anticholinergic therapy for chronic asthma in children over two years of age. Cochrane Database 3:CD003535, 2003.

Mullen M, Mullen B, Carey M: The association between βagonist use and death from asthma. JAMA 270:1842–1845, 1993.

Niven AS, Argyros G: Alternate treatments in asthma. Chest 123:1254–1265, 2003.

Richalet J-P, Rivera M, Bouchet P, et al: Acetazolamide: A treatment for chronic mountain sickness. Am J Resp Crit Care Med 172:1427–1433, 2005.

Rodrigo GJ, Castro-Rodriguez JA: Anticholinergics in the treatment of children and adults with acute asthma: A systematic review with meta-analysis. Thorax 60:740–746, 2005.

Rowe BH, Bretzlaff JA, Bourdon C, et al: Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database 4:1–22, 2005 Vincken W, van Noord JA, Greefhorst APM, et al: Improved health outcomes in patients with COPD during 1 year’s treatment with tiotroprium. Eur Respir J 19;209–216, 2002.

Wagenaar M, Vos P, Heijdra Y, et al: Comparison of acetazolamide and medroxyprogesterone as respiratory stimulants in hypercapneic patients with COPD. Chest 123:1450–1459, 2003.

Westby M, Benson M, Gibson P: Anticholinergic agents for chronic asthma in adults. Cochrane Database 3:CD003269, 2004.

151 Intubation and Upper Airway Management C. William Hanson III

Erica R. Thaler

I. UPPER AIRWAY ANATOMY AND CLINICAL RELEVANCE II. UPPER AIRWAY MANAGEMENT III. TECHNIQUES AND EQUIPMENT

VI. MASKS VII. EXTRAGLOTTIC AIRWAY DEVICES VIII. TRACHEAL INTUBATION IX. CONCLUSION

IV. AIRWAYS V. RESUSCITATION BAGS

The first known use of positive pressure ventilation (PPV) as a medical intervention dates back to the sixteenth century, as described in Vesalius’ de Humani Corporis Fabrica: But that life may in a manner of speaking be restored to the animal, an opening must be attempted in the trunk of the trachea, into which a tube of reed or cane should be put; you will then blow into this, so that the lung may rise again and the animal take in air. Indeed with the slight breath in the case of the living animal, the lung will swell to the full extent of the thoracic cavity, and the heart become strong . . . for when the lung, long flaccid, has collapsed, the beat of the heart and arteries appears wavy, creepy, twisting; but when the lung is inflated at intervals, the motion of the heart and arteries does not stop. . . .

Vesalius subsequently resuscitated a Spanish nobleman by inflating his lungs through the trachea, resulting in resumption of cardiac activity and nearly in Vesalius’ death at the hands of the Inquisitors. Vesalius, an excellent anatomist who disproved many of the cherished teachings of Galen that had been accepted as absolute truth for 13 centuries, was viewed as a heretic by his peers. In fact, one described him as “an impious madman who is poisoning all of Europe with his vaporings.”

Because of lack of enthusiasm in response to Vesalius’ findings, a 100-year hiatus attended the next attempt at

endotracheal ventilation. In 1667, Robert Hooke, a prominent mathematician, geologist, and paleontologist kept a dog alive by intermittently insufflating air into its trachea using a set of bellows. One century later, in 1744, John Fothergill, one of the founders of the British Humane Society, described successful mouth-to-mouth resuscitation.

Because of concerns over development of emphysema and tension pneumothorax as complications of PPV (recognized as early as 1827), research on artificial ventilation in the nineteenth and early twentieth centuries focused on negative-pressure ventilation (NPV). Iron lungs, tank ventilators, cuirass ventilators, and a variety of strange and remarkable differential pressure chambers and boxes were developed in the United States and Europe. The devices were powered by hand, water, steam, or electricity, and, in some cases, by the patient himself. However, PPV became incorporated into the resuscitation strategy of the Dutch Humane Society, which advocated mouth-to-mouth ventilation in conjunction with external thoracic and abdominal compression. In 1776, John Hunter described an apparatus that blew fresh air into the lungs with one set of bellows and sucked “bad” air out with a second set.

By the end of the nineteenth century, a surge in the evolution of thoracic surgery led to the use of tracheal intubation and PPV through cuffed tubes as acceptable components of medical care. An American surgeon, Joseph O’Dwyer,

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designed a series of metal tubes that were inserted between the vocal cords of children afflicted with diphtheria. Rudolph Matas referred to O’Dwyer’s devices in describing “intralaryngeal intubation” and “insufflation” and noted that, “the procedure that promises the most benefit in preventing pulmonary collapse in operations is . . . the rhythmic maintenance of artificial respiration by a tube in the glottis.” In the early part of the twentieth century, Franz Kuhn, a German surgeon, described techniques for oral and nasal intubation using flexible metal tubes introduced into the trachea with the assistance of the operator’s index finger; the procedure was preceded by application of topical anesthesia using cocaine.

The airway was then sealed with a supralaryngeal flange and gauze packing.

Among the further advances that followed was the first laryngoscope created by Alfred Kirstein in Berlin. However, his model was never widely accepted. Chevalier Jackson developed a U-shaped laryngoscope that otorhinolaryngologists still use for endoscopy but was never adopted by anesthesiologists. In 1913, Janeway described an endotracheal tube with a removable cuff, an anesthesia ventilator, and a batterypowered laryngoscope. From 1900 to 1920, Dorrance, Elsberg, L¨owen, and Sievers published methods for tracheal intubation and PPV. The most influential figure in the history of endotracheal intubation is Sir Ivan Magill. Along with Stanley Rowbotham, he used anesthetics on Royal Army casualties during World War I (in particular, on patients with disfiguring facial injuries). Their patients were often intubated nasally to allow freer access to the face by the surgeon. Magill’s inventions include the Magill forceps, which is still used to facilitate nasal intubation, semirigid endotracheal tubes fashioned from mineralized rubber, and the Magill circuit, an L-shaped laryngoscope. He is also credited with describing the “sniffing position.”

Arthur Guedel, an American contemporary of Magill, refined the cuffed endotracheal tube and, by extensive experimentation on animal tracheas, determined that the best position for the cuff was just below the vocal cords. He popularized use of the cuffed endotracheal tube by publicly anesthetizing his pet dog, “Airway,” and immersing the animal in a tank of water. Upon awakening, the dog shook itself off and departed the arena.

In current practice, access to the trachea through the nasopharynx or oropharynx takes advantage of laryngoscope blades invented in the 1940s by Robert Miller, a Texas clinician, and Robert Macintosh, an Oxford professor. The Miller blade was an advance over similar straight blades; it was designed to pick up the epiglottis and expose the vocal cords. The curved Macintosh blade differed from previous models and was designed for insertion between the epiglottis and tongue.

Although many variants of the two blades are available today, including those with different angulations, prisms, and fiberoptic bundles, the Miller and the Macintosh blades remain the mainstays of the anesthesiologist’s armamentarium.

The first departments of anesthesiology were founded in the early 1940s. Thereafter, the skills required for management of the upper airway and endotracheal intubation became widely disseminated in the United States and the United Kingdom.

UPPER AIRWAY ANATOMY AND CLINICAL RELEVANCE The two functional conduits between the trachea and atmosphere—the oropharynx and the nasopharynx (Fig. 151-1)—join at the level of the base of the skull to form the hypopharynx. The oropharynx includes the base of the tongue,

Figure 151-1 Comparative anatomy of adult and infant airways. (Courtesy of Barash P, et al (eds.): Clinical Anesthesia, Philadelphia, Lippincott, 1989, p 544, D. Factor, illustrator.)

2647 Chapter 151

uvula, and tonsils. The nasopharynx is separated from the oropharynx by the mobile soft palate. The hypopharynx includes the vallecula, which is the space posterior to the tongue and anterior to the cervical esophageal inlet. Typically, the adult epiglottis is crescentic, moderately stiff, and thin. Because of its ligamentous attachments, the adult epiglottis can be lifted indirectly using a curved laryngoscope blade applied to the base of the tongue. The U-shaped infant epiglottis is longer and floppier than the epiglottis of the adult. Therefore, a straight blade is typically required to lift the infant epiglottis directly during endotracheal intubation.

The adult and infant airways differ in several other respects. The narrowest portion of the adult airway is the rima glottidis, the area between the vocal cords; in contradistinction, the cricoid is the narrowest portion of the infant’s airway. The infant larynx is also situated relatively more cephalad than the larynx of the adult; in addition, the vocal cords of the infant are angled, whereas the vocal cords of the adult are perpendicular to the airway.

In an awake patient, with the head in the neutral position (i.e., neither flexed nor extended), air moves freely through both the oropharynx and nasopharynx. In most normal subjects, the same is true during sleep. Abnormalities of any of the component parts of the upper airway can impede airflow during respiration while awake; alternatively, impeded airflow may only become evident during sleep (e.g., as snoring or obstructive apnea). Consequently, a directed history and physical examination should be performed prior to any procedure on the airway.

A history of nasal polyps or nasal septal deviation mandates caution prior to nasotracheal intubation, transnasal passage of a fiberoptic scope, or insertion of a nasal airway. The patient’s sleeping partner is often the best source of information about snoring and apnea, manifestations that may result from a variety of upper airway abnormalities, including soft tissue redundancy, masses, polyps, stenosis, or lymphoid hypertrophy from the nose to the hypopharynx and larynx. Vocal changes or abnormalities may suggest abnormalities of the vocal cords and warrant preintubation evaluation.

The physical examination of the airway is preceded by a conversation with the patient. Hoarseness, stridor, tachypnea, and coughing suggest potential upper airway problems.

The examination then can be pursued systematically beginning with the nasopharynx. The patient’s ability to breathe through a single nostril (when the mouth is closed and the other nostril occluded) indicates that the passage is relatively patent. Asymmetry often exists between the two sides and, whenever possible, instrumentation should be performed on the more patent side.

The ability to open the mouth is limited in patients with temporomandibular joint disease. The temporalis muscle may be scarred or fibrotic (e.g., secondary to prior radiation) resulting in restricted mandibular mobility. Fractures to the mandible produce limited ability to open the mouth that, when the limitation is caused by muscle spasm, disappears with anesthesia. Some fractures functionally affect the mobility of the jaw, irrespective of anesthetic state. Inability

Intubation and Upper Airway Management

to open the mouth more than 40 mm is considered to be clinically significant.

The patient’s dentition should also be assessed prior to elective management of the airway. Protruding maxillary incisors (“buck teeth”) interfere with direct laryngoscopy by restricting the extent to which the laryngoscope blade can be aligned with the trachea. Dental caps and other prostheses are fragile and easily damaged during laryngoscopy. The laryngoscope may become lodged in gaps between the maxillary teeth during instrumentation and interfere with intubation.

Severe dental caries or periodontal diseases make it easier to dislodge teeth during airway instrumentation. The edentulous patient often has an atrophic mandible and large tongue and may be difficult to ventilate by mask because of poor fit of the mask. Intubation of the trachea in such a patient becomes difficult because the tongue, no longer constrained by the teeth, interferes with visualization of the larynx.

Abnormalities of the tongue, hard palate, tonsillar pillars, and hypopharyngeal structures can impede or prevent intubation. Normally the tongue is small and sufficiently flexible to be displaced by a laryngoscope blade during visualization of the vocal cords. However, the tongue is enlarged in obese patients, those with angioedema or impaired lymphatic drainage (e.g., after cervical surgical procedures or trauma), or in the setting of certain neoplasms. Burns, scars, or radiation of the submandibular soft tissue prevent lateral displacement of the tongue into the oropharynx during laryngoscopy.

Similarly, in patients with small jaws (“receding chins”), displacement or flattening of the tongue during laryngoscopy is difficult, making intubation a challenge. A hyomental distance (the distance from the hyoid bone to tip of the mandible) of less than 6 cm should raise awareness of potential difficulty with intubation.

A cleft or high, arched palate is seen in a variety of congenital abnormalities of the facial bones, including the Treacher-Collins, Pierre Robin, Klippel-Feil, Goldenhar, Beckwith-Wiedemann, and Crouzon’s syndromes, as well as the mucopolysaccharidoses. Affected patients are difficult or impossible to intubate using standard approaches.

Intraoral, oropharyngeal, hypopharyngeal, and laryngeal lesions, as well as tonsillar hypertrophy, can interfere with both laryngoscopy and ventilation by mask. The epiglottis can be infiltrated, inflamed, floppy, or enlarged by fat. The retropharyngeal and lateral pharyngeal spaces are continuous with and therefore subject to expansion by processes that involve the mediastinum (e.g., the presence of edema, blood, pus, or soft-tissue emphysema). Patients with epiglottitis and parapharyngeal swelling often exhibit a characteristic posture, sitting upright in the sniffing position and drooling.

The preferred position for visualization of the vocal cords is the sniffing position (Fig. 151-2). However, this position may be unsuitable in some patients or impossible to achieve in others.

The normal range for flexion and extension of the neck ranges from 90 to 165 degrees. A variety of disorders limit this range. Patients with cervical osteophytes or ankylosing spondylitis, who are often fixed in an anteroflexed head

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objectively the airwayâ&#x20AC;&#x2122;s suitability for placement of the endotracheal tube. The ability to visualize the soft palate, fauces, tonsillar pillars, and uvula is used to predict the degree of difficulty in exposing the larynx. A careful examination of the airway, coupled with attention to difficulties during prior procedures and the physical features described above, permit adequate preparation for instrumentation of the difficult airway.

UPPER AIRWAY MANAGEMENT Figure 151-2 The sniffing position with the oral, pharyngeal, and tracheal axes.

position, may be difficult to intubate. Halo fixation imposes similar constraints. Rheumatoid arthritis, which may affect the cervical spine even in asymptomatic patients, may be problematic. By the age of 75 years, the normal aging process results in as much as a 20 percent reduction in cervical spine mobility. Injury to the cervical spine or the presence of a cervical collar also impairs the ability of the laryngoscopist to position the head. Finally, patients with short, muscular necks have limited neck mobility and redundant soft tissue in the mouth and submandibular space, making airway visualization a challenge.

A variety of other anatomic features, including large breasts or a barrel chest, can complicate airway management by interfering with the excursion of the butt of the laryngoscope blade. During pregnancy, the oral and pharyngeal mucosae are swollen and bleed easily. When associated with a diminished functional residual capacity and increased volume of acidic gastric contents, intubation becomes quite hazardous.

Based upon anatomical considerations, clinicians commonly employ the Mallampati scale (Table 151-1) to evaluate

Table 151-1 Mallampati Scale for Characterizing the Airway Class I Soft palate, fauces, uvula, and tonsillar pillars visible Class II Soft palate, fauces, and uvula visible Class III Soft palate and base of uvula visible Class IV Soft palate only visible

Airway management is well suited to the use of algorithms.

The American Society of Anesthesiologists has a â&#x20AC;&#x153;difficult airwayâ&#x20AC;? algorithm for use in the operating room. In addition, algorithms for the critical care unit and trauma setting have been developed. In using an algorithm-based approach, the first decision branch point typically addresses the need for endotracheal intubation, since short-term respiratory insufficiency often can be managed noninvasively.

Factors that must be considered in the care of patients with respiratory compromise include the level of consciousness, clinical context (e.g., the perioperative setting, emergency circumstances, etc.), anticipated duration of respiratory problem, risk of gastric aspiration, airway patency, concurrent medical problems, and anticipated relative ease of noninvasive (i.e., spontaneous or mask ventilation) vs. invasive (i.e., endotracheal intubation) management of the airway.

In the patient with neurological depression due to injury of the central nervous system, noninvasive management is usually inappropriate due to the potential for developing hypercarbia or hypoxia and exacerbation of the primary injury. Conversely, in the patient sedated or obtunded by drugs or seizures, the clinical state is often brief in duration, so temporizing measures may be appropriate.

Several factors differentiate elective perioperative airway management from emergency care. During surgery, an anesthesiologist or anesthetist is constantly present; the patient is properly prepared (i.e., the stomach is empty and a drying agent has been administered) and the environment is designed to facilitate airway management (i.e., there is ready access to suction, a ventilator, etc.). Under these circumstances, caregivers may choose to sedate the patient to the point of semiobtundation. Conversely, in an emergency, the setting is usually less than optimal. Airway management is usually only one component of the care rendered during cardiac or trauma resuscitation, and definitive airway intervention is essential in order to allow care providers to concentrate on other problems.

Potentially quickly reversible processes (e.g., some attacks of asthma or episodes of pulmonary edema) may be appropriately managed without intubation. In other instances (e.g., blunt chest injury), the initial problem can be expected to worsen, and early intubation is warranted.

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The volume and acidity of the patient’s gastric contents must be factored into any decision about management of the airway. Aspiration of solid food can be catastrophic, as can large volumes of acidic, enzymatically active gastric fluid.

Most studies have indicated that aspirated stomach contents with a pH lower than 2.5 or volume greater than 0.5 to 1.0 cc/kg are likely to cause lung damage. The lung damage is manifested by loss of ciliated and nonciliated epithelial cells in the trachea, destruction of type I and II pneumocytes, depletion of surfactant, and increased vascular permeability (see Chapter 144). Pain and narcotics may alter gastric emptying or change gastric pH, as can a number of disease states, such as intestinal obstruction, diabetic gastroparesis, and obesity.

Unless the patient has fasted for more than 8 h and is not subject to the confounding factors noted above, a full stomach should be presumed, and airway management handled accordingly.

The patient’s coexisting medical problems and expected course must also be considered in management of the airway.

For example, endotracheal intubation can be a dangerous stress to a patient with coronary artery disease and can be performed more safely after suitable preparation than under emergency circumstances. As another example, a patient with Fournier’s gangrene and normal lungs is appropriately managed by maintaining intubation and sedation between trips to the operating room for debridement, rather than by performing multiple extubations and reintubations. Similarly, elective intubation and mechanical ventilation can prevent aspiration or atelectasis in a patient with hepatic encephalopathy who is awaiting liver transplantation, thereby improving the likelihood of a successful outcome.

Some degree of airway obstruction can be managed without intubation by proper positioning of the head, use of an oral or nasal airway, or application of positive airway pressure (PAP) by mask. A rolled towel or small pillow placed behind the neck or occiput reproduces the sniffing position.

Oral and nasal airways can alleviate airway obstruction due to redundant airway soft tissue or muscle relaxation. The application of positive pressure to the mouth and nose (mask continuous positive airway pressure or mask CPAP) distends the soft tissue of the airway. For this reason, nasal mask CPAP is frequently used in the management of obstructive sleep apnea (see Chapter 97). These measures can be used as shortterm, temporizing alternatives to intubation in the patient who is ventilating spontaneously in the intensive care unit or operative setting.

Although a growing literature exists on the use of noninvasive ventilation in a variety of settings that previously would have mandated endotracheal intubation, anesthesia is frequently administered in the operating room by mask using positive pressure. True mask ventilation is readily accomplished in the anatomically normal patient. However, some anatomic features, such as a beard, flat or sharp nose, or sunken cheeks (in the edentulous patient) can make maskassisted ventilation difficult or impossible.

Indications for tracheal intubation (Table 151-2) fall broadly under several categories: respiratory failure, airway

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Table 151-2 Indications for Intubation of the Trachea Ventilatory failure Cardiac arrest, primary lung disease, neuromuscular disease or weakness Airway obstruction Primary airway process, neurogenic obstruction Airway protection Upper airway bleeding or injury (burn), central nervous system depression Pulmonary toilet Inability to manage secretions

protection, hemodynamic instability, and perioperative management. If intubation is indicated, the clinician must decide upon the route and technique.

TECHNIQUES AND EQUIPMENT Although expertise is a function of experience, several principles are generally applicable in any approach to airway management. The first applies to correct head positioning, which facilitates mask management, oral or nasotracheal intubation, and fiberoptic examination of the airway. Incorrect positioning impedes each procedure.

The previously noted sniffing position refers to extension of the head on the neck while the neck is flexed on the thorax (Fig. 151-3). The hypopharynx is at its maximal circumference in this position, and the tongue is farthest from the posterior pharyngeal wall. Anterior displacement of the jaw can be accomplished by pulling it forward or applying pressure on the angle of the mandible (the “jaw thrust” maneuver).

Figure 151-3 The sniffing position modified by additional head extension for oral intubation, with alignment of the oral, pharyngeal, and tracheal axes.

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This serves to open further the retrolingual space. Pulling the tongue forward while grasping it with gauze or an instrument accomplishes the same goal. The position is appropriate for spontaneous respiration because it limits soft-tissue obstruction to airflow.

Nasotracheal intubation is easiest in the sniffing position, because the tip of the endotracheal tube is best aligned with the larynx and least likely to be deflected by the walls of the pharynx. Nasal and oral fiberoptic procedures are also easier in this position in which the oral, pharyngeal, and tracheal axes are well aligned (Fig. 151-3). The sniffing position may be modified by further head extension and flattening of the back of the tongue by the laryngoscope blade during oral intubation.

A second general principle underlining airway management is that saliva and blood interfere with mask ventilation, direct visualization of the airway, and fiberoptic procedures. When circumstances permit, pretreatment with an antisialogogue, such as atropine, glycopyrrolate, or scopolamine, significantly diminishes saliva production. Suction must be available prior to initiation of any elective procedure (as well as on the emergency cart) to clear secretions or deal with regurgitation of gastric contents. A suction tip with a large bore, such as the Yankauer tonsil suction tip, is commonly used; suction should be maximized in order to clear thick, viscous oral secretions.

A third general principle of airway management refers to preparation of the patient and airway. Small, titrated doses of sedatives, topical anesthesia, and vasoconstrictor agents markedly enhance the ease with which procedures, such as fiberoptic, nasotracheal, or oral intubation, are performed while the patient is awake. Narcotics are more likely to suppress the cough reflex than are other agents. Topical cocaine has anesthetic and vasoconstrictor properties, but because of its classification as a controlled agent, the combination of lidocaine and phenylephrine is often used as an alternative.

The light source of a laryngoscope or fiberoptic scope should be checked prior to instrumentation, and, with the latter, the focus adjusted. Finally, a backup plan for airway management is essential in case the primary plan should go awry.

Finally, perhaps the most important principle of airway management is that a source of oxygen and means of ventilation should be available. This implies that the pressure in nearby oxygen tanks should be checked, as should the proximity of a source of wall oxygen. In the absence of an oxygen source, a self-inflating resuscitation bag can provide a method for ventilation, obviously using only room air (see below). Bags used for most anesthesia circuits require a gas source for inflation.

Figure 151-4 Oral and nasal airways and face masks.

a beveled tip, permitting insertion through narrow nasal passages. Oral airways are curved, designed to lie over and behind the tongue. Some are fashioned with slots for ready passage of a suction catheter, whereas others have a central channel designed to accommodate a fiberoptic scope. Binasal airways are designed to be fitted to a ventilation circuit, permitting ventilation in anesthetized patients without endotracheal intubation.

RESUSCITATION BAGS Resuscitation bags are available in many styles (Fig. 151-5) and are designed with several common features. They are self-inflating, and can, therefore, be used in the absence of a gas source. An internal flap valve system directs inflowing gas to the patient or reservoir, permitting application of positive pressure by mask or endotracheal tube and venting exhaled gas to the atmosphere. Inspired oxygen concentration is ordinarily limited to 40 to 60 percent when oxygen inflow is 10 L/min; bag reinflation is rapid, since room air is entrained with each breath. Addition of an oxygen reservoir, usually in the form of a sleeve or tail at the back of the bag, permits administration of oxygen concentrations of 75 to 90 percent at 10 to 15 L/min. Some bags are equipped with adjustable valves for application of positive end-expiratory pressure.

AIRWAYS MASKS A large variety of nasal and oral airways, designed for children and adults of different sizes (Fig. 151-4), are available.

Nasal airways are generally made of flexible rubber and have

Although a large variety of masks are available (Fig. 1514), all have three features in common: the body, seal, and

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Figure 151-5 Self-inflating resuscitation bag.

connector. The body is usually made of malleable or moldable material and adjustable to individual facial anatomy.

The body of some masks is made of clear plastic to allow diagnosis of regurgitation of gastric contents. The seal is usually a cushioned rim (which can be inflated or deflated) attached to the body, although some are detachable.

Some seals are flanged and not cushioned. The connector is designed with a universal fitting (22-mm internal diameter) for attachment to any ventilating circuit. Many are equipped with retaining straps for attachment to mask straps (which pass behind the patient’s head, freeing the hand of the operator).

hypopharynx; its correct positioning is verified by assessment of breath sounds.

The LTA is similar to the LMA. The device has two cuffs, one of which is designed to seal the lower pharynx and esophagus and the other the upper pharynx. A lumen exists between the two.

The esophageal obturator airway (EOA) is similar to the LTA in that it also has two cuffs and a single lumen.

However, the distal end of the device is designed to lie in the esophagus. A newer device, the Combitube (Armstrong Medical Industries), addresses a concern that the tip of the EOA may inadvertently enter the trachea, making ventilation impossible. The Combitube is designed to permit ventilation and airway isolation regardless of whether its tip lies in the esophagus or trachea.

EXTRAGLOTTIC AIRWAY DEVICES A number of extraglottic or supraglottic airway devices exist, and new ones are described every year. Some are cuffed, while others are uncuffed; some are nasally inserted, while others are orally inserted. A few devices are based on cannulation of the esophagus. The most familiar devices are cuffed, orally inserted, hypopharyngeal airways, such as the laryngeal mask airway (LMA) and the laryngeal tube airway (LTA).

The LMA (Fig. 151-6) is analogous to the facial mask: It has a compliant cuff that is applied to the dorsal surface of the larynx, isolating the airway from the mouth and esophagus.

The LMA came into common intraoperative usage in the early 1990s. While used most extensively in surgical patients, the LMA has also been used for awake, fiberoptic bronchoscopy, in the intensive care unit, and in emergency resuscitation.

Variants are specifically designed to be flexible, disposable, or to permit passage of an endotracheal tube through the device’s lumen. The LMA is inserted through the mouth into the

TRACHEAL INTUBATION Four approaches are commonly employed in tracheal cannulation: nasal, oral, laryngeal, and tracheal. The first two are noninvasive, whereas the latter two require surgical incisions.

Nasotracheal intubation can be done “blindly” (i.e., without tracheal lumen visualization) or using a laryngoscope and forceps. A blind nasotracheal intubation, when performed by a skilled operator, allows rapid control of the airway in an awake patient and minimal suppression of protective airway reflexes. The technique is used widely by paramedics in prehospital patient care, as a component of many difficult airway algorithms, and as an integral part of Advanced Trauma Life Support algorithms.

In performing blind nasotracheal intubation in a nonemergency setting, the operator examines the nasal passages for patency, septal deviation, or the presence of polyps.

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Figure 151-6 The laryngeal mask airway.

If the patient is able to cooperate, the larger nasal passage is selected by alternately occluding each nostril and choosing the one with better airflow. A topical anesthetic and vasoconstrictor agent are sprayed in the nostril or applied with cotton pledgets. Anesthetic is also sprayed into the back of the mouth in order to anesthetize the hypopharynx.

An appropriately sized tube (6 to 7 mm for women, 7 to 8 mm for men) is selected and lubricated. Lubrication eases passage of the tube and minimizes abrasion of the nasal

mucosa, making bleeding less likely. The patient is placed in the sniffing position and the tube inserted and advanced using slow, firm pressure. The natural slope of the tube is oriented so that the tip initially points toward the occiput and curves in a caudad direction as it is advanced.

During the procedure in an awake patient, the operator listens for breath sounds as the tip approaches the vocal cords. A commercially available whistle attachment (Bamm, Great Plains Ballistics, Inc., Lubbock, TX) enhances the operatorâ&#x20AC;&#x2122;s ability to hear breath sounds (Fig. 151-7). The tube is

Figure 151-7 Standard endotracheal tube with whistle tip attachment to amplify breath sounds during blind nasal intubation.

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Figure 151-8 Endotracheal tube modified with a ‘‘trigger” permitting anteroflexion of the tip of the tube during blind nasal intubation. Univent tube for lung isolation (see text).

advanced into the airway during inspiration. Slight clockwise or counterclockwise rotation of the tube at the nose can be used to correct for lateral misalignment. A commercially available endotracheal tube (Endotrol, Mallinckrodt, Athlone, Ireland) allows the operator to anteroflex the tip of the tube with a “trigger” at the connector (Fig. 151-8). This is especially effective in patients with anteriorly positioned vocal cords or those who cannot assume the sniffing position (e.g., due to the presence of a cervical collar).

When nasotracheal intubation is performed in an anesthetized patient, the endotracheal tube tip is advanced into the hypopharynx above the vocal cords, laryngoscopy is performed, and the tube is then advanced into the trachea under direct visualization. Magill forceps (Fig. 151-9) are often used to grasp the tube and direct its tip between the vocal cords.

Care must be taken to avoid grasping the tube by the cuff, which is easily perforated.

Correct position of the tube can be verified using a number of methods. Audible or palpable air passage (in the spontaneously breathing patient), a visible vapor trail within the tube, or auscultatory evidence of breath sounds over the lung fields are standard approaches. End-tidal capnometry showing phasic variation in carbon dioxide levels is the gold standard and has become more feasible in nonoperative settings because of the development of portable and disposable devices.

Extensive literature exists on the pros and cons of nasal versus oral intubation in the intensive care environ-

ment. Nasal intubation is associated with a higher incidence of bleeding, nasal discomfort, and hemodynamic alterations during tube placement. A minimal increase in the dead space of the equipment (less than 10 cc) without significant difference in airflow resistance occurs with nasotracheal intubation compared with the orotracheal route.

Literature regarding the incidence of sinusitis and pneumonia as a result of each of the two methods is conflicting; one prospective, randomized trial showed no differences. In general, early tracheostomy is increasingly preferred in critically ill patients who are likely to be intubated for prolonged periods.

By far, direct laryngoscopy with orotracheal intubation is the most common approach that is applied to secure the airway. With the patient’s head in the sniffing position, the operator inserts a Macintosh or Miller blade (Fig. 151-10) into the right side of the mouth using the left hand (regardless of the handedness of the operator). While some anatomic situations make it advantageous to use one blade rather than the other (e.g., the Miller blade in the setting of an anatomically anterior larynx), most operators become familiar with one blade and use it preferentially.

The blades of both instruments are flanged to keep the tongue to the left and out of the visual field. Larger adult blades (Macintosh no. 4 or Miller no. 3) are used for patients with long mandibles, whereas shorter blades (Macintosh no.

3 or Miller no. 2) are used in normal patients. Smaller blades are used for children.

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Figure 151-9 Magill forceps (see text) and light wand for transillumination of the trachea during blind oral intubation.

Figure 151-10 Macintosh and Miller blades.

During the procedure, the operatorâ&#x20AC;&#x2122;s right hand pulls the upper and lower lips out of the way, so that they are not caught and injured between the blade and teeth. The tip of the laryngoscope blade is advanced along the tongue until the epiglottis is visible. If the Macintosh blade is used, it is advanced between the tongue and epiglottis; when the Miller blade is used, the epiglottis is elevated directly. The cords should be visible immediately below the epiglottis. Most infants are intubated using a Miller blade. The shape, length, and pliancy of the infant epiglottis are such that it must be â&#x20AC;&#x153;picked upâ&#x20AC;? by the tip of the Miller laryngoscope so that the cords can be seen.

Because some patients are difficult to intubate due to anatomic considerations, a number of alternate approaches have evolved. These include fiberoptic laryngoscopy, by which the trachea is entered using a bronchoscope and an endotracheal tube advanced into the airway over the device. A flexible light wand (see Fig. 151-9) can be used to transilluminate and identify the airway; an endotracheal tube is then advanced into the airway using the wand as a stylet. Retrograde techniques involve percutaneous cannulation of the trachea in the neck and retrograde passage of a wire or catheter into the oropharynx. The wire is grasped and secured to an endotracheal tube and used to guide its passage back into the trachea.

Percutaneous cricothyrotomy kits are available for emergency access to the airway, as are percutaneous tracheostomy kits. Percutaneous ventilation has been taught in airway management portions of Advanced Cardiac Life Support (ACLS), Advanced Trauma Life Support (ATLS), and

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Table 151-3 Indicators of a Potentially Difficult Airway Poor mouth opening Temporomandibular joint disease Mandibular fracture Dental problems “Buck” anterior teeth Caries Dental hardware (caps, dentures) Gaps Abnormalities of the tongue Large (e.g., in obesity) Swollen Edema (surgical) Angioedema (allergic) Fixed Scarring (radiation) Tumor Presence of other intraoral structures Tumors Enlarged tonsils Small jaw “Anterior larynx” Decreased neck mobility Cervical disease or injury Suspected fracture Rheumatoid arthritis Ankylosing spondylitis Increased age (presence of cervical osteophytes) Congenital syndromes Cleft palate Treacher-Collins Pierre Robin Klippel-Feil

Intubation and Upper Airway Management

Pediatric Advanced Life Support (PALS) courses. The technique requires insertion of a needle or intravenous catheter through the cricothyroid membrane in order to insufflate oxygen during emergency airway management.

Anatomic features indicative of the difficult airway are listed in Table 151-3. While a full discussion of the management of the potentially problematic airway is beyond the scope of this chapter, adequate preparation by the operator can prevent a catastrophe.

Early assessment of the anatomy to determine whether difficulty with intubation alone or intubation and ventilation should be anticipated is important. An anteriorly placed larynx is usually associated with difficulty in intubation alone, whereas an obese patient is more likely to present a challenge with regard to both intubation and ventilation.

An additional important determination is whether interventional airway management is actually necessary. Can the procedure be performed under regional, rather than general, anesthesia? If regional anesthesia cannot be employed, awake intubation using sedation and topical airway anesthesia may be an excellent alternative. Direct laryngoscopy and fiberoptic bronchoscopy are equally appropriate adjuncts in intubating cooperative patients.

If difficulty in airway management is unexpectedly encountered in an already anesthetized patient, ensuring adequate ventilation and oxygenation is critical. A mask or, if necessary, one of the invasive approaches described above, may be used. Establishment of reliable ventilation allows time for alternate approaches, including abandonment of the procedure (allowing the patient to awaken) or tracheostomy.

A large number of endotracheal tubes are commonly employed in a variety of clinical settings.

Single-lumen, reusable, red rubber tubes with separate cuffs were used as recently as the mid-1970s, and red rubber double-lumen tubes were in common use 5 to 10 years ago. Disposable tubes are now widely available, and a host of different design modifications have been made to make the tubes safer and accommodate different surgical procedures.

The cuff of the adult tube has been changed from a low-volume, noncompliant cuff to a higher volume, very compliant cuff; a corresponding decrease in the incidence of tracheal stenosis has been observed. Pediatric tubes are generally uncuffed because children are more vulnerable to development of subglottic stenosis due to tube contact with the trachea. Uncuffed tubes also maximize the cross-sectional area of the airway. Oral and nasal RAE tubes (Fig. 151-11) are preconfigured to permit facial and oral surgery without interference from the proximal portion of the endotracheal tube.

A variety of special tubes are used for laser surgery.

These tubes are less likely to burn when contacted by the laser beam. Reinforced or anode tubes have an embedded wire or nylon filament spiral in the wall of the tube that prevents kinking or collapse due to external pressure (see Fig. 151-11).

The Hi-Lo Jet endotracheal tube (Mallinckrodt) has four

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Figure 151-11 Oral and nasal preshaped tubes (RAE tubes).

Anode, wire-wrapped tubes to prevent kinking.

Figure 151-12 Endotracheal tube tip with Murphy eye and bevel (see text).

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Figure 151-13 Right- and left-sided double-lumen endotracheal tubes. Note oblique bronchial cuff on the rightsided tube to accommodate right upper-lobe bronchial orifice.

lumens: one for entrained gas, a second for jet ventilation, a third for cuff inflation, and a fourth for pressure monitoring.

All single lumen tubes have a 15 mm outer diameter and connect to any standard ventilation device. Most also have a radioopaque stripe that permits tube localization on chest roentgenograms. The tip of the tube is beveled (Fig. 151-12); the bevel faces to the left because endotracheal tubes are generally inserted from the right by right-handed operators. An extra hole (Murphy eye) lies opposite to the bevel on many tubes and is designed to permit suctioning or antegrade gas flow if the bevel becomes occluded.

Finally, disposable double-lumen endotracheal tubes are now available. The Carlens and White tubes that were used in the past were equipped with a carinal hook for correct tube placement. These tubes have largely been abandoned in favor of the Robertshaw design, which has tracheal and bronchial cuffs and no hook. The tube is available in four adult sizes (35, 37, 39, and 41 French) in both right- and left-sided designs (Fig. 151-13). The right-sided tube has an oblique bronchial cuff to accommodate the takeoff of the right upper lobe orifice. Correct placement of a double-lumen tube has become easier with development of bronchoscopes small enough to pass through the narrow tube lumens.

An alternative to the double-lumen tube (the Univent tube, introduced in 1982) has a self-contained endobronchial blocker. The tube is inserted in the standard fashion, and the endobronchial blocker is then advanced (blindly or under direct vision) into the right or left main bronchus. A central lumen in the endobronchial blocker allows for inflation or deflation. While the bronchial blocker is integrated into the Univent tube construction, the same functionality can be achieved by using the Arndt wire-guided endobronchial

blocker (Cook Critical Care, Bloomington, IN). The device is a multiport airway adapter, which can be used without a tube change (unlike the Univent tube) and can be “swapped” for a standard Y-piece connector, when desired.

CONCLUSION While some of the skills developed by the early pioneers may be lost to current practitioners (Fig. 151-14), advances in pharmacology, equipment, and equipment manufacturing

Figure 151-14 Earlier diagnostic airway intervention. (From Kirstein: Archiv Laryngol Rhinol 3:156–164, 1895. Courtesy of Cushing/ Whitney Medical Library.)

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standards have greatly facilitated airway management and have made new surgical procedures possible.

SUGGESTED READING Ahrens T, Kollef MH: Early tracheostomy: Has its time arrived? Crit Care Med 32:1796–1797, 2004.

American Society of Anesthesiologists Task Force on Management of the Difficult Airway: Practice guidelines for management of the difficult airway: An updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269– 1277, 2003.

Asai T, Morris S: The laryngeal mask airway: Its features, effects and role. Can J Anaesthesiol 41:930–960, 1994.

ATLS Manual, 7th ed. American College of Surgeons, Chicago, IL 2005.

Blot F, Melot C, Commission d’Epidemiologie et de Recherche Clinique: Indications, timing, and techniques of tracheostomy in 152 French ICUs. Chest 127:1347–1352, 2005.

Brimacombe J: A proposed classification system for extraglottic airway devices. Anesthesiology 101:559, 2004.

Brimacombe J, Berry A, Verghese C: The laryngeal mask airway in critical care medicine. Int Care Med 21:361–364, 1995.

Calverlay RK: Arthur E. Guedel (1883–1956), in Rupreht J, van Lieburg MJ, Lee JA, et al (eds), Anaesthesia Essays on Its History. Berlin, Springer Verlag, 1985, pp 49–53.

Cuvelier A, Muir JF: Acute and chronic respiratory failure in patients with obesity-hypoventilation syndrome: A new challenge for noninvasive ventilation. Chest 128:483–485, 2005.

Esteban A, Frutos-Vivar F, Ferguson ND, et al: Noninvasive positive-pressure ventilation for respiratory fail-

ure after extubation. N Engl J Med 350:2452–2460, 2004.

Griffiths J, Barber VS, Morgan L, et al: Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. Br Med J 330:1243, 2005.

Holzapfel L, Chevret S, Madinier G, et al: Influence of longterm oro- or nasotracheal intubation on nosocomial maxillary sinusitis and pneumonia: Results of a prospective, randomized, clinical trial. Crit Care Med 21:1132–1138, 1993.

Keenan SP, Sinuff T, Cook DJ, et al: Does noninvasive positive pressure ventilation improve outcome in acute hypoxemic respiratory failure? A systematic review. Crit Care Med 32:2516–2523, 2004.

L’Her E: Noninvasive ventilation outside the intensive care unit: A new standard of care? Crit Care Med 33:1642–1643, 2005.

Majid A, Hill NS: Noninvasive ventilation for acute respiratory failure. Curr Opin Crit Care 11:77–81, 2005.

Mallampati SR, Gatt SP, Gugino LD, et al: A clinical sign to predict difficult tracheal intubation: A prospective study.

Can Anaesth Soc J 32:429, 1985.

Moller MG, Slaikeu JD, Bonelli P, et al: Early tracheostomy versus late tracheostomy in the surgical intensive care unit.

Am J Surg 189:293–296, 2005.

Morch ET: History of mechanical ventilation, in Kirby RR, Banner MJ, Downs JB (eds), Clinical Applications of Ventilatory Support. New York, Churchill Livingstone, revised edition 1999:1–61.

Murphy FJ: Two improved intratracheal catheters. Anesth Analg 20:102–105, 1941.

Reynolds SF, Heffner J: Airway management of the critically ill patient: Rapid-sequence intubation. Chest 127:1397– 1412, 2005.

Smith DW: Recognizable Patterns of Human Malformation, 3rd ed. Philadelphia, WB Saunders, 1987.

152 Hemodynamic and Respiratory Monitoring in Acute Respiratory Failure Barry D. Fuchs

Patrick Neligan

I. GENERAL PRINCIPLES II. INDICATIONS FOR MONITORING HEMODYNAMICS III. METHODS FOR MONITORING HEMODYNAMICS History and Physical Examination Arterial Blood Pressure Laboratory Tests Central Venous Catheterization Pulmonary Artery Catheterization Noninvasive Alternatives to the Pulmonary Artery Catheter

GENERAL PRINCIPLES Patients with acute respiratory failure (ARF) sustain significant morbidity and mortality, with adverse outcomes resulting from both the primary insult responsible for the ARF and secondary complications, many of which are preventable.

Admission of these patients to the intensive care unit (ICU) allows more for intensive monitoring in an attempt to diminish risks and guide therapeutic interventions. This chapter reviews methods currently available for monitoring hemodynamics and respiratory function in patients with ARF. A number of important goals of ICU monitoring can be identified. One is to ensure adequacy of respiratory and circulatory functions in patients who appear clinically stable.

Another is to provide close surveillance for early signs of respiratory and circulatory instability, with the presumption that early detection improves outcome. In addition, measurement of the response to therapeutic interventions, including application of supportive devices, such as endotracheal tubes and mechanical ventilators, is routinely performed in the ICU. Although life-saving, these devices, like all therapeutic interventions, are associated with risks that must be monitored.

IV. METHODS FOR MONITORING RESPIRATORY FUNCTION Oxygenation Ventilation Endotracheal Tube Placement Respiratory System Mechanics Ventilator Waveforms Inspiratory Muscle Strength Imaging in Acute Lung Injury

Finally, monitoring respiratory and hemodynamic derangements over hours to days provides valuable insight about prognosis, since the trend in physiological derangements over time predicts outcomes far better than does the severity of abnormalities on admission. Consequently, failure to improve over days, despite full support and appropriate treatment, suggests the need for alternative therapeutic strategies, including patient comfort as the primary goal of care.

Physiological parameters normally vary in critically ill patients. Furthermore, the devices used to measure these parameters are often imprecise and, at times, inaccurate. Therefore, clinical assessment and decision making should not be based, in general, on single data points. Rather, trends in data add reliability to interpretation of measurements.

INDICATIONS FOR MONITORING HEMODYNAMICS When managing patients with ARF, intensivists are regularly required to make judgments about circulatory function

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that can often be made confidently using routine monitoring equipment. However, several clinical questions become more challenging without application of more invasive or sophisticated measuring devices. These questions include: 1. For the patient with pulmonary edema, is the edema cardiogenic or noncardiogenic in origin?

2. Is hypoperfusion causing, or contributing to, the patientâ&#x20AC;&#x2122;s end-organ dysfunction?

3. Recognizing the risk of worsening hypoxemia in ARF following administration of intravenous fluids, should the patient with ARF who presents with or develops shock be given fluids? If so, how much?

4. For those patients with volume overload, given the risk of causing or exacerbating organ dysfunction, how much fluid should be removed by using diuretics or dialysis to reduce lung water and improve respiratory function?

The first question requires an estimate of ventricular preload, the second an estimate of cardiac output, and the third and fourth an assessment of the inter-relationship of both preload and cardiac output.

Varieties of both noninvasive and invasive techniques are available to monitor hemodynamics and are discussed below.

resulted in no change in vital signs. In addition, a variety of nonhemodynamic conditions (e.g., pain or anxiety) may cause significant changes in vital signs.

The remainder of the physical examination may provide information about the adequacy of perfusion and help to establish the type and cause of shock. The adequacy of cardiac output is assessed by evaluating heart rate, mean arterial pressure, pulse pressure, urine output, mental status, and extremity and skin perfusion (as reflected by peripheral temperature, capillary refill, and absence of mottling or livedo reticularis). Estimates of right and left ventricular filling pressure based on assessment of jugular venous distention or the presence or absence of lung crackles provides a presumptive diagnosis of the type of shock and helps guide initial resuscitation. When coupled with other physical findings (e.g. unequal breath sounds) the specific etiology of shock may be determined.

Despite the potential usefulness of a careful physical examination, several studies have shown that clinical assessment correlates poorly with objective measurements of central hemodynamics, including cardiac filling pressures and cardiac output. Thus, if accurate hemodynamic measurements are needed to make safe clinical decisions, use of more sophisticated monitoring devices or diagnostic evaluation is required.

Arterial Blood Pressure METHODS FOR MONITORING HEMODYNAMICS Assessment and monitoring of hemodynamics are based on a spectrum of clinical tools, ranging from a detailed history and physical examination to a variety of noninvasive and invasive techniques.

History and Physical Examination While patients with ARF may require heavy sedation, some do not, and the clinician should routinely attempt to obtain a focused history from all intubated patients.

The physical examination is equally important, providing valuable visual, auditory, and tactile information. Alterations in the general appearance of the patient, including restlessness, agitation, delirium or ventilator dyssynchrony, may be readily apparent and should be investigated as a potential first sign of a serious underlying circulatory problem, particularly in the heavily sedated patient. Alterations in heart rate and blood pressure often accompany significant pathophysiological changes (e.g., severe hypoxemia), but they may also be seen as a side effect of medications or cardiac ischemia.

A reduction in blood pressure, while attributable to many potential causes, may be a late manifestation of shock and always requires emergent evaluation. Unfortunately, changes in vital signs have limited sensitivity and specificity. In one study of normal subjects, a 25 percent reduction in blood volume

Mean arterial pressure (MAP) is the primary determinant of cerebral and myocardial blood flow. In the setting of hypotension, cardiovascular homeostatic mechanisms maintain MAP in a narrow range, in part through compensatory vasoconstriction in other, less vital, organs. However, MAP is not a useful measure of the adequacy of cardiac output. A low MAP may accompany shock, but it is a late manifestation, occurring when cardiovascular reserves are exhausted. Conversely, acute elevations in MAP may also be associated with injury to vital organs.

Patients with chronic hypertension should be maintained at a higher MAP, given the likelihood of vascular wall thickening which may limit vasodilator capacity for autoregulation. A general rule is that the MAP should be maintained within 25 percent of the patientâ&#x20AC;&#x2122;s baseline value in order to minimize the likelihood of myocardial or cerebral ischemia.

In contrast, patients with chronic liver disease may have adequate organ perfusion despite a low MAP. Nevertheless, normalizing the MAP is a primary goal in circulatory resuscitation. In patients with a normal baseline MAP, resuscitation to a goal greater than or equal to 65 mmHg has been recommended, since higher resuscitation targets fail to improve organ perfusion. Once the MAP resuscitation goal is met, other parameters more sensitive to organ perfusion are used to guide the adequacy of resuscitation.

Measurement of arterial blood pressure may be accomplished using invasive or noninvasive methods. Although in healthy patients noninvasive measurements of blood pressure

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correlate well with invasive measurements, invasive methods are preferred in patients with ARF. Noninvasive methods are unreliable in shock states, which are not uncommon in patients with ARF. Continuous monitoring of arterial blood pressure during resuscitation or titration of vasoactive agents minimizes the chance of missing a critically low or high recording between measurements. Furthermore, an indwelling arterial catheter is often required for monitoring arterial blood gases.

In contrast to MAP, the pulse pressure provides information about cardiac output that is useful in the assessment of shock. Pulse pressure is determined primarily by stroke volume and aortic compliance. Since the latter doesn’t change beat-to-beat and is assumed to be normal in most patients (except the elderly), pulse pressure changes in proportion to stroke volume. Thus, in a patient with tachycardia, a normal or stable pulse pressure suggests normal or high cardiac output, while a reduced pulse pressure indicates a low cardiac output.

In animals subjected to graded hemorrhage, the magnitude of respiratory phase-related changes in systolic arterial pressure and pulse pressure correlate with the degree of hypovolemia. Numerous studies have corroborated these findings, establishing a potential role for use of systolic and pulse pressure variation in determining fluid responsiveness in critically ill patients. Indeed, in the hypovolemic patient, central veins collapse more easily following a positive pressure breath, and ventilator-induced changes in right atrial pressure are greatest when the right atrium is underfilled and most compliant. Furthermore, hypovolemia increases the likelihood that mechanical insufflation will collapse pulmonary capillaries, increasing pulmonary vascular resistance and decreasing left ventricular filling. Finally, when the left ventricle is underfilled and operating on the steep (linear) portion of its Starling curve, it is more sensitive to changes in right ventricular output. Hence, the greater the variation in systolic and pulse pressure during a single cycle of mechanical ventilation, the more underfilled the ventricles and the more likely the response to a fluid challenge (“preload responsiveness”).

These principles may also be used to monitor the titration of positive end-expiratory pressure (PEEP) by assessing variation in systolic or pulse pressure as PEEP is applied.

PEEP can reduce cardiac output, thereby limiting or negating any improvement in arterial oxygenation on oxygen delivery.

When systolic or pulse pressure begins to vary with each mechanical breath, the level of PEEP has likely decreased cardiac preload, suggesting the need for a fluid challenge.

Respiratory variations in systolic and pulse pressure have been shown to accurately predict fluid responsiveness in critically ill patients with respiratory failure, with or without septic shock. Once validated, these findings may be more useful in predicting fluid responsiveness than other, more traditional, estimates of cardiac preload, including central venous pressure, pulmonary artery occlusion pressure, or left ventricular end-diastolic volume (LVEDV).

Hemodynamic and Respiratory Monitoring in Acute Respiratory Failure

Laboratory Tests Two laboratory tests deserve special mention for their potential role in hemodynamic monitoring: B-type natriuretic peptide (BNP) and lactic acid.

Serum levels of BNP (either B-type or N-terminal proB-type) correlate with the degree of cardiac dysfunction and have shown promise as a tool to diagnose, monitor, and predict outcome of patients with congestive heart failure (CHF) in outpatient and emergency department settings. Accordingly, interest has arisen in using BNP as a noninvasive test to monitor volume status in critically ill patients.

Unfortunately, in patients with ARF, BNP levels do not correlate with pulmonary artery occlusion pressure. BNP increases with right heart dysfunction, sepsis (with or without cardiac dysfunction), and ARF, reflecting low test specificity.

Furthermore, hypotensive patients who are in a non–steadystate condition may present acutely with an elevated BNP, despite hypovolemia, because of preexisting cardiac disease.

On the other hand, a low BNP level may be useful in ruling out cardiac dysfunction.

In assessing the net “result” of cardiac performance, namely, end-organ perfusion, an absolute value for cardiac output or index cannot be used to diagnose shock. In addition to the physical examination and assessment of selected parameters, including urine output and central or mixed venous oxygen saturation (see below), measurement of venous lactate levels represents a useful screening tool for determining the adequacy of global and regional hemodynamics.

Elevated lactate levels have also been shown to correlate with patient outcome in the ICU, although in individual patients, lactate clearance (change in level over time) is a more accurate predictor of outcome. With newer assays and sampling techniques (e.g., by finger stick) lactate levels are readily available.

In patients with ARF, lactic acidosis is most commonly caused by cellular hypoxia due to hypoperfusion or hypoxemia. Although cellular hypoxia may contribute to lactic acidosis associated with sepsis, particularly early in its course, endotoxin and other mediators may also cause lactate release due to cytopathic hypoxia via direct inhibition of the mitochondrial enzyme that metabolizes pyruvate. When a patient has an elevated lactate not explained by hypoxemia, global and regional hypoperfusion must be excluded immediately.

If the physical examination and central or mixed venous oxygen saturations (see below) are normal (suggesting normal cardiac output), ischemic bowel or extremity compartment syndrome must be considered, as should “occult sepsis,” certain drugs, or liver disease.

Central Venous Catheterization Since most patients with ARF require a central venous catheter (CVC) for administration of medications, no additional rationale or risk-benefit considerations are required to justify insertion of the line. However, the type of catheter inserted determines the extent of monitoring permitted. All

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CVCs, regardless of lumen diameter or length, can be used to transduce central venous pressure (CVP) and measure central venous blood oxygen saturation (Scvo2 ), a surrogate for true mixed venous oxygen saturation (Sco2 ). However, in order to monitor Scvo2 continuously, a special oximetric catheter (Pre-SEP, Edwards Scientific) is required.

The internal jugular (IJ) or subclavian vein (SV) is the preferred access site, since femoral lines are associated with increased rates of infection and deep venous thrombosis. The choice between SV and IJ sites is dependent on many factors, but, in general, the IJ is safer because the vein is compressible, amenable to ultrasound localization, and associated with a reduced rate of pneumothorax. However, the Centers for Disease Control and Prevention (CDC) recommends the SV site over the IJ because of a presumed lower risk of infection. Both sites are reasonable, and the decision is a function of specific patient issues and operator experience and preference.

Central Venous Pressure CVP is the downstream pressure that governs the rate of venous return to the right heart; it represents a good approximation of mean right atrial (RA) pressure. CVP can be measured accurately through a variety of catheter types, including triple lumen, tunneled, and percutaneously placed varieties. Commonly employed CVP catheter sites include the IJ, subclavian, and femoral veins.

CVP has been used to assess volume status in the diagnosis and management of shock and to infer the etiology of pulmonary edema. However, numerous studies have demonstrated flaws in this approach. Although, in some cases, a very low (less than 5 mmHg) or a very high (greater than 20 mmHg) CVP may be helpful in guiding decisions about volume status, in most patients, a single CVP value is rarely helpful.

The central venous or RA pressure is the pressure within the RA relative to atmospheric pressure. However, right ventricular preload, which is best defined as right ventricular end-diastolic volume (RVEDV), is equally dependent on the extracardiac (i.e., intrathoracic) pressure and right ventricular compliance, neither of which can be determined reliably at the bedside. Applied or intrinsic PEEP and intra-abdominal hypertension, among other conditions, may also increase extracardiac pressure.

Even if CVP correlated with RVEDV, the latter correlates poorly with LVEDV in patients with ARF because of discordance in ventricular afterload and contractility. Indeed, lung disease and the PEEP used to treat it increase pulmonary vascular resistance and may produce right ventricular failure. Furthermore, since the pericardium limits ventricular dilatation, ventricular interdependence further increases the disparity in LVEDVs and RVEDVs when differential contractility or loading conditions are present. This occurs because ventricular dilatation displaces the septum laterally and compresses the adjacent ventricle. Use of CVP in lieu of measurement of pulmonary artery occlusion pressure (PAOP) in

determining whether pulmonary edema is of cardiogenic or noncardiogenic origin is equally tenuous.

In contrast, measurement of dynamic changes in CVP and the diameters of the superior and inferior vena cavae in response to changes in intrathoracic pressure provides more clinically useful information about cardiac preload. The basis for these dynamic responses is similar to that discussed previously. Unfortunately, lack of standardization, rigorous validation of the techniques, or outcome studies preclude recommending routine clinical use.

Mixed Venous Oxygen Saturation Normally, the circulation delivers oxygen to tissues at a rate sufficient to maintain an intracellular (mitochondrial) oxygen tension above a critical threshold. If oxygen delivery (Do2 ) fails to meet tissue oxygen requirements (Vo2 ), shock exists and anaerobic metabolism ensues; if prolonged, cell death occurs.

If Do2 decreases and tissue Vo2 remains constant, a reduction in the oxygen content in mixed venous blood (Svo2 ) is observed, reflecting an increase in oxygen extraction which occurs as a result of increased diffusion. The reduced Do2 causes mitochondrial and tissue Po2 to fall, which, in turn, increases the gradient for oxygen diffusion from capillary blood to tissue. The result is a reduction in end-capillary and, hence, venous Po2 .

Since blood flow to organs is not equally distributed, and since rates of oxygen utilization are heterogeneous among organs, the venous oxygen content of blood draining from organs varies. The mixed venous oxygen content measured in the pulmonary artery (Svo2 ), which reflects “global” oxygen delivery, represents a weighted average of the product of blood flow and oxygen content from all organs. Thus, Svo2 is not sensitive to localized tissue ischemia (e.g., bowel ischemia)— an important limitation of this monitoring tool.

Based on an understanding of the determinants of Svo2 , the clinician can use the Fick equation (Eq. 1, below) to elucidate the mechanism of shock and, perhaps, to target therapy: Vo2 = CO × (arterial O2 content − venous O2 content) (1) where CO is cardiac output. Recalling that O2 content of either arterial or venous blood is the sum of hemoglobin (Hgb)-bound oxygen (1.34 ml O2 /g Hgb × [Hgb]/100 ml blood × % hemoglobin saturation) and dissolved oxygen (0.003 ml O2 /mm Hg), the following expression (Eq. 2) for mixed venous O2 is derived: Svo2 ∼ (arterial O2 content × [Hgb] × CO)/Vo2

(2)

Thus, if Sao2 is stable, Svo2 decreases if either CO or [Hgb] decreases or Vo2 increases. Since Sao2 and [Hgb] are readily measured and changes in Vo2 can be grossly estimated, the cause of a decrease in Svo2 can usually be determined quickly. Compared with alternative methods of monitoring CO, Svo2 reflects the adequacy of CO relative to oxygen requirements, which is a more valuable measurement than is

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the absolute CO. In this regard, Svo2 is also more sensitive than measurement of blood lactate (see below) as a measure of the adequacy of CO.

drostatic pressure. If PAOP never exceeds 18 mmHg, hydrostatic pulmonary edema can be excluded; however, transient spikes in left atrial pressure occurring between normal PAOP measurements can be missed. A PAOP greater than 18 mmHg is consistent with a hydrostatic cause of pulmonary edema, but high-permeability edema cannot be excluded.

Goal-Directed Therapy Recent studies indicate that when a central venous oxygen saturation (Scvo2 ) of greater than or equal to 70 percent is achieved early in the resuscitation of patients with severe sepsis, survival increases significantly. Indeed, achievement of this target as part of “goal-directed therapy” has been embraced by the critical care community, and a consensus guideline for treatment of sepsis has been published. The guideline, developed by experts from 11 multidisciplinary, international critical care societies, recommends routine monitoring of central venous oxygen saturation to guide initial resuscitation of patients with severe sepsis.

Pulmonary Artery Catheterization The pulmonary artery catheter (PAC) was first introduced into clinical practice in 1970. Since that time, the PAC has been the most commonly used device for monitoring hemodynamics in critically ill patients. It is also the most controversial. The PAC represents a reference standard for testing the accuracy and precision of noninvasive methods of assessing volume status and hemodynamic parameters. Indeed, the breadth of directly measured and derived parameters obtained using a PAC is unparalleled. However, more recently, use of the catheter has been curtailed because of data suggesting increased complications with its use and no evidence of any benefit to patient outcome.

Pulmonary Artery Occlusion Pressure The PAC is used to estimate right and left ventricular filling pressures, PAOP or “wedge” pressure, and cardiac output.

When the balloon of the catheter, “wedged” into a branch of the pulmonary artery, is inflated, a static column of blood is created downstream from the catheter tip, which extends to the point of confluence with other, unoccluded pulmonary veins. Without blood flow, a pressure drop across the static column of blood is absent, making the column a direct extension of the fluid column between the tip of the PAC and the pressure transducer. In the absence of disease in the pulmonary veins, left atrium, or mitral valve, the mean endexpiratory PAOP approximates left ventricular end-diastolic pressure (LVEDP). If “a” and “v” waves are visible in the transduced pressure recording, the mean value of the “a” wave (halfway between the top of the “a” wave and the bottom of x descent) is used to indicate the PAOP. PAOP is also used to estimate pulmonary capillary pressure in determining whether pulmonary edema is due to increased capillary permeability or hydrostatic pressure. In contrast to measuring PAOP as an estimate of LVEDP, the mean of the end-expiratory tracing is always used, even when large “v” waves are present, since the systolic pressure spike (‘v” wave) is transmitted with an equal contribution to the capillary hy-

Cardiac Output Cardiac output (CO) is measured routinely in the ICU using the thermodilution (TD) technique. The principle of TD is that by lowering the temperature of blood flowing through the right heart by injecting a bolus of saline at room temperature, the resultant change in blood temperature over time, as recorded by a thermistor at the distal port of the PAC (i.e., the area under the curve of a plot of temperature versus time), will provide an approximation of CO. With TD, CO can be measured intermittently using manual methods, or continuously using automated techniques. The manual method is based on the average value determined from 4 to 6 successive 10-ml boluses of saline injected into the proximal right atrial port of the PAC. For continuous measurements a specialized catheter with a proximal thermal filament, which heats the blood repeatedly using a brief thermal pulse, is used. Although limitations of TD methods are recognized—most notably, errors in measurement in the setting of tricuspid regurgitation—the technique provides a reasonably accurate measurement of CO. Measurement of CO using TD and a PAC is considered the gold standard to which other CO technologies are compared.

CO can also be measured indirectly with the PAC using the Fick method, based on the fact that CO is equal to oxygen consumption (Vo2 ) divided by the difference in O2 content across the circulation (i.e., the arteriovenous O2 difference).

Since Vo2 is usually not measured directly, the method is limited by inaccuracies in estimating Vo2 using body surface area alone in a critically ill patient. Hence, in patients with ARF, CO should be measured using TD unless significant tricuspid regurgitation is present. Application of the Fick method may be reasonable when values obtained by TD are unexpected.

Oxygen consumption varies significantly over time in any given patient and among patients with ARF. Furthermore, since CO normally increases directly in proportion to Vo2 and inversely with hemoglobin concentration and O2 saturation, no normal or range of normal for CO has been established in patients with ARF. Normalizing CO to body surface area for comparison with reference values is also tenuous. From a management perspective, the most important questions in these patients are whether CO is adequate for the patient’s needs, whether CO can be improved with intravenous fluids, and whether fluid can be removed by diuresis or dialysis without significant compromise of CO. Outcome Studies In the mid-1990s, a study addressing the effectiveness of the PAC purported to show that use of the PAC increased

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mortality. The report stimulated a great deal of concern about the safety and use of the PAC and promoted significant efforts at improving education about use of the catheter. Use of the PAC fell dramatically following publication of the study.

Subsequently, several randomized controlled trials were conducted to assess the value of the PAC in a variety of critically ill patients. The findings can be summarized as follows: use of the PAC does not alter patient outcome in patients undergoing high-risk surgery, those with septic shock, acute respiratory distress syndrome (ARDS) or CHF, or in patients deemed critically ill enough to require the PAC. Cautions in Using Pulmonary Artery Catheters Based on the outcome studies summarized previously, one can legitimately question whether the PAC should be used at all in patients with ARF. Proponents of PAC use cite several observations as the basis for their argument. The studies only evaluated whether use of the PAC improved overall outcome.

None included explicit, standardized treatment protocols to direct patient management using the catheter. In addition, no systematic effort was made to minimize errors in measurement and interpretation of data, particularly errors due to respiratory variation (see below). In all but one of the studies inclusion criteria were based on disease or condition, rather than a specific clinical question, thus making it difficult to rule out a potential benefit with more selective application of the catheter.

Given all of the information provided by use of the PAC, why have studies failed to show improved patient outcomes?

Several hypotheses have been proposed, including an adverse physical effect of the PAC, inaccurate data, and misinterpretation of data, promoting misguided therapeutic interventions.

Although physical complications from use of the PAC are well recognized, most are related to insertion of the central venous catheter through which the PAC is inserted. The few physical complications attributable to PAC, itself, are rare. In contrast, studies do support the notion that inaccuracies in pressure measurements or misinterpretation of data may lead to misguided treatment decisions and adverse outcomes.

Studies using standardized tests demonstrate that clinicians from a variety of countries, disciplines, and levels of experience have inadequate knowledge about the PAC and difficulty reading pressure measurements accurately. In one study, the difficulty in reading tracings was due primarily to misidentification of end-expiration; interobserver variability in PAOP measurements was greatest when recordings showed marked phasic respiratory variation.

Traditionally, clinicians have been taught to record all vascular pressures at end-expiration in order to minimize the effect of intrathoracic (i.e., juxtacardiac) pressure. Unfortunately, widely available resources for PAC education have misleading instructions on identification of end-expiration; in particular, these resources suggest that end-expiration in patients on mechanical ventilation is defined by the lowest point on the vascular pressure waveform. However, it is well known that patients may actively inspire during assist-control

A

B

Figure 152-1 A. In this patient on mechanical ventilation in the AC-mode, pulmonary artery occlusion pressure (PAOP) is read conventionally at the lowest vascular pressure (arrow), which is 3 mmHg. B . With airway pressure (PAW ) displayed concurrently, in place of the electrocardiogram tracing, it becomes obvious that vascular pressure falls throughout inspiration due to inspiratory effort. The true end-expiratory time point is shown by the arrow, which is a PAOP of 15 mmHg.

mechanical ventilation, causing intrathoracic (and, hence, vascular) pressure to fall, rather than rise. Consequently, in such patients the lowest point on the vascular pressure waveform corresponds to end-inspiration, while end-expiration coincides with the highest point on the tracing (Fig. 1521A). Erroneous selection of the nadir pressure results in vascular pressure readings (including CVP and PAOP) that may markedly underestimate the true values; the magnitude of the error is proportional to patient inspiratory effort. The significance of this potential error has likely increased in the last 5 years because of a trend toward use of minimal sedation and reduced tidal volumes in patients with ARF, each of which may increase respiratory effort and further lower pleural pressure during inspiration.

Attempts to visually quantify and coordinate patient ventilatory efforts with the waveform displayed on a bedside monitor can be problematic, especially with higher respiratory frequencies observed in patients ventilated with lower tidal volumes. Addition of a simultaneous airway pressure (PAW ) signal to strip chart recordings of CVP and PAOP may provide a reliable signal for accurately timing end-expiration and significantly reduce interobserver variability (Fig. 1521B). Intensivists who use the PAC should consider concurrent

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30 — 20 — 10 — 0— A

30 —

Figure 152-2 A. In this patient on mechanical ventilation in AC-mode, an airway pressure (PAW ) tracing (not shown) confirms that end-expiratory pulmonary artery occlusion pressure (PAOP) is 25 mmHg (arrows) with respiratory variation of greater than 20 mmHg. B . Immediately after paralysis with succinylcholine repeat PAOP is 12 mmHg with minimal respiratory variation.

20 — 10 — 0— B

1. How does one account for the effect of forced expiration when interpreting CVP or PAOP? 2. How does one recognize when forced expiration is present?

With regard to the first question, studies performed in patients with significant respiratory variation in PAOP demonstrated that the PAOP before and after muscular paralysis was similar to the PAOP measured as the midpoint between values recorded at end-expiration (peak) and end-inspiration (nadir) prior to paralysis—a value more closely approximated by the mean PAOP (Figs. 152-2 and 152-3).

Recognition of forced expiration is necessary to determine when to apply this “midpoint” rule in the measurement of PAOP. In the absence of significant (greater than 8 mmHg) respiratory variation in PAOP, one can rule out forced expiration. Abdominal inspection and palpation usually confirm forced expiration if inward movement of the lateral and anterior abdominal walls occurs during expiration. Of note, if sig-

nificant respiratory variation occurs in the absence of forced expiration (from isolated inspiratory muscle effort alone), the pressures read at end-expiration are accurate. If it is not clear from the physical examination whether forced expiration is present, simultaneous measurement of CVP or PAOP and intra-abdominal pressure can be performed. Forced expiration is easily identified if PAOP and intra-abdominal pressure increase concordantly during expiration (Fig. 152-4), and is ruled out if the phasic changes in the two pressure recordings are discordant.

Additional factors may result in misinterpretation of PAOP as an estimate of left ventricular preload. For example, PAOP may correlate poorly with LVEDV because of alterations in juxtacardiac pressure (e.g., from increases from set or occult PEEP or intra-abdominal hypertension) or ventricular compliance (e.g., due to ischemia or hypoxia). Finally,

40 Mid-point (mmHg)

monitor display of PAW and vascular pressures when recordings show significant (greater than 8 mmHg) respiratory variation in CVP or PAOP. Patients with significant phasic respiratory variation may also exhale forcefully, and significant errors in interpretation of hemodynamic data may occur despite measurement of PAW . Expiratory muscle use during exhalation increases abdominal pressure, which is transmitted directly across the relaxed diaphragm, resulting in increased end-expiratory pleural pressure. This, in turn, increases all vascular pressures in the thorax. Since transmural filling pressures of the right and left ventricles are unchanged, if unrecognized, forced expiration causes CVP and PAOP to be overestimated by an amount directly proportional to expiratory muscle effort (Fig. 152-2).

The significance of forced expiration raises two important questions:

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Relaxed Ppao (mmHg)

Figure 152-3 Relationship between the relaxed pulmonary artery occlusion pressure (PAOP) (post-paralysis) and the midpoint PAOP (obtained during active respiratory effort). (From Hoyt JD, Leatherman JW: Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure. Intensive Care Med 23:1125, 1997.) (Reproduced with permission.)

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IABP

PAOP

30201006040200A

IABP

3020100-

PAOP

6040200B

Figure 152-4 Arrows indicate end-exhalation. A. In this strip chart recording from a patient on AC-mechanical ventilation, there is minimal respiratory variation in pulmonary artery occlusion pressure (PAOP). Note, intra-abdominal blood pressure (IABP) rises during inhalation and falls during exhalation, paralleling the change in PAOP. B . On the same ventilator settings with less sedation, there is marked respiratory variation (â&#x2C6;ź30 mmHg) in PAOP. PAOP falls during inspiration consistent with active respiratory effort. Forced exhalation is confirmed by seeing a rise in IABP during exhalation (â&#x2C6;ź20 mmHg), in parallel with the PAOP. If IABP falls during exhalation in this setting, forced exhalation can be ruled out (not shown).

because of pericardial constraint of ventricular enlargement, right ventricular overload may cause PAOP and LVEDV to change reciprocally (increases in PAOP associated with decreases in LVEDV).

Given the limitations of using pressure measurements to estimate cardiac preload (end-diastolic volume), a modified PAC was developed to allow continuous measurements of RVEDV using TD. The catheter contains a proximally located thermal filament which emits thermal pulses to heat the blood, while a sensitive and rapidly responsive thermistor located at the distal end of the catheter records temperature in the pulmonary artery. Input from the electrocardiogram allows timing of ventricular systole and a beat-to-beat analysis of the temperature decay curve. Right ventricular ejection fraction is computed from the exponential slope of the temperature decay curve and mean heart rate; RVEDV is calculated as stroke volume divided by ejection fraction.

Studies have shown that RVEDV correlates well with CO, and specified thresholds of RVEDV may distinguish patients with hypovolemia who are fluid-responsive. However, other studies have not corroborated these thresholds and have failed to show that RVEDV can reliably predict preload responsiveness. Thus, routine use of these catheters cannot be recommended.

Even if the problems with measuring, recording, and interpreting PAOP and CO could be eliminated, PAC-guided care will likely be limited by lack of standardized guidelines for treatment based on the hemodynamic data obtained.

Noninvasive Alternatives to the Pulmonary Artery Catheter A variety of noninvasive techniques, including echocardiography, have been used as alternatives to PACs. They are described briefly below.

Echocardiography Echocardiography is the most commonly used technique for cardiac imaging in critically ill patients, providing unique and important diagnostic information for the evaluation of shock, including assessment of biventricular volumes, contractility, valvular function, and pericardial anatomy.

In patients who are adequately resuscitated, but who continue to have low output shock, early use of echocardiography to assess biventricular volumes and function is important. In the setting of an elevated PAOP and low CO, systolic dysfunction cannot be differentiated from any of the many states of ventricular compression, including cardiac

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tamponade, massive pleural effusion, mediastinal fluid collections, auto-PEEP, pneumothorax, or ventricular interdependence. When right ventricular dysfunction is suspected as the primary cause of shock, echocardiographic findings may assist in establishing the etiology.

The presence of pulmonary arterial hypertension, which can be estimated in most critically ill patients, suggests pulmonary embolism, nonthrombotic pulmonary embolism, ARDS, or severe lung hyperinflation; right ventricular infarction is unlikely. Furthermore, in the setting of pulmonary hypertension, the echocardiogram may point to an acute process (e.g., pulmonary emboli, rather than chronic pulmonary hypertension), if regional akinesia of the right ventricular free wall and normal apical wall motion is found (“McConnell sign”). The diagnosis of acute pulmonary embolism is highly likely if a free floating clot is seen in the right atrium or ventricle, and the diagnosis is confirmed if a clot is visualized in the proximal pulmonary arteries.

Both volumetric and Doppler-based techniques have been developed to allow echocardiographic estimates of cardiac preload and CO. Volumetric measurements using twodimensional imaging of ventricular size during diastole and systole provide the basis for estimates of preload, stroke volume, and contractility. Signs of hypovolemia on the twodimensional echocardiogram include a hyperdynamic ventricle and appearance of “kissing walls” at end-systole. CO can be determined using volumetric estimates of stroke volume, calculated as the difference in end-systolic and end-diastolic volumes. However, Doppler-based measurements of CO are more accurate.

The Doppler method relies on the principle that flow in a cylinder (e.g., the aorta) is equal to cross-sectional area of the aorta times the blood-flow velocity. Velocity, in turn, is determined according to the principle that when ultrasonic waves are emitted perpendicular to flowing blood, the change in frequency of the sound waves reflected back is proportional to the blood-flow velocity. Stroke volume is derived from these two measurements; when multiplied by heart rate, CO is determined. Doppler-based estimates of CO have been shown to correlate reasonably well with those obtained

by TD. Doppler techniques can also be used to estimate PAOP by assessing the relative velocity of blood flow through the mitral valve during early and late diastole. However, estimates of PAOP using this technique do not correlate well with direct measurements using a PAC. In any event, given the limitations of PAOP as a measure of preload, there is little utility in estimating PAOP using this technique, except to provide a rough estimate about whether or not pulmonary edema is on a cardiogenic basis.

Echocardiography is performed at the bedside using either the transthoracic esophageal (TTE) or transesophageal (TEE) routes. Since rapidity of diagnosis is important, TTE is the initial study of choice in the ICU, given the technique’s widespread availability. TTE provides adequate assessment in the vast majority of mechanically ventilated patients; morbid obesity and emphysema may necessitate TEE. TEE is also

recommended as the initial study to rule out aortic dissection. Although considered a very low-risk procedure, TEE is not risk free. TTE is associated with trauma to the upper gastrointestinal tract and is contraindicated in patients with known or suspected pathology of the esophagus or cervical spine.

One of the major limitations of both TTE and TEE is that neither allows for continuous hemodynamic monitoring.

To fill this need, an esophageal catheter with a distal Doppler probe that allows measurement of CO continuously has been developed. The device is easy to use and eliminates the need for a specialist in Doppler signal acquisition, although some operator experience is required to ensure proficiency. Numerous studies have evaluated the accuracy of these devices relative to TD-based assessment of CO. A recent review concluded that esophageal Doppler does not provide accurate assessment of absolute CO, but its validity is high for monitoring changes in CO in critically ill patients.

Finally, imaging dynamic changes in the diameter of the central veins and assessment of the velocity of aortic blood flow may predict preload responsiveness. Using portable echocardiography in completely sedated patients in septic shock respiratory collapse of the inferior or superior vena cavae in response to a large (8 to 10 ml/kg) mechanically delivered breath suggests hypovolemia and potential fluid responsiveness.

In conclusion, bedside echocardiography is the diagnostic study of choice for unexplained or persistent circulatory shock. For patients who require continuous monitoring of CO, esophageal Doppler is a reasonable alternative to a PAC. The technique can be used to guide fluid resuscitation for optimization of CO in acute shock and guide a diuresis strategy to minimize pulmonary edema without adversely affecting peripheral perfusion. Although esophageal Doppler monitoring has been increasingly used as a substitute for a PAC, we still favor use of the PAC over esophageal Doppler for monitoring hemodynamics continuously in selected patients.

Other Methods Several other noninvasive methods have been developed for determining CO, including expired carbon dioxide (CO2 ) analysis (indirect Fick method), lithium dilution method, measurement of thoracic impedance, and pulse contour analysis. The techniques are approved by the Food & Drug Administration (FDA) and are currently available, but none have been validated sufficiently to justify their routine use in critically ill patients.

Indirect Fick Method

By imposing a brief period of partial rebreathing through the addition of dead space to the breathing circuit, changes in CO2 elimination and end-tidal CO2 concentration can be effected. Comparison of the new resultant steady-state values compared to baseline allows calculation of CO using the Fick principle. The technique has serious limitations in patients

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with ARF. Spontaneous breathing and hypocapnea limit its accuracy. Steady-state conditions must be achieved to assure accuracy, and intrapulmonary shunt affects the sensitivity of the measurement.

METHODS FOR MONITORING RESPIRATORY FUNCTION A number of respiratory parameters are routinely monitored in patients with ARF and are discussed briefly below.

Thoracic Electrical Bioimpedance

Thoracic electrical bioimpedance is based on the principle that the chest is an electrical conductor whose impedance is altered by changes in blood volume and blood-flow velocity with each heartbeat. By placing electrical currenttransmitting and voltage-sensing electrodes on the chest, stroke volume may be calculated based on an equation incorporating values for the baseline and maximum rate of change in chest impedance. Unfortunately, although noninvasive, measurement of thoracic electrical bioimpedance is confounded by too many factors in patients with ARF to support its routine clinical use.

Transpulmonary Indicator Dilution Techniques: Thermodilution and Lithium Dilution

Transpulmonary indicator dilution techniques are based on intravenous injection of an indicator solution (e.g., cold saline or lithium chloride) and measurement of the change in temperature or lithium concentration, respectively, over time using a special arterial catheter. For the TD technique, the catheter is equipped with a thermistor at its tip; for the lithium-based technique, blood samples must be drawn successively for external measurement using a lithium-sensitive electrode. The greater the degree of indicator dilution (i.e., the less the change in temperature or lithium concentration) over time, the greater the CO. Values derived from each of these techniques correlate well with PAC-determined values. However, more data are needed to determine the accuracy of these techniques under a wide variety of clinical conditions.

Pulse Contour Analysis

This method is based on the concept that changes in the contour of the arterial pressure waveform are proportional to stroke volume and are dependent on the mechanical properties of the aorta. Since the latter is relatively constant from beat to beat, changes in the pulse pressure correlate with changes in stroke volume. The technique requires calibration with an independent measurement of CO—currently accomplished by combining the indicator dilution technique (to determine mean CO) with assessment of beat-to-beat variability in the arterial pressure waveform (as a measure of stroke volume). Most studies have shown fair to good agreement of the technique with that of PAC-based measurements. Major limitations include the requirements for a femoral or axillary arterial catheter and frequent recalibration in patients who are hemodynamically unstable. Although the technique is promising, more studies are required to validate its usefulness and applicability in critically ill patients with ARF.

Oxygenation In the ICU, oxygenation is generally monitored using pulse oximetry, arterial blood gas analysis, or transcutaneous methods.

Pulse Oximetry Pulse oximeters are universally deployed in the monitoring of perioperative and critically ill patients. Unique as monitoring devices, they provide useful data regarding oxyhemoglobin saturation (Spo2 ), heart rate, pulse volume, and tissue perfusion.

Pulse oximeters use the spectrophotometric characteristics of pulsatile arterial blood to determine oxygen saturation and heart rate. Oxygenated blood absorbs light at 660 nm (red light), while deoxygenated blood absorbs light preferentially at 940 nm (infrared light). The oximeter consists of two light-emitting diodes (wavelengths, 600 nm and 940 nm) and two light-collecting sensors that measure the amount of red and infrared light emerging from tissues traversed by the light rays. The relative light absorption by oxyhemoglobin and deoxyhemoglobin is analyzed by the device and an oxygen saturation is calculated. The sensing function of the device is directed at pulsatile arterial blood, while local “noise” arising from the tissues is ignored. The result is a continuous qualitative measurement of oxyhemoglobin saturation.

Use of pulse oximetry has not been shown to improve clinical outcomes, but epidemiological data have demonstrated a significant reduction in anesthesia-related morbidity. Although the technique accurately predicts arterial oxygen tension, the relationship between Pao2 and Spo2 is nonlinear, as dictated by the oxyhemoglobin dissociation curve. Accuracy falls off substantially at low-oxygen tensions, and saturation readings of less than 80 percent cannot be used reliably to guide oxygen therapy.

The use of pulse oximeters is limited by a number of factors. The devices are designed to measure levels of oxygenated and deoxygenated hemoglobin, but no provision is made for measurement error in the presence of dyshemoglobinemias, including carboxyhemoglobinemia and methemoglobinemia. Since carboxyhemoglobin absorbs red light, conventional oximeters cannot distinguish oxy- from carboxyhemoglobin. In clinical situations where carbon monoxide poisoning is suspected, co-oximetry is essential. Co-oximeters measure reduced hemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin.

An additional source of error in using oximeters is abnormal patient movement (e.g., due to agitation). Low blood flow, hypotension, vasoconstriction, or hypothermia reduce pulsatility of capillary blood, resulting in underreading or

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no reading of oxygen saturation. Conversely, increased venous pulsation, such as occurs with tricuspid regurgitation, may result in an erroneously low reading by the device. Finally, oximetry-determined saturation is inaccurate on the steep part of the oxyhemoglobin dissociation curve. While the trend between directly measured arterial saturation and Spo2 appears accurate, the correlation between the two is not; a drop in Spo2 below 90 percent must be considered a potentially significant clinical event.

Ptco2 accurately represents Po2 ; however, the values are not identical, with Ptco2 approximately equal to 80 percent of Pao2 . Under conditions of hypoperfusion, the relationship may vary dramatically. In addition, various tissues have different values for Ptco2 , depending on local perfusion, skin thickness, and anatomic location (e.g., trunk versus limb).

In order to prevent burns, the electrodes must be changed every 4 to 6 h, and the membrane must be changed and calibrated before each use. Despite these limitations and lack of widespread use, transcutaneous oxygen monitoring remains a useful device in multicomponent oxygen monitoring systems.

Arterial Blood Gases Blood gas analyzers have been available for 40 years and provide accurate measurement of Pao2 , Paco2 , and pH. From these primary determinations, a number of parameters are calculated, including serum bicarbonate, base deficit or base excess, and oxyhemoglobin saturation.

Through application of the alveolar gas equation (see Chapters 11 and 34) arterial blood gas analysis is used commonly in calculating the alveolar-arterial oxygen gradient, a number that reflects the severity of ventilation-perfusion abnormalities. A significant limitation of the alveolar-arterial oxygen gradient is that it varies directly with FIo2 ; consequently, changes in the value may not reflect changes in the underlying disease process. An alternative calculation—the ratio of Pao2 to FIo2 , (“PF ratio”), which does not vary with FIo2 —has been used as a measure permitting comparisons of gas exchange at differing levels of FIo2 .

The PF ratio has been incorporated into consensus definitions of ARDS and acute lung injury (ALI). A PF ratio less than or equal to 300 defines ALI; a ratio less than or equal to 200 defines ARDS. Neither the alveolar-arterial oxygen gradient nor the PF ratio takes into account differences in mean airway pressure. Although comparisons using the PF ratio would be more accurate if arterial blood was sampled uniformly at end-expiration and in the absence of PEEP, clinical constraints may preclude such sampling conditions.

Ventilation Clinical assessment of CO2 metabolism is usually considered with regard to the amount of gas that is dissolved in plasma (Paco2 ), the amount present in the exhaled tidal volume (endtidal CO2 ), and the total extracellular content (total CO2 or bicarbonate concentration). In the setting of respiratory failure, these measurements provide information on adequacy of ventilation, percentage of physiological dead space, acid-base balance, and nutritional status.

In progressive chronic respiratory failure, as the ability to eliminate CO2 declines, total body CO2 stores (bicarbonate) increase. The ratio of total CO2 to bicarbonate concentration provides an indication of the acuity of the respiratory failure. Changes in Paco2 may also be related to changes in base deficit or excess.

Assessment of CO2 elimination forms the basis of calculating the ratio of dead space to tidal volume—a useful physiological construct in gauging the severity of underlying lung disease in respiratory failure. Through application of the modified Bohr equation (see Chapter 34), the ratio of dead space to tidal volume (Vd /Vt ) is calculated in Eq. (3) as follows: Vd /Vt = (Paco2 − PEco2 )/Paco2

Transcutaneous Oxygen Monitoring The commonly employed oxygen electrode is based on a modification of the electrode developed in 1956. The device is constructed of a platinum wire tip surrounded by glass.

Covered by a polyurethane membrane which is permeable to oxygen, the electrode responds in a linear fashion to oxygen in the gaseous or liquid phase over a concentration range of 1 to 100 percent. The margin of error is less than 1 percent.

Although the oxygen electrode has been employed predominantly for blood gas measurements, it can be modified for use in the continuous, noninvasive measurement of transcutaneous oxygen tension (Ptco2 ). Electrode heating of the skin changes the structure of lipoproteins in the stratum corneum from the gel to the sol state, allowing rapid diffusion of oxygen from subcutaneous tissues through the skin. In addition, electrode heating prevents local vasoconstriction, ensuring that Ptco2 closely reflects Pao2 . In hemodynamically stable patients who have good tissue perfusion,

(3)

where PEco2 is mean expired CO2 . PEco2 can be measured using a metabolic monitor that collects expired gas over 5 min. Alternatively, main stream or side stream capnometry can be used to measure PEco2 .

In the normal lung, alveolar Pco2 is equivalent to Paco2 and can be estimated by sampling expired end-tidal gas. However, in the presence of significant physiological dead space (as in ARF), end-tidal CO2 grossly underestimates Paco2 .

Given this limitation, aside from confirming endotracheal tube placement, end-tidal CO2 measurements are not used routinely in managing patients with ARF.

Endotracheal Tube Placement Monitoring endotracheal tube (ETT) position is an important aspect of critical care. An extremely common complication of intubation is misplacement of the ETT, with passage into the right main bronchus. Ideally, the ETT tip should be located 4 to 5 cm above the carina. In the case of a tracheotomy,

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the tube tip should be located about halfway between the tracheotomy stoma and the carina.

ETT placement can be confirmed in several ways: (1) by assessing for the presence of bilateral breath sounds during breath delivery, (2) by palpation of the ETT cuff in the jugular notch, (3) with chest radiography, or (4) using fiberoptic bronchoscopy.

In addition to tube placement, pressure within the ETT cuff should be measured regularly. The cuff is inflated to create a seal between the side wall of the ETT and the tracheal wall. Since capillary perfusion pressure of the tracheal mucosa is approximately 25 cm H2 O, cuff pressure should be kept below this level to prevent ischemia, which may lead to ulceration, inflammation, and, if severe, tracheal dilatation.

In addition, the injured tracheal segment may develop fibrosis and, ultimately, stenosis. On the other hand, evidence exists that low cuff pressures may increase the risk of pneumonia, presumably by promoting microaspiration. Thus, the current recommendation for optimal tracheal cuff pressure is 20 to 25 cm H2 O. Following intubation and ETT positioning, the tube cuff should be slowly and progressively inflated just to the point of loss of gas leak occurring with ventilation—the socalled “minimal occluding pressure” technique (some experts advocate use of the “minimal leak” technique). To measure cuff pressure, an aneroid manometer is connected to the cuff ’s pilot tube (the tube from which the balloon is inflated). If excessive cuff pressure is required to maintain an adequate tracheal seal, the ETT is likely too narrow for the patient’s trachea. If cuff pressure increases over time, tracheomalacia should be suspected and the tube changed to one with a foam cuff.

The presence of a cuff leak may be problematic, particularly in patients who are critically ill. Signs of leak include an audible noise during inspiration, audible patient phonation, frothy mouth secretions with each breath, a difference between set and exhaled tidal volumes, inadequate ventilatory volumes, hypoxemia, and the presence of a thrill over the trachea. Cuff leaks may be caused by rupture or herniation of the cuff, proximal displacement of the ETT, pilot tube valve malfunction, or inadvertent cuff deflation.

Respiratory System Mechanics Assessment of respiratory system mechanics may be useful in differentiating the etiology of ARF (e.g., restrictive versus obstructive disease or upper versus lower airway obstruction), troubleshooting the cause of new episodes of clinical instability, assessing the effectiveness of therapeutic interventions (e.g., use of bronchodilators or application of PEEP), or minimizing the risk of ventilator-induced lung injury.

Airway Pressure Airway pressure is an important variable which is routinely monitored during mechanical ventilation. Respiratory pressures are usually referenced to atmospheric pressure (“single-ended” pressures). Electromechanical transducers

(or aneroid manometers), which convert pressure to electrical current, may be located in the patient’s ventilator circuit or esophagus. The most common site of pressure transduction is the wye connector (the connector that joins the inspiratory and expiratory limbs of the ventilator circuit), although the distal ETT can also be used. Pressure measured within the ventilator or ventilator circuit is referred to as “airway pressure,” Paw (or, more correctly, airway opening pressure, Pao ), while that measured at the tip of the ETT is referred to as “tracheal pressure,” Ptr . Pressure measured within the esophagus is referred to as “esophageal pressure,” Pes .

Five different pressure measurements are commonly made during the respiratory cycle: (1) peak airway pressure (Ppeak ), (2) plateau pressure (Pplat ), (3) mean airway pressure (Pmean ), (4) positive end-expiratory pressure (PEEP), and (5) auto-PEEP (also called intrinsic PEEP). Measurement of tracheal pressure at the tip of the distal ETT provides an assessment of pressure in the native airway, as the effect of flow through the ETT is eliminated. Esophageal pressure provides an estimate of pleural pressure. Although not used routinely in clinical practice, esophageal pressure can be used to estimate transpulmonary pressure, which is a more accurate measure of alveolar distending pressure than is plateau pressure.

Accurate measurement of airway resistance requires that airway pressures be determined using constant flow conditions (i.e., a square flow-wave profile) (Fig. 152-5). Most modern ventilators make the flow-wave profile adjustment automatically when the “mechanics function” of the device is selected. In addition, since airway pressures are altered by respiratory muscle contraction, patients must be fully relaxed and exert minimal breathing effort. These conditions may be accomplished by using ventilator settings designed to fully support the patient (e.g., by providing a level of ventilatory support that exceeds patient demand, or administration of sedation). For quality control, ventilator waveforms should

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PPEAK Airflow resistance PPLAT PEEP

Respiratory system compliance

lpm 50 25 0 −25 −50 −75 −100

Figure 152-5 Inspiratory hold maneuver during constant flow in a volume-controlled breath. Note the significant difference between the patient’s peak airway pressure (48 cm H2 O) and plateau pressure (26 cm H2 O), indicative of increased airways resistance.

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be assessed during the mechanics maneuver to ensure the conditions have been met.

Ppeak represents the total pressure the ventilator must generate in order to overcome the impedance of the respiratory system, including airflow resistance, elastic load (lung and chest wall distention), and any threshold load due to dynamic hyperinflation (from auto-PEEP). When interpreting Ppeak , in addition to impedance, several other factors must be considered, including peak flow rate, waveform profile (square or decelerating), and tidal volume. This is a very important point in clinical practice, since Ppeak may erroneously be considered as the primary determinant of barotrauma. When a high Ppeak is observed (as commonly seen in obstructive lung diseases), an attempt to lower Ppeak by reducing inspiratory flow rate may achieve the opposite effect. The risk of barotrauma may be increased by the resulting increment in plateau pressure that occurs as a consequence of reduced expiratory time and increased auto-PEEP. Pplat reflects the pressure within the alveoli at endinhalation and is the most important pressure to monitor in preventing barotrauma. The goal is less than or equal to 30 mmHg in all cases of ARF, including those due to obstructive airway disease. Pplat is measured at end-inspiration during a period of zero flow, which is achieved by applying an inspiratory “hold” during volume-controlled ventilation (see Fig. 152-5). Pplat is always lower than Ppeak by an amount equal to the pressure required to drive inspiratory flow through the ventilator circuit, ETT, and airways.

For the patient with a high Paw , the clinician can determine rapidly whether the problem is resistive (airway) or elastic (lung or chest wall) in nature by assessing the pressure gradient between Ppeak and Pplat and between Pplat and total PEEP (set PEEP plus auto-PEEP) (see Fig. 152-5).

For instance, if the differential between Ppeak and Pplat increases, airflow resistance must have increased; potential causes include bronchospasm, a kink in the ETT, and increased airway secretions. In contrast, if the rise in Paw is unaccompanied by an increase in the Ppeak –Pplat pressure gradient (i.e., both Ppeak and Pplat increase relative to total PEEP), the elastic load must have increased; causes include loss of lung volume (e.g., right main bronchus intubation; lobar atelectasis; or an alveolar filling process, such as pneumonia or CHF) or a stiffer chest wall apparatus (e.g., pleural effusion or intra-abdominal hypertension).

These routinely measured airway pressures are also used to calculate additional important measures of respiratory mechanics, including airway resistance and respiratory compliance.

Dividing the Ppeak –Pplat pressure gradient by inspiratory flow rate yields airway resistance. The normal value depends on the size of the ETT, but it is typically about 5 to 15 cm H2 O/L/s.

Respiratory system compliance, expressed as ml/cm H2 O, is calculated as tidal volume divided by the difference between Pplat and total PEEP. Failure to consider autoPEEP in the calculation results in overestimation of compli-

ance. Normal respiratory system compliance is greater than 60 ml/cm H2 O. Auto-PEEP Auto-PEEP (also known as “intrinsic” PEEP) refers to the positive pressure within alveoli at end-expiration that has not been generated by a ventilator. A form of naturally occurring auto-PEEP may be observed with forced exhalation that occurs during heavy exercise. In this case, lung mechanics may be normal, and expiratory muscle force maintains positive intrathoracic and airway pressures throughout expiration; functional residual capacity (FRC) may be normal or decreased.

In contrast, two other types of auto-PEEP are associated with dynamic hyperinflation. In one, auto-PEEP results from a high minute ventilatory requirement, as occurs in ARDS, where insufficient expiratory time promotes incomplete expiration before delivery of the next breath. In the other, more common variety, auto-PEEP results primarily from delayed emptying of alveoli due to airflow obstruction, as most commonly seen in status asthmaticus or an acute exacerbation of chronic obstructive pulmonary disease.

The development of auto-PEEP is determined by three factors: tidal volume, expiratory time, and the respiratory system expiratory time constant (the product of resistance and compliance). Auto-PEEP poses significant problems in pressure-targeted mechanical ventilation, where the additional PEEP reduces ventilator driving pressure, and consequently, tidal volume. In contrast, in volume-targeted ventilation, auto-PEEP causes Paw and Pplat to increase, which, in turn, increase end-inspiratory lung volumes and alveolar “stretch.”

In a mechanically ventilated patient, auto-PEEP is most easily identified by examining the ventilator flow waveform and observing that expiratory flow does not return to zero before initiation of the next breath (Fig. 152-6). Quantification of the magnitude of auto-PEEP is achieved by implementing a prolonged “expiratory hold” maneuver, during which equilibration of pressure throughout the ventilatory circuit is achieved (Fig. 152-7). A mechanically ventilated patient who is generating spontaneous breaths presents a challenge for measurement of auto-PEEP, as airway occlusion usually incites increased respiratory drive. Under these circumstances, an esophageal balloon catheter may be used to estimate pleural pressure, and auto-PEEP calculated by measuring the magnitude of the negative deflection in esophageal pressure from the start of inspiratory effort to onset of inspiratory flow. This method underestimates auto-PEEP in patients with significant airway obstruction.

If auto-PEEP arises as a result of hyperinflation due to expiratory flow limitation in a spontaneously breathing, ventilated patient, external PEEP upto, but not exceeding, the level of auto-PEEP can be applied to offset the increased work of breathing associated with the additional inspiratory threshold load. The applied PEEP does not impact expiratory flow or lung volume. The applied PEEP should be no greater than 85 percent of the measured auto-PEEP.

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Volume Normal lung

Expiration

FLOW UIP

ARDS lung

Figure 152-6 The presence of auto-PEEP is identified from the flow waveform. The next breath commences before expiratory flow returns to zero.

Pressure

Pressure-Volume Curves In the normal lung, compliance is greatest at FRC, decreasing progressively as lung volume increases (Fig. 152-8). In patients with diffuse parenchymal lung disease (e.g., ARDS) FRC declines, and pressure application at low lung volume yields little increase in volume. With increasing levels of inflation pressure, a point is reached (the lower inflection point, or LIP) beyond which compliance improves dramatically. With further increments in inflation pressure, another point is reached beyond which the pressure-volume curve flattens, defining the upper inflection point (UIP).

A significant reduction in mortality has been demonstrated in patients with ARF using PEEP levels greater than LIP as part of a ventilator protocol based on pressure-control, inverse-ratio, and pressure-limited techniques. The findings may relate to a reduction in the lung injury thought to be related to phasic opening and closing of lung units (“atelectrauma”) and resulting epithelial disruption, local inflammation, cytokine release, and tissue destruction. Therefore, some have advocated as an optimal ventilation strategy for minimizing ventilator-induced lung injury (VILI) application of

Valve closed Auto PEEP level

Flow

Ins

Valve closed

Exp Figure 152-7 Expiratory hold technique to quantify auto-PEEP. The expiratory valve is closed during an expiratory ‘‘hold” at the end of a set expiratory time. When flow equals zero, airway pressure rises to the auto-PEEP level.

LIP Pressure

Figure 152-8 Pressure-volume curves of normal and diseased lungs. In the curve in acute respiratory distress syndrome (ARDS), two inflection points have been identified: a lower inflection point (LIP) and an upper inflection point (UIP).

a PEEP level 2 cm H2 O above the LIP and maintenance of Pplat just below the UIP. However, although many believe that the LIP represents the critical opening pressure of the majority of atelectatic alveoli, alveolar recruitment has been shown to continue for the duration of inspiration. In addition, investigators have found no such inflection point in patients with obvious alveolar recruitment demonstrated by computed tomography (CT).

Esophageal Pressure Measurement of respiratory system compliance includes the mechanical properties of the lung and chest wall. By measuring pleural pressure, the transmural distending pressure of the lung can be calculated. Although regional variation in pleural pressure exists, measurement of lung compliance is based on the change in pleural pressure, rather than its absolute value.

Pleural pressure is usually estimated from esophageal pressure, which is recorded using an esophageal catheter.

The typical device consists of a latex balloon which is 10 cm long and has several holes. The catheter is inserted into the lower esophagus (usually to a depth of about 40 cm). At this level, artifact from the beating heart is minimized. The adequacy of esophageal balloon positioning is confirmed by having the patient perform inspiratory attempts against an occluded airway. The esophageal pressure changes should be equal (±10 percent) to airway pressure changes. In the paralyzed patient, external chest compressions are used to create pressure fluctuations.

Ventilator Waveforms Most modern ventilators include a spirometer or flow monitor to measure the volume and flow of gas passing through the ventilator circuit with each breath. Data are analyzed by a microprocessor in the ventilator and are graphically represented

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as waveforms. The most commonly displayed waveforms include volume, pressure, and flow. Plots of flow versus volume (flow-volume loops) and pressure versus volume can be constructed electronically from the measurements. Monitoring of ventilator waveforms provides useful information about patient-ventilator synchrony, circuit leaks, patient-ventilator disconnection, development of auto-PEEP, and airway obstruction.

resulting electrical potential is measured, and the process is repeated for numerous configurations of applied current.

Potential applications for the technique include titration of PEEP, evaluation of alveolar recruitment maneuvers, and investigation of phasic atelectasis. At present, EIT remains a research tool.

The use of CT has dramatically changed the way in which clinicians view ARDS. Because of the diffuse, widespread distribution of abnormalities seen on conventional radiographs, ARDS was traditionally considered a homogeneous pathological process. However, application of CT imaging in ARDS has demonstrated that the disorder is quite heterogeneous. Furthermore, the advent of high-resolution, multidetector scanners will expand the number of applications of this technology—for example, in the diagnosis of the etiology of the lung injury (pulmonary versus extrapulmonary), nature of the injury (pneumonia versus lung contusion), or progression of injury from inflammation to fibrosis. In addition, the presence of complications (e.g., occult barotrauma or pleuropulmonary infection) and the response to interventions (e.g., adjustment of PEEP, implementation of alveolar recruitment maneuvers, incorporation of spontaneous breathing during mechanical ventilation, or determination of the need for insertion of chest drains) will be more readily discerned.

Inspiratory Muscle Strength Respiratory muscle strength may be assessed by measuring maximum inspiratory and expiratory pressures generated against an occluded airway. This is most easily measured using an aneroid manometer. Inspiratory strength is measured at FRC, where the length-tension relationship of the inspiratory muscles is optimal. The pressure determined by this maneuver is known as the negative inspiratory force (NIF) or maximal inspiratory pressure (MIP). Clearly, the measurement is dependent on the intensity of the inspiratory effort, which may be suboptimal in uncooperative or unconscious patients. The problem can be circumvented by performing the maneuver off the ventilator, using a one-way valve; the NIF is measured over 10 sequential breaths or 30 s. By measuring over time, progressively lower lung volumes are reached and the inspiratory drive increases progressively, promoting a maximal effort. Although the utility of the NIF as a predictor of weaning outcome has fallen out of favor, it remains a useful measurement in troubleshooting reasons for ventilator dependence.

Maximal expiratory pressure (MEP) is measured at total lung capacity, where the expiratory muscle lengthtension relationship is optimal. Although not routinely employed in clinical practice, MEP may have use in predicting extubation outcome in selected patient populations.

Imaging in Acute Lung Injury A variety of imaging techniques may be useful in monitoring patients with ARF, including diaphragm ultrasound, electrical impedance activity (EIT), and CT. The thickness of the diaphragm changes dynamically between the relaxed phase and maximum inspiration. Ultrasound can be used to evaluate changes in diaphragm thickness in the so-called “zone of apposition,” where the lateral portions of the diaphragm lie adjacent and parallel to the lateral chest walls. The technique is noninvasive, inexpensive, and free of ionizing radiation. Diaphragm ultrasound has proved useful in the diagnosis of diaphragm paralysis in the context of ARF. EIT is a relatively new bedside imaging technique in which an image of gas distribution within the chest is constructed during different phases of respiration. Although the technique’s spatial resolution is limited in comparison with CT, its temporal resolution is better. With EIT, a series of eight pairs of electrodes are placed around the chest circumference and a current applied between electrode pairs. The

SUGGESTED READING Al-Kharrat T, Zarich S, Amoteng-Adjepong Y, et al: Analysis of observer variability in measurement of pulmonary artery occlusion pressures. Am J Respir Crit Care Med 160:415, 1999.

Breen PH: Arterial blood gas and pH analysis. Clinical approach and interpretation. Anesth Clin North Am 19:885– 906, 2001 Caples SM, Hubmayr RD: Respiratory monitoring tools in the intensive care unit. Curr Opin Crit Care 9:230–235, 2003.

Chaney J, Derdack S: Minimally invasive hemodynamic monitoring for the intensivist: Current and emergent technology. Crit Care Med 30:2338–2345, 2002.

Chazal I, Hubmayr RD: Novel aspects of pulmonary mechanics in intensive care. Br J Anaesth 91:81–91, 2003.

Connors AF Jr, Speroff T, Dawson NV, et al: The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators [comment].

JAMA 276:889, 1996.

Dellinger RP, Carlet JM, Masur H, et al: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 32:858, 2004.

Gattinoni L, Caironi P, Pelosi P, et al: What has computed tomography taught us about the acute respiratory distress syndrome? Am J Respir Crit Care Med 164:1701–1711, 2001.

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Georgopoulos D, Prinianakis G, Kondili E: Bedside waveforms interpretation as a tool to identify patient-ventilator asynchronies. Intensive Care Med 32:34–47, 2006.

Harvey S, Harison DA, Singer M, et al: Assessment of the clinical effectiveness of PAC in management of patients in intensive care (PAC-MAN): A RCT. Lancet 366:472, 2005.

Hoyt JD, Leatherman JW: Interpretation of the pulmonary artery occlusion pressure in mechanically ventilated patients with large respiratory excursions in intrathoracic pressure. Intensive Care Med 23:1125, 1997.

Michard F, Teboul JL: Predicting fluid responsiveness in ICU patients: A critical analysis of the evidence. Chest 121:2000, 2002.

Puybasset L, Gusman P, Muller JC, et al: Regional distribution of gas and tissue in acute respiratory distress syndrome.

III. Consequences for the effects of positive end-expiratory pressure. CT Scan ARDS Study Group. Adult Respiratory Distress Syndrome. Intensive Care Med 26:1215–1227, 2000.

Reinhart K, Bloos F: The value of venous oximetry. Curr Opin Crit Care 11:259, 2005.

Richard, C, Warszawski J, Anguel N, et al: Early use of the PAC and outcomes in patients with shock and acute respiratory distress syndrome. A randomized controlled trial. JAMA 290:2713, 2003.

Rivers E, Nguyen B, Havstad S, et al: Early goal directed therapy in the treatment of severe sepsis and septic shock.

N Engl J Med 345:1368, 2001.

Rizvi K, deBoisblanc BP, Truwit JD, et al: The effect of airway pressure display on interobserver variability in the assessment of vascular pressures in patients with acute lung injury and ARDS. Crit Care Med 33:98, 2005.

Schuster DP, Seeman MD: Temporary muscle paralysis for accurate measurement of pulmonary artery occlusion pressure. Chest 84:593, 1983.

Stenqvist O: Practical assessment of respiratory mechanics.

Br J Anaesth 91:92–105, 2003.

Zakynthinos SG, Vassilakopoulos T, Zakynthinos E, et al: Contribution of expiratory muscle pressure to dynamic intrinsic positive end-expiratory pressure. Am J Respir Crit Care Med 162:1633, 2000.

153 Principles of Mechanical Ventilation Martin J. Tobin

I. OBJECTIVES AND INDICATIONS FOR MECHANICAL VENTILATION II. MODES OF MECHANICAL VENTILATION Controlled Mechanical Ventilation Assist-Control Ventilation Intermittent Mandatory Ventilation Pressure-Support Ventilation New Modes III. VENTILATOR SETTINGS Triggering Tidal Volume Respiratory Rate

The historical evolution of mechanical ventilation is rich and built on advances in many fields, including endeavors by anatomists, chemists, explorers, physiologists, and clinicians. In 1543, Vesalius demonstrated that positive-pressure ventilation could be used to resuscitate a dying animal. Bellows ventilation was advocated by various lay bodies in the resuscitation of near-drowning victims late in the eighteenth century. In 1827, however, Leroy demonstrated that overzealous bellows inflation could result in pneumothoraces. Official bodies condemned the technique, and, thus, early in its infancy, positive-pressure ventilation was banned from use.

Around this time, negative-pressure ventilators were developed and later popularized as a panacea for a wide variety of ailments.

The modern era of mechanical ventilation was ushered in by Bjorn Ibsen in response to epidemic of bulbar poliomyelitis in Copenhagen in 1952. In the first 3 weeks of the epidemic, 31 patients had been treated with negativepressure respirators, and 27 had died. Ibsen advised immediate tracheostomy and the use of positive-pressure ventilation with manual positive pressure from a rubber bag, as was then customary in the operating room. Hundreds of medical students worked in relays, delivering bag ventilation during

Inspiratory Flow Rate Fractional Inspired Oxygen Concentration Positive End-Expiratory Pressure IV. BRONCHODILATOR THERAPY V. MONITORING AND COMPLICATIONS VI. WEANING Causes of Weaning Failure Timing of the Weaning Process Weaning Trials Extubation

the epidemic; shortly thereafter, machines were introduced to deliver positive-pressure ventilation. Over the following 40 years, ventilators changed enormously in appearance, becoming more sophisticated and versatile and having enhanced capabilities for monitoring and alarming.

OBJECTIVES AND INDICATIONS FOR MECHANICAL VENTILATION The objectives of mechanical ventilation are listed in Table 153-1. In isolation, hypoxemia of mild to moderate severity can be managed by administration of oxygen (O2 ) through a face mask. With more severe hypoxemia secondary ˙ mismatching, it is to shunt or ventilation-perfusion (V˙ a /Q) difficult to guarantee the delivery of a high fractional inspired oxygen concentration (Fio2 ) through a face mask. Moreover, these patients are commonly in considerable distress.

Thus, intubation helps by ensuring delivery of the required Fio2 , and positive-pressure ventilation helps by recruiting collapsed lung units, leading to improved matching of ventilation and perfusion.

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Table 153-1 Objectives of Mechanical Ventilation Improve pulmonary gas exchange Reverse hypoxemia Relieve acute respiratory acidosis Relieve respiratory distress Decrease oxygen cost of breathing Reverse respiratory muscle fatigue Alter pressure-volume relationships Prevent or reverse atelectasis Improve lung compliance Prevent further lung injury Permit lung and airway healing Avoid complications

with atelectasis or acute lung injury because breathing occurs on the low, flat portion of the pressure-volume curve.

By shifting tidal ventilation to the steep, compliant portion of the curve, mechanical ventilation can decrease respiratory work.

Commonly listed indications for mechanical ventilation include acute respiratory failure, exacerbation of chronic respiratory failure (e.g., secondary to infection, bronchoconstriction, or heart failure), coma, and neuromuscular disease. Many patients with these same conditions, however, do not require ventilator assistance. Indeed, the most common, and honest, reason that mechanical ventilation is instituted is a tautology: A physician thinks that “the patient looks like he (or she) needs to be placed on the ventilator.”

Mechanical ventilation is most commonly instituted based on a physician’s clinical gestalt, formed through assessing a patient’s signs and symptoms, rather than because a patient satisfies a certain set of criteria on a checklist. It is important to ground this decision on solid knowledge of pulmonary pathophysiology.

source: From: Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056–1061, 1994, with permission.

Acute progressive respiratory acidosis is a major indication for mechanical ventilation, although simpler measures can sometimes reverse the process. For example, among patients with acute severe asthma and hypercapnia, hypercapnia resolves with standard bronchodilator therapy, without the need for mechanical ventilation, in more than 90 percent of patients. If a patient has severe respiratory depression that is expected to be slow in resolving (e.g., certain drug overdoses), intubation and mechanical ventilation should be instituted without delay.

A substantial proportion of patients who require (and benefit from) mechanical ventilation have relatively normal arterial blood gases but have clinical signs of increased work of breathing: nasal flaring; vigorous activity of the sternomastoid muscles; tracheal tug; recession of the suprasternal, supraclavicular, and intercostal spaces; paradoxical motion of the abdomen; and pulsus paradoxus. This picture of a patient “tiring out” is the most common reason for instituting mechanical ventilation. The increase in work of breathing may be the result of increased airway resistance, increased stiffness of the lungs or chest wall, or the presence of a threshold inspiratory load secondary to auto- or intrinsic positive end-expiratory pressure (PEEPi ).

Increased respiratory work increases the O2 cost of breathing to as much as 50 percent of total O2 consumption. By decreasing respiratory work, mechanical ventilation allows precious O2 stores to be rerouted to other vulnerable tissue beds. To substantially reduce patient effort, the ventilator must cycle in unison with the patient’s central respiratory rhythm (Fig. 153-1). For perfect synchronization, the period of mechanical inflation must match the period of neural inspiratory time (the duration of inspiratory effort), and the period of mechanical inactivity must match the neural expiratory time. Work of breathing is increased in patients

MODES OF MECHANICAL VENTILATION The term mode refers to the relationship among various breath types (mandatory, assisted, supported, and spontaneous), as well as inspiratory phase variables.

Controlled Mechanical Ventilation In controlled mechanical ventilation, the ventilator delivers all breaths at a preset rate, and the patient cannot trigger the machine. In the volume-targeted mode, the breaths have a preset volume—so-called volume-controlled ventilation. When the breaths are pressure limited and time cycled, the mode is termed pressure-controlled ventilation. Use of volume-controlled ventilation is largely restricted to patients who are apneic as a result of brain damage, sedation, or paralysis.

Assist-Control Ventilation In the assist-control mode, the ventilator delivers a breath either when triggered by the patient’s inspiratory effort (pressure- or flow-triggered) or, independently, if such an effort does not occur within a preselected time period. All breaths are delivered under positive pressure by the machine, but unlike controlled mechanical ventilation, the patient’s triggering effort can exceed the preset rate. If the patient’s spontaneous rate drops below the preset back-up rate, controlled ventilation is provided. The pressure to achieve the set tidal volume may be provided solely by the machine or, in part, by the patient. By design, delivered tidal volume is not influenced by patient effort. The more the patient contributes, the less pressure is provided by the machine, and ventilator-generated pressure bears an inverse relationship to patient-generated pressure.

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Figure 153-1 Flow, airway pressure, and inspiratory and expiratory muscle activity in a patient with chronic obstructive pulmonary disease who received pressure-support ventilation at an airway pressure of 20 cm H2 O. The electromyograms in the lower portion of the figure show inspiratory muscle activity in the patient’s diaphragm and expiratory muscle activity in the transversus abdominis. The patient’s increased inspiratory effort caused the airway pressure to fall below the set sensitivity (−2 cm H2 O), and inadequate delivery of flow by the ventilator resulted in a scooped contour on the airway-pressure curve during inspiration. While the ventilator was still pumping gas into the patient, his expiratory muscles were recruited, causing a bump in the airway-pressure curve. That the flow never returned to zero throughout expiration reflected the presence of PEEPi . The broken red line shows airway pressure in another patient, who generated just enough effort to trigger the ventilator and in whom there was adequate delivery of gas by the ventilator. (Data are from Jubran A, Van de Graaff WB, Tobin MJ: Variability of patient-ventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:129– 136, 1995; Parthasarathy S, Jubran A, Tobin MJ: Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:1471–1478, 1998. Reproduced with permission from Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001.)

The ventilator cycles off when the preset tidal volume is reached, and machine inspiratory time may be shorter or longer than the patient’s intrinsic (neural) inspiratory time.

If the set tidal volume is reached before the end of neural inspiratory time, the machine cycles off while the patient’s inspiratory effort continues. If the patient’s inspiratory effort ceases before the set tidal volume is reached, the machine increases pressure to provide continued inspiratory flow. The amount of active work performed by a patient ventilated in the assist-control mode is critically dependent on the trig-

ger sensitivity and inspiratory flow settings. Even when these settings are selected appropriately, patients actively perform about one-third of the work performed by the ventilator during passive conditions.

Intermittent Mandatory Ventilation With intermittent mandatory ventilation (IMV), the patient receives periodic positive-pressure breaths from the ventilator at a preset volume and rate, but the patient can also breathe

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Figure 153-2 Electromyograms of the diaphragm (EMGdi) and sternocleidomastoid muscles (EMGscm) in a patient receiving synchronized intermittent mandatory ventilation. Similar intensity and duration of electrical activity during assisted (A) and spontaneous (S) cycles are demonstrated. Paw = airway pressure; Pes = esophageal pressure. (From Imsand C, Feihl F, Perret C, et al: Regulation of inspiratory neuromuscular output during synchronized intermittent mechanical ventilation. Anesthesiology 80:13– 22, 1994, with permission.)

spontaneously between these mandatory breaths. A problem unforeseen at the time IMV was introduced is the difficulty that patients encounter in trying to adapt to the intermittent nature of ventilator assistance. It had been assumed that the degree of respiratory muscle rest achieved by IMV would be proportional to the number of mandatory breaths delivered.

Studies, however, have demonstrated that inspiratory effort is equivalent for spontaneous and assisted breaths during IMV (Fig. 153-2). Indeed, the tension-time index for both spontaneous and assisted breaths is above the threshold associated with respiratory muscle fatigue at IMV rates of 14 breaths per minute or less. At a moderate level of machine assistance (at which the ventilator accounts for 20 to 50 percent of total ventilation), electromyographic activity of the diaphragm and sternocleidomastoid muscles is equivalent for assisted and spontaneous breaths. These findings suggest that respiratory center output is preprogrammed and does not adjust to breath-to-breath changes in load, as occur during IMV. As a result, IMV may contribute to development of respiratory muscle fatigue or prevent its recovery.

Pressure-Support Ventilation Pressure-support ventilation is patient triggered, like assistcontrol ventilation and IMV, but differs in that it is pressure targeted and flow cycled. The physician sets a level of pressure that augments every spontaneous effort, and the patient can alter respiratory frequency, inspiratory time, and tidal

volume. Tidal volume is determined by the pressure setting, the patient’s effort, and pulmonary mechanics, in contrast to assist-control ventilation and IMV, in which a guaranteed volume is delivered. With volume-targeted ventilation, the inspiratory flow setting is a crucial determinant of patient work. There is no flow setting with pressure-support ventilation, although the initial peak flow determines the speed of pressurization and the initial pressure ramp profile.

The level of pressure delivered by the ventilator is usually adjusted in accordance with changes in the patient’s respiratory frequency. However, the frequency that signals a satisfactory level of respiratory muscle rest has never been well defined, and recommendations range from 16 to 30 breaths per minute.

Several investigators have shown that pressure support is very effective in decreasing the work of inspiration. The degree of inspiratory muscle unloading, however, is variable, with a coefficient of variation of up to 96 percent among patients. Pressure-support does not decrease PEEPi in patients with chronic obstructive pulmonary disease (COPD). Thus, at a pressure support of 20 cm H2 O, PEEPi may account for two-thirds of total inspiratory effort.

Cycling to exhalation is triggered by a decrease in inspiratory flow to a preset level, such as 5 L/min or 25 percent of peak inspiratory flow, depending on the manufacturer’s algorithm (Fig. 153-3). The algorithm for “cyclingoff ” of mechanical inflation causes problems in patients with COPD, because increases in resistance and compliance produce a slow time constant (of the respiratory system). The longer time needed for flow to fall to the threshold value can cause mechanical inflation to persist into neural expiration.

Figure 153-3 Airway pressure (Paw ) and inspiratory (Insp) and expiratory (Exp) flow during pressure support ventilation in patients with normal and obstructed airways. Patient effort triggers the ventilator to deliver a preset pressure, and inspiratory assistance continues until the flow rate falls to 25 percent of the peak inspiratory flow. In patients with airway obstruction who have a prolonged time constant, more time is required for flow to decrease to this threshold value, so that neural expiration commences before the termination of mechanical inflation. The resulting activation of the expiratory muscles hastens the fall in flow, but it also results in dyssynchrony between the patient’s neuromuscular activity and the mechanical phase of the ventilator–-socalled ‘‘fighting the ventilator.”

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In 12 patients with COPD receiving pressure support of 20 cm H2 O, investigators found that five recruited their expiratory muscles while the machine was still inflating the thorax. Interestingly, the patients who recruited their expiratory muscles during mechanical inflation had an average time constant of 0.54 seconds, as compared with an average of 0.38 seconds in the patients who did not exhibit expiratory muscle activity.

The persistence of mechanical inflation into neural expiration is very uncomfortable, as well recognized with use of inverse-ratio ventilation.

New Modes New modes of mechanical ventilation are frequently introduced. Each has an acronym, and the jargon is inhibiting to those unfamiliar with it. Yet each new mode involves nothing more than a modification of the manner in which positive pressure is delivered to the airway and of the interplay between mechanical assistance and the patient’s respiratory effort. The purpose of a new mode may be to enhance respiratory muscle rest, prevent deconditioning, improve gas exchange, prevent lung damage, enhance coordination between ventilator assistance and patient respiratory effort, and foster lung healing; the priority given to each goal varies.

VENTILATOR SETTINGS Ventilator settings are based on the patient’s size and clinical condition. Determination of the settings is a dynamic

Principles of Mechanical Ventilation

process, based on a patient’s physiological response, rather than on a fixed set of numbers. The settings require repeated readjustment over the period of ventilator dependency. Such an iterative process requires careful respiratory monitoring.

Triggering Many ventilators employ pressure triggering, whereby a decrease in circuit pressure is required to initiate ventilator assistance. Patients reach the set sensitivity by activating their inspiratory muscles. When the threshold is reached, however, inspiratory neurons do not simply switch off. Consequently, the patient may expend considerable inspiratory effort throughout a machine-cycled inflation. The level of patient effort during this post-trigger phase is closely related to a patient’s respiratory drive at the point of triggering. As such, measures that decrease respiratory drive may enhance respiratory muscle rest during mechanical ventilation.

If respiratory drive at the point of triggering is important, one might expect that effort during the time of triggering would determine patient effort during the remainder of inspiration. To elucidate this issue, investigators applied graded levels of pressure support in eleven critically ill patients. They achieved a fourfold reduction in overall patient effort. Yet patient effort during the time of triggering did not change. The constancy of effort during the trigger phase was probably secondary to different factors becoming operational as the level of ventilator assistance was varied (Fig. 1534). Thus, increases in the level of ventilator assistance do

Figure 153-4 Graded increases in pressure support produced a decrease in total pressure-time product (PTP) per breath (closed symbols), although PTP during the trigger phase (open symbols) did not change (left panel). The constancy of PTP during triggering probably resulted from different factors becoming operational at different levels of assistance (right panel). At low levels of pressure support, respiratory drive (dP/dt) and PEEPi were high, but triggering time was short, resulting in a large change in pleural pressure over a brief interval. At high levels of pressure support, dP/dt and PEEPi were low, but triggering time was long, resulting in a smaller change in pleural pressure over a longer time. (Based on data from Leung P, Jubran A, Tobin MJ: Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med 155:1940–1948, 1997; Tobin MJ, Jubran A, Laghi F: Patient-ventilator interaction. Am J Respir Crit Care Med 163:1059–1063, 2001, with permission.)

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to counterbalance the elastic recoil; it then must reach the set sensitivity.

The time at which a patient initiates an expiratory effort (in relation to the cycling of the ventilator) partly determines the success of the ensuing inspiratory effort in triggering the machine. The relationship between the onset of expiratory muscle activity and termination of mechanical inflation by the ventilator has been quantified. At a pressure support of 20 cm H2 O, mechanical inflation continues for a longer time into neural expiration in the breaths preceding nontriggering attempts. Continuation of mechanical inflation into neural expiration counters expiratory flow, and also decreases the time available for unopposed exhalation. Consequently, elastic recoil increases. In turn, a greater inspiratory effort will be needed to achieve effective triggering. In this way, the time at which a patient commences an expiratory effort (in relation to cycling-off of mechanical inflation) partly determines the success of the ensuing inspiratory effort in triggering the ventilator.

Tidal Volume Figure 153-5 Recordings of tidal volume, inspiratory (I) and expiratory (E) flow, airway pressure (Paw ), and esophageal pressure (Pes ) in a patient with COPD receiving pressure-support ventilation. Approximately half of the patient’s inspiratory efforts do not succeed in triggering the ventilator. Triggering occurs only when the patient generates Pes more negative than −8 cm H2 O (indicated by the interrupted horizontal line), a pressure equal in magnitude to the opposing elastic recoil pressure. Expiratory flow exhibits a biphasic pattern, with momentary braking signaling ineffective inspiratory effort. Thus, monitoring of expiratory flow provides a more accurate measurement of the patient’s intrinsic respiratory rate than does the number of machine cycles displayed on the bedside monitor. (From Tobin MJ, Jubran A: Pathophysiology of failure to wean from mechanical ventilation. Schweiz Med Wochenschr 124:2138–2145, 1994, with permission.)

not substantially decrease patient effort during the time of triggering.

The display of airway pressure and flow tracings on ventilator screens has increased awareness that inspiratory effort is frequently insufficient to trigger the ventilator. At high levels of mechanical assistance, up to one-third of a patient’s inspiratory efforts may fail to trigger the machine (Fig. 153-5).The number of ineffective triggering attempts increases in direct proportion to the level of ventilator assistance. Surprisingly, unsuccessful triggering is not the result of poor inspiratory effort. In a study of factors contributing to ineffective triggering, effort was noted to be more than one-third greater when the threshold for triggering the ventilator was not reached than when it was. Breaths that do not reach the threshold for triggering the ventilator have higher tidal volumes and shorter expiratory times than do breaths that do trigger the ventilator. Consequently, elasticrecoil pressure builds up within the thorax in the form of PEEPi . To trigger the ventilator, the patient’s inspiratory effort has to first generate a negative intrathoracic pressure in order

In the past, use of a tidal volume setting of 10 to 15 ml/kg had been the standard recommendation. This setting is still used by many anesthesiologists for patients without lung disease who are undergoing surgery. Since the early 1990s, however, lower tidal volumes have been used when ventilating patients in medical intensive care units (ICUs). The change in practice was precipitated by research in experimental animals that provided convincing evidence of severe lung injury induced by alveolar overdistension. A 1990 retrospective study of patients with the acute respiratory distress syndrome (ARDS) revealed a 60 percent decrease in the expected mortality rate with use of lower tidal volumes. Subsequent randomized trials, including that conducted by the ARDS Network investigators, revealed a significantly lower mortality with a tidal volume of 6 ml/kg compared with a tidal volume of 12 ml/kg.

Three other controlled trials, however, did not reveal a lower mortality using the lower tidal volume.

To understand the discrepant findings among the five randomized trials, a meta-analysis was undertaken. The analysis focused on plateau pressure, which is the airway pressure during an end-inspiratory pause. The low tidal volume arms of the three negative studies had plateau pressures that were at least as low as in the two positive studies. Thus, authors of the meta-analysis concluded that use of low tidal volumes did not lower mortality. The control arms of the three negative studies had plateau pressures that were comparable to those of usual practice (as reflected by plateau pressures before randomization). The control arms of the two positive studies, however, had plateau pressures higher than those used in usual practice (plateaus above 35 cm H2 O versus plateaus of 29 to 31 cm H2 O). Thus, the conclusion from the meta-analysis was that the control arms of the two positive studies were associated with increased mortality.

A subsequent analysis of the data from the ARDS Network study revealed that respiratory compliance had a major

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influence on the response to the setting of tidal volume. If compliance was low before randomization, lowering of tidal volume decreased mortality from 42 to 29 percent. If compliance was high, however, lowering of tidal volume increased mortality from 21 to 37 percent. Thus, a low tidal volume is not appropriate for every patient with ARDS. Instead, it is essential to characterize each patient’s pathophysiology and to customize the ventilator settings accordingly.

Respiratory Rate Correct setting of the ventilator rate depends on the mode of ventilation employed. With assist-control ventilation, the ventilator supplies a breath in response to each patient effort. With this mode, physicians commonly pay little attention to the machine rate, which may be set much lower than the patient’s spontaneous rate. This gap results in two problems: (a) If the patient has a sudden decrease in respiratory center output, a low machine rate results in serious hypoventilation. (b) A large discrepancy between the patient’s spontaneous rate and the machine’s back-up rate results in a respiratory cycle with an inverse inspiratory-to-expiratory time (I:E) ratio.

Development of an inverse I:E ratio arises because inspiratory time (Ti) on the machine remains fixed at the initial setting and does not change in response to increases in the patient’s spontaneous rate (Fig. 153-6). For example, if the machine rate is initially set at 12 breaths per minute (Ttot of 5 seconds) and Ti set at 1.65 seconds (either set directly or indirectly as a consequence of the volume and flow settings), then Te will be 3.35 seconds. The I:E ratio will be 1:2.

If the patient’s spontaneous respiratory rate is increased to 25 breaths per minute, TTOT will be 2.4 seconds. Because Ti remains fixed at 1.65 seconds, Te will be 0.75 s, and the I:E ratio will be 2:1. Such inverse-ratio ventilation is very uncomfortable and may lead to increased sedative use, or even to use of neuromuscular blockade, simply because of inappropriate

Figure 153-6 Effect of interaction between a patient’s respiratory rate and the ventilator back-up rate on inspiratory time– expiratory time ratio (I:E) during assist-control ventilation. Ventilator back-up rate is 12 breaths per minute and inspiratory time (TI) 1.65 seconds. Left panel. If the patient’s intrinsic respiratory (fpt ) rate is also 12 breaths per minute, the total respiratory cycle time (TTOT ) is 5.0 seconds, the expiratory time (TE) is 3.35 seconds, and the I:E ratio is 1:2. Right panel. If the patient’s respiratory rate increases to 25 breaths per minute, the new TTOT is 2.4 seconds, TE is 0.75 seconds, and I:E is 1:0.45 (or, as more conventionally noted, 2.2:1).

Principles of Mechanical Ventilation

setting of the back-up rate. Based on these considerations, the back-up rate during assist-control ventilation should be set at approximately four breaths less than the patient’s spontaneous rate.

With IMV, the ventilator (or mandatory) rate is initially set high and then gradually reduced according to patient tolerance. Unfortunately, titration is often based on data from arterial blood gases, and even a small number of ventilator breaths can result in acceptable values for Pao2 and Paco2 but achieve little or no respiratory muscle rest in patients with increased work of breathing. In ventilator-dependent patients, work of breathing at IMV rates of 14 breaths per minute or less may be sufficient to induce respiratory muscle fatigue.

With PS ventilation, the ventilator rate is not set.

Inspiratory Flow Rate Clinicians initially set the inspiratory flow rate at a default value, such as 60 L/min. Many critically ill patients, however, have an elevated respiratory drive, and the initial flow setting may be insufficient to meet flow demands. As a result, patients will struggle against their own respiratory impedance and that of the ventilator. Consequently, work of breathing increases.

Clinicians sometimes increase flow in order to shorten the inspiratory time and increase the expiratory time. However, an increase in flow causes immediate and persistent tachypnea; as a result, expiratory time may be shortened. In a study of healthy subjects, increases in inspiratory flow from 30 L/min to 60 and 90 L/min caused increases in respiratory rate of 20 and 41 percent, respectively.

One of the main reasons that clinicians increase inspiratory flow is to decrease inspiratory time, in hope of allowing more time for expiration and, thereby, decreasing PEEPi , especially in patients with COPD. Because increased flow usually leads to an increase in respiratory rate, the expected shortening of expiratory time might actually increase PEEPi .

An investigation of this phenomenon was conducted in 10 patients with COPD (Fig. 153-7). As with healthy subjects, an increase in flow from 30 to 90 L/min caused respiratory rate to increase from 16 to 21 breaths per minute. Despite the increase in rate, PEEPi fell from 7.0 to 6.4 cm H2 O. The decrease in PEEPi arose because of an increase in expiratory time (from 2.1 to 2.3 seconds), which allowed more time for lung deflation. Why did expiratory time increase? An increase in inspiratory flow is usually achieved by shortening of mechanical inspiratory time. The shortened inspiratory time combined with time-constant inhomogeneity of COPD causes overinflation of some lung units to persist into neural expiration. Continued inflation during neural expiration causes stimulation of the vagus nerve, which prolongs expiratory time.

When adjusting the flow rate and trigger sensitivity, examination of the contour of the airway pressure waveform is helpful (Fig. 153-8). Ideally, the waveform should show a smooth rise and convex appearance during inspiration. In

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Figure 153-7 Continuous recordings of flow, esophageal pressure (Pes), and the sum of rib cage and abdominal motion, in a patient with chronic obstructive pulmonary disease receiving assist-control ventilation at a constant tidal volume. As flow increased from 30 to 60 and 90 L/min (from right to left), frequency increased (from 18 to 23 and 26 breaths/min, respectively), PEEPi decreased (from 15.6 to 14.4 and 13.3 cm H2 O, respectively), and end-expiratory lung volume also fell. Increases in flow from 30 L/min to 60 and 90 L/min also led to decreases in the swings in Pes from 21.5 to 19.5 and 16.8 cm H2 O, respectively. (Reproduced from Laghi F, Segal J, Choe WK, et al: Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:1365–1370, 2001.)

contrast, a prolonged negative phase, with excessive scalloping of the tracing, indicates unsatisfactory settings of sensitivity or flow.

Fractional Inspired Oxygen Concentration Correction of hypoxemia and its prevention are major goals in mechanically ventilated patients. Many predictive equations have been published to aid in selecting an appropriate

Figure 153-8 Airway-pressure waveforms recorded during assist-control ventilation. The tracings represent changes in airway pressure during inspiration in a completely relaxed patient, and in patients making slight (center tracing) and strenuous efforts (tracing on right) to breathe. The distance between the dashed line (representing controlled ventilation) and the solid line (representing spontaneous breathing) is proportional to the patient’s work of breathing. (From Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056–1061, 1994, with permission.)

Fio2 , but none is sufficiently accurate to substitute for a trialand-error approach. Initially, Fio2 is set at a high value (often 1.0) to ensure adequate oxygenation. Thereafter, the lowest Fio2 that achieves satisfactory arterial oxygenation should be selected. The usual target is a Pao2 of 60 mmHg or an arterial saturation (Sao2 ) of 90 percent; higher values do not substantially enhance tissue oxygenation. Although it is customary to wait 30 min to assess the response to a change in Fio2 , the effect is usually well defined within 10 min. When using arterial blood samples to assess oxygenation, a target of 90 percent for Sao2 is appropriate. If pulse oximetry is employed, a Spo2 target may result in values for Pao2 as low as 41 mmHg. In white patients, a target of 92 percent for Spo2 indicates satisfactory oxygenation. In black patients, however, this target may still result in significant hypoxemia.

In experimental animals, hyperoxia produces diffuse alveolar damage, with histologic changes that are indistinguishable from ARDS resulting from any other cause. No diagnostic tests distinguish O2 -induced injury from progression of the underlying disease. Thus, the possibility of O2 toxicity should be considered in any patient receiving an Fio2 of more than 0.50 to 0.60 for 24 to 48 hours or longer. Healthy human subjects who inhale 100 percent O2 develop acute tracheobronchitis, manifested as substernal discomfort, cough, sore throat, nasal congestion, eye and ear discomfort, paresthesias, and fatigue. Symptoms begin within 4 hours; bronchoscopic features of tracheal inflammation are evident after

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6 hours. Retrosternal discomfort also occurs with an Fio2 of 0.75 but not with an Fio2 of 0.50. Hyperoxia causes absorption atelectasis in lung units with low V˙ a /Q˙ ratios, because the rate of absorption of O2 from the alveoli into the bloodstream is faster than the rate of replenishment from inspired gas. Such atelectasis results in a small shunt (approximately 3 percent) in healthy elderly subjects and requires only about 6 minutes to develop.

A decrease in vital capacity is probably the best indicator of O2 toxicity. In several studies of healthy volunteers breathing 50 percent O2 over 7 to 28 days, little, if any, change in vital capacity was observed. When healthy subjects breathed 100 percent O2 , a decrease in static lung compliance was observed within 3 hours. This decrease resolved readily with deep breathing, suggesting that the decreased compliance was caused by absorption atelectasis, rather than direct toxicity.

Exposure of healthy subjects to 100 percent O2 for as long as 4 days resulted in only modest reductions in vital capacity, and gas exchange function returned to normal with air breathing.

Overall, studies in human subjects reveal much less parenchymal injury than has been observed in animals. It has been suggested the risk of O2 toxicity might be greater in patients who have coexisting lung injury, but ironically, indirect data suggest that patients with ARDS have a reduced risk of O2 toxicity. Exuded plasma proteins and intra-alveolar hemorrhage provide a medium that is rich in antioxidant enzyme capacity and helps to protect against O2 toxicity. Death in experimental animals exposed to prolonged hyperoxia is usually attributed to acute lung injury. Several investigators, however, have reported a terminal course characterized by severe cardiac embarrassment associated with focal areas of myocardial necrosis on microscopy.

In the face of potential O2 toxicity, the only possible strategy is to reduce the Fio2 to the lowest level compatible with adequate systemic oxygenation. Thus, excess O2 demand should be minimized, and measures to enhance systemic oxygenation optimized. Although excessive O2 administration should be avoided, there is more to fear from severe hypoxemia than from the potential damage that might result from hyperoxia.

Positive End-Expiratory Pressure The beneficial effects of positive end-expiratory pressure (PEEP) include improvement in arterial oxygenation, improvement in lung compliance, alleviation of excessive respiratory work secondary to PEEPi in patients with airflow limitation, and, possibly, a decrease in lung injury resulting from repeated alveolar collapse and reopening. The principal beneficial effect of PEEP is an increase in Pao2 , which permits a decrease in Fio2 and a reduction in the risk of O2 toxicity.

The major mechanism for the increase in Pao2 with PEEP is an increase in end-expiratory lung volume (Table 153-2).

Patients with ARDS develop alveolar instability and collapse (see Chapters 144 and 145). Consequently, functional residual capacity falls below closing volume, and small air-

Principles of Mechanical Ventilation

Table 153-2 Mechanisms of Increased Pao2 with PEEP Increase in end-expiratory lung volume Distention of patent lung units Recruitment of collapsed lung units Redistribution of fluid within the lung Decrease in shunt Increase in end-expiratory lung volume Decrease in cardiac output

ways close during tidal breathing, leading to intrapulmonary shunt and hypoxemia. PEEP increases end-inspiratory lung volume by distending lung units that are already open, preventing collapse of unstable alveoli at end-expiration, recruiting collapsed lung units, and redistributing liquid within the lung. The decrease in venous admixture with PEEP is proportional to alveolar recruitment. It had been thought that the decrease in venous admixture with PEEP resulted largely from a decrease in cardiac output. This view has been shown to be erroneous.

At one time PEEP was thought to decrease extravascular lung water by “pushing” alveolar fluid back into the circulation. On the contrary, PEEP can actually increase lung water. As alveoli expand with application of PEEP, interstitial pressure in the extra-alveolar space decreases, leading to an increase in transmural pressure across the vessel wall. If intravascular pressures remain the same or increase, the filtration of fluid across the vessel wall increases, causing an increase in pulmonary edema; if PEEP causes a decrease in cardiac output and vascular pressures, lung water does not change. The beneficial action of PEEP in pulmonary edema is produced by redistribution of edema fluid from the alveolar space into the perivascular cuffs. This redistribution of lung water, in association with an increase in end-expiratory lung volume, is the major mechanism underlying the increase in Pao2 with PEEP. In patients with acute respiratory distress syndrome, PEEP is often used for the purpose of recruiting previously nonfunctioning lung tissue (see Chapter 145). Selecting the right level of PEEP for a given patient is difficult, however, because the severity of injury varies throughout the lungs.

PEEP can recruit atelectatic areas, but it may also overdistend normally aerated areas. In one study involving six patients with acute lung injury, the use of PEEP at 13 cm H2 O resulted in recruitment of nonaerated portions of lung, with a gain of 320 ml in lung volume; however, three patients had overdistention of already aerated portions of lung, with an excess volume of 238 ml.

Overall, about 30 percent of patients with acute lung injury either do not benefit from PEEP or experience a fall in Pao2 . With the patient in the supine posture, PEEP generally

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Figure 153-9 Respiratory pressure-volume curve and the effects of traditional versus protective ventilation in a 70-kg patient with acute respiratory distress syndrome. The lower and upper inflection points of the inspiratory pressure-volume curve (center panel) are at 14 and 26 cm H2 O, respectively. With conventional ventilation at a tidal volume of 12 ml/kg and zero end-expiratory pressure (left panel), alveoli collapse at the end of expiration. The generation of shear forces during the subsequent mechanical inflation may tear the alveolar lining, and attaining an endinspiratory volume higher than the upper inflection point causes alveolar over-distention. With protective ventilation at a tidal volume of 6 ml/kg (right panel), the end-inspiratory volume remains below the upper inflection point; the addition of PEEP at 2 cm H2 O above the lower inflection point may prevent alveolar collapse at the end of expiration and provide protection against the development of shear forces during mechanical inflation. (Reproduced Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986â&#x20AC;&#x201C;1996, 2001, with permission.)

recruits the regions of the lung closest to the apex and sternum. Conversely, PEEP can increase the amount of nonaerated tissue in the regions close to the spine and diaphragm.

Among patients in the early stages of ARDS, those with pulmonary causes, such as pneumonia, are less likely to benefit from PEEP than are patients with nonpulmonary causes, such as intra-abdominal sepsis or extrathoracic trauma. This distinction may be related to the type of morphologic involvement: Pulmonary causes of ARDS are characterized by alveolar filling, whereas nonpulmonary causes are characterized by interstitial edema and alveolar collapse. In the later stages of ARDS, remodeling and fibrosis may eliminate this distinction between pulmonary and nonpulmonary causes.

Even if a pressure-volume curve is not performed at the bedside, it is useful to select the PEEP level according to this conceptual framework (Fig. 153-9). A level above the lower bend in the pressure-volume curve is thought to keep alveoli open at the end of expiration, thereby preventing injury that can result from shear forces created by the opening

and closing of alveoli. This level of PEEP may also prevent an increase in the amount of nonaerated tissue and, thus, atelectasis. However, the notion that the lower bend of the pressure-volume curve signals the level of PEEP necessary to prevent end-expiratory collapse, and that pressure above the upper bend signal alveolar overdistention, is a gross oversimplification. The relation between the shape of the pressurevolume curve and events at the alveolar level is confounded by numerous factors and is the subject of ongoing research and debate. An understanding of this relation is also impeded by the difficulty in distinguishing collapsed lung units from fluid-filled units on computed tomography scans.

BRONCHODILATOR THERAPY Several obstacles are encountered when inhaled drugs are administered to ventilated patients. As a result, drug deposition to the lower respiratory tract is less than that in

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ambulatory patients. Determinants of aerosol deposition include the configuration of the endotracheal tube and ventilator circuit, ventilator mode and settings, and patient-related factors.

Nebulizers have been used traditionally for the delivery of bronchodilators, but they have a number of disadvantages.

Nebulizer contamination causes aerosolization of bacteria, and lack of attention to this matter by health care providers has led to epidemics of nosocomial pneumonia. Tidal volume and inspiratory flow must be adjusted to compensate for nebulizer flow. This factor is inconsequential in most adults, but instances of hypoventilation have occurred in patients who are unable to trigger the ventilator. Another shortcoming of nebulizers is the considerable variation in efficiency of different commercial brands, as well as among various batches of the same brand.

In contrast, metered-dose inhalers (MDIs) are easy to administer, involve less personnel time, and provide reliable dosing. Moreover, when MDIs are used with a collapsible cylindrical spacer, it is not necessary to disconnect the ventilator circuit for each treatment. Thus, risk of ventilatorassociated pneumonia is decreased. Using MDIs instead of nebulizers results in substantial cost savings. The combination of an MDI and a chamber device achieves a four- to sixfold greater delivery of aerosol than MDI actuation into a connector attached directly to the endotracheal tube or into an in-line device that lacks a chamber. Aerosol delivery is increased with use of a higher tidal volume and longer fractional inspiratory time (TI /TTOT ). Aerosol delivery is decreased by a high inspiratory flow rate; heating and humidification of inhaled gas reduce aerosol deposition by about 40 percent.

When an aerosol is carried by a low-density gas, such as an 80:20 helium-oxygen mixture, aerosol delivery from a MDI is increased by more than 50 percent.

A dose-response study of four, eight, and 16 puffs of albuterol (administered with an MDI and cylindrical spacer) conducted in ventilated patients with COPD (Fig. 153-10) demonstrated a decrease in airway resistance after four puffs of albuterol; no additional effects were noted after cumulative doses of 12 and 28 puffs. In another study in ventilated patients with COPD, the bronchodilator effect of a single dose of four puffs of albuterol was sustained for at least 60 minutes. The bronchodilator effect obtained with four puffs of albuterol from an MDI was comparable to that obtained with six to 12 times the same dose given by a nebulizer.

Based on research conducted over the past decade, it is possible to formulate specific steps to achieve maximum bronchodilator effect with use of MDIs in ventilated patients (Table 153-3). Therapy can be given in combination with either controlled or assisted ventilation, provided aerosol administration is synchronized with inspiratory flow. Based on the recommended technique for use of an MDI in ambulatory patients, some authors recommend use of a postinspiratory breath hold; with optimal technique, however, this maneuver does not influence bronchodilator response in ventilated patients. Although humidification of the circuit re-

Principles of Mechanical Ventilation

Figure 153-10 Effect of albuterol on minimal inspiratory resistance (Rrsmin ) in 12 stable mechanically ventilated patients with chronic obstructive pulmonary disease. Significant decreases in resistance occurred within 5 minutes of administration of four puffs of albuterol. The addition of eight and 16 puffs (cumulative doses of 12 and 28 puffs, respectively) did not achieve a significantly greater effect than that with four puffs ( p > 0.05).

Bars represent SE. ∗∗p < 0.001. (Modified from Dhand R, Duarte AG, Jubran A, et al: Dose-response to bronchodilator delivered by metered-dose inhaler in ventilator-supported patients. Am J Respir Crit Care Med 154:388–393, 1996, with permission)

duces aerosol deposition, it is advisable not to bypass the humidifier. Even with a humidified circuit, significant bronchodilation can be achieved with as few as four puffs of a bronchodilator aerosol when the MDI technique is carefully executed.

MONITORING AND COMPLICATIONS Several devices can be used to monitor pulmonary gas exchange, respiratory neuromuscular function, respiratory mechanics, and patient-ventilator interaction. Use of the derived information permits the physician to better tailor ventilator settings to an individual patient’s requirements, with the promise of enhancing patient comfort. Monitoring of key variables helps to minimize the risk of iatrogenic complications and alerts the physician to the likelihood of an impending catastrophe, allowing sufficient time for the institution of lifesaving measures. A detailed discussion of techniques used for monitoring of ventilator-supported patients can be found in Chapter 152 and in other textbooks.

Patients receiving mechanical ventilation are at risk for numerous complications, including O2 toxicity, volutrauma and air leaks, decreased cardiac output, and endotracheal tube–related issues. These problems are discussed elsewhere in this volume.

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Table 153-3 Technique for Using Metered-Dose Inhalers in Mechanically Ventilated Patients 1. Assure VT > 500 ml (in adults) during assisted ventilation.

2. Aim for an inspiratory time (excluding the inspiratory pause) >0.30 of total breath duration.

3. Ensure that the ventilator breath is synchronized with the patient’s inspiration.

4. Shake the metered-dose inhalers vigorously.

5. Place canister in actuator of a cylindrical spacer situated in inspiratory limb of ventilator circuit.∗ 6. Actuate metered-dose inhalers to synchronize with precise onset of inspiration by the ventilator.† 7. Allow a breath hold at end-inspiration for 3–5 s.

8. Allow passive exhalation.

9. Repeat actuations after 20–30 s until total dose is delivered.‡ ∗ With metered-dose inhalers, it is preferable to use a spacer that remains in

the ventilator circuit to avoid disconnecting the ventilator circuit for each bronchodilator treatment. Although bypassing the humidifier can increase aerosol delivery, it prolongs each treatment and requires disconnecting the ventilator circuit. † In ambulatory patients with metered-dose inhalers placed inside the mouth, actuation is recommended briefly after initiation of inspiratory airflow. In mechanically ventilated patients using a metered-dose inhaler and spacer combination, actuation should be synchronized with onset of inspiration. ‡ The manufacturer recommends repeating the dose after 1 min.

Metered-dose inhalers’ actuation within 20–30 s after the previous dose does not compromise drug delivery. source: Modified from Dhand R, Tobin MJ: Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 156:3–10, 1997.

WEANING The term weaning literally means a slow, gradual decrease in the amount of ventilator support. However, the term is used more commonly to refer to all methods of discontinuing mechanical ventilation.

Causes of Weaning Failure After discontinuation of mechanical ventilation, up to 25 percent of patients experience respiratory distress severe enough to necessitate the reinstitution of ventilator support. Our understanding of the basis for weaning failure in patients has advanced considerably in recent years. Among patients who cannot be weaned, disconnection from the ventilator is followed almost immediately by an increase in respiratory frequency and fall in tidal volume; that is, rapid, shallow breathing (Fig. 153-11). As a trial of spontaneous breathing is continued over the next 30 to 60 minutes, respiratory ef-

Figure 153-11 A time-series, breath-by-breath plot of respiratory frequency and tidal volume in a patient who failed a weaning trial. The arrow indicates the point of resuming spontaneous breathing. Rapid, shallow breathing developed almost immediately after discontinuation of the ventilator. (From Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111–1118, 1986, with permission.)

fort increases considerably, reaching more than four times the normal value at the end of this period (Fig. 153-12).

The increased effort is caused mainly by worsening respiratory mechanics. Respiratory resistance increases progressively, reaching about seven times the normal value at the end of a failed weaning trial; lung stiffness also increases, reaching five times the normal value; and gas trapping, measured as PEEPi , more than doubles over the course of the trial.

Before weaning is started, however, respiratory mechanics in such patients are similar to patients in whom subsequent weaning is successful. Thus, unknown mechanisms associated with the act of spontaneous breathing cause the worsening of respiratory mechanics in patients who are weaning failures.

In addition to the increase in respiratory effort, an unsuccessful attempt at spontaneous breathing causes considerable cardiovascular stress. Patients can experience substantial increases in right- and left-ventricular afterload during a trial of spontaneous breathing, with increases of 39 and 27 percent in pulmonary and systemic arterial pressures, respectively. The changes are most likely attributable to the extreme negative swings in intrathoracic pressure. At the completion of a weaning trial, the level of O2 consumption is equivalent in patients who can be weaned and in those who cannot. How the cardiovascular system meets the O2 demand differs in the two groups of patients.

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Principles of Mechanical Ventilation

Figure 153-12 Tidal volume, pleural pressure, and pulmonary-artery pressure during assist-control ventilation and at the start and end of a failed weaning trial. During mechanical ventilation, the patient’s inspiratory effort is in the normal range, and the pulmonary-artery pressure is 45/22 mmHg. At the start of the weaning trial, tidal volume falls to 200 ml, respiratory frequency increases to 33 breaths per minute, and a swing of 11 cm H2 O in pleural pressure is noted; the pulmonary-artery pressure at the end of expiration is 60/28 mmHg. At the end of the trial, 45 minutes later, the tidal volume and respiratory frequency are unchanged, a swing in pleural pressure of 19 cm H2 O is evident, and PEEPi is 4 cm H2 O; pulmonary artery pressure is 60/31 mmHg. The values in a healthy subject are tidal volume, 380 ml; respiratory frequency, 17 breaths per minute; pleural-pressure swing, 3 cm H2 O; and pulmonary artery pressure, 18/8 mmHg. (Data are from Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111–1118, 1986; Jubran A, Mathru M, Dries D, et al: Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763–1769, 1998; Jubran A, Tobin MJ: Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 155:906–915, 1997. Reproduced from Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001, with permission.)

In patients who are successfully weaned, O2 demand is met through an increase in O2 delivery, mediated by the expected increase in cardiac output on discontinuation of positive-pressure ventilation. In patients who cannot be weaned, O2 demand is met through an increase in O2 extraction; these patients have a relative decrease in O2 delivery. The greater O2 extraction causes a substantial decrease in mixed venous O2 saturation, contributing to the arterial hypoxemia that occurs in some patients.

Over the course of a trial of spontaneous breathing, about half of patients in whom the trial fails have an increase in Paco2 of 10 mm Hg or more. The hypercapnia is not usually a consequence of a decrease in minute ventilation. Instead, hypercapnia results from rapid, shallow breathing, which causes an increase in dead-space ventilation. In a

small proportion of patients who cannot be weaned, primary depression of respiratory drive may be responsible for the hypercapnia.

Timing of the Weaning Process One of the major challenges in the management of ventilatorsupported patients is deciding on the right time to discontinue mechanical ventilation. If the physician is too conservative and postpones weaning onset, the patient is placed at an increased risk of life-threatening, ventilator-induced complications. Conversely, if weaning is begun prematurely, the patient may suffer cardiopulmonary or psychological decompensation of sufficient severity to set back a patient’s clinical course.

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In randomized trials of different weaning techniques, most patients who had received mechanical ventilation for a week or longer were able to tolerate ventilator discontinuation on the first day that weaning-predictor tests were measured. It is likely that many of these patients would have tolerated extubation a day or so earlier. As such, one of the main sources of weaning delay is the failure of the physician to think that the patient just might come off the ventilator. It is possible to speed up the weaning process by undertaking physiological assessment early in the patient’s clinical course.

A cardinal precept of diagnostic testing is to begin with a screening test and follow with a confirmatory test. The characteristics of these test types differ. A single diagnostic test rarely fulfills both functions. The fundamental job of a weaning-predictor test is screening. Because the goal is to not miss anyone with the condition under consideration, a good screening test has a very low rate of false-negative results; to achieve this goal, a higher false-positive rate is acceptable.

Thus, an ideal screening test has a very high sensitivity. The ratio of respiratory frequency to tidal volume (f/VT ) meets this requirement; numerous studies have documented that its sensitivity is 0.90 or higher.

The f/VT ratio must be calculated during spontaneous breathing. Measurements of f/VT in the presence of pressure support or CPAP will result in inaccurate predictions of weaning outcome. The higher is the f/VT ratio, the more rapid and shallow the breathing and the greater the likelihood of unsuccessful weaning. A ratio of 100 discriminates between successful (less than 100) and unsuccessful (greater than 100) attempts at weaning.

Because the results of screening tests are often negative, an ideal screening test should be simple, expeditious, and safe. Measurement of f/VT takes a minute or so to perform.

In contrast, a trial of spontaneous breathing takes one-half to 2 hours to perform, during which time attendants commonly leave the patient’s room. Accordingly, a spontaneous breathing trial does not satisfy the criteria for a desirable screening test, and commencing weaning with such a trial is likely to prolong the weaning process.

If clinicians obtain weaning-predictor tests at the earliest point that a patient might tolerate extubation, the results will be negative at least half the time. In studies of weaningpredictor tests, however, positive results have been obtained at least 75 percent of time. Such a high rate of positive test results indicates that clinicians were being too slow in initiating the weaning process.

When a screening test is positive, the diagnostician proceeds to a confirmatory test. A positive confirmatory test result essentially rules in a condition: The likelihood of a patient tolerating a trial of extubation is very high. An ideal confirmatory test has a very low rate of false-positive results, i.e., a high specificity. The specificity of a weaning trial is not known and will never be known, since its determination would require an unethical experiment—extubating all patients who fail a weaning trial and noting how many require reintubation.

Weaning Trials Four methods can be used for conducting a weaning trial. The oldest is to perform trials of spontaneous breathing several times a day, using a T-tube circuit that contains an enriched supply of O2 . Initially 5 to 10 minutes in duration, T-tube trials are extended and repeated several times a day until the patient can sustain spontaneous ventilation for several hours.

This approach has become unpopular because it requires considerable time on the part of ICU staff.

For many years, IMV was the most popular methods of weaning. With IMV, the mandatory rate from the ventilator is reduced in steps of one to three breaths per minute, and an arterial blood gas is obtained about 30 minutes after each rate change. Unfortunately, titrating the number of breaths from the ventilator in accordance with the results of arterial blood gases can produce a false sense of security. As few as two to three positive-pressure breaths per minute can achieve acceptable blood gases, but these values provide no information regarding the patient’s work of breathing (which may be excessive). As noted previously, at IMV rates of 14 breaths per minute or less, patient inspiratory efforts are increased to a level likely to cause respiratory muscle fatigue. Moreover, this occurs not only with the intervening spontaneous breaths, but also with ventilator-assisted breaths. Consequently, use of IMV may actually contribute to the development of respiratory muscle fatigue or prevent its recovery.

When pressure support is used for weaning, the level of pressure is reduced gradually (decrements of 3 to 6 cm H2 O) and titrated on the basis of the patient’s respiratory frequency.

When the patient tolerates a minimal level of pressure support, he or she is extubated. What exactly constitutes a “minimal level of pressure support” has never been defined. For example, pressure support of 6 to 8 cm H2 O is widely used to compensate for the resistance imposed by the endotracheal tube and ventilator circuit. It is reasoned that a patient who can breathe comfortably at this level of pressure support will be able to tolerate extubation. However, if the upper airways are swollen because an endotracheal tube has been in place for several days, the work engendered by breathing through the swollen airways is about the same as that caused by breathing through an endotracheal tube. Accordingly, any amount of pressure support overcompensates and may give misleading information about the likelihood that a patient can tolerate extubation.

The fourth method of weaning is to perform a single daily T-tube trial, lasting for 30 to 120 minutes. If this trial is successful, the patient is extubated. If the trial is unsuccessful, the patient is given at least 24 hours of respiratory muscle rest with full ventilator support before another trial is performed.

Until the early 1990s, it was widely believed that all weaning methods were equally effective, and the physician’s judgment was regarded as the critical determinant. However, the results of randomized, controlled trials clearly indicate that the period of weaning is as much as three times as long with IMV as with trials of spontaneous breathing. In a study involving patients with respiratory difficulties on weaning,

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trials of spontaneous breathing halved the weaning time as compared with pressure support; in another study, the weaning time was similar with the two methods. Performing trials of spontaneous breathing once a day is as effective as performing such trials several times a day but is much simpler.

In a recent study, half-hour trials of spontaneous breathing were as effective as 2-hour trials. This study, however, involved all patients being considered for weaning, not just those for whom there were difficulties with weaning.

In conclusion, to minimize the likelihood of either delayed weaning or premature extubation, a two-step diagnostic strategy is recommended: measurement of weaning predictors followed by a weaning trial. The critical step is for the physician to contemplate the possibility that a patient just might be able to tolerate weaning. Such diagnostic triggering is facilitated through use of a screening test, which is the rationale for measurement of weaning-predictor tests. It is important not to postpone this first step by waiting for a more complex diagnostic test, such as a T-tube trial.

Extubation Decisions about weaning and extubation are commonly conflated. When a patient tolerates a weaning trial without distress, a clinician feels reasonably confident that the patient will be able to sustain spontaneous ventilation after extubation. Before removing the endotracheal tube, however, the clinician also has to judge whether or not the patient will be able to maintain a patent upper airway after extubation.

Of patients who are expected to tolerate extubation without difficulty, about 10 to 20 percent fail and require reintubation. Mortality among patients who require reintubation is more than six times as high as mortality among patients who can tolerate extubation. The reason for the higher mortality is unknown. It might be related to the development of new problems after extubation or complications associated with reinsertion of a new tube. A more likely explanation is that the need for reintubation reflects greater severity of the underlying illness.

Because of the high mortality associated with reintubation, clinicians are eager to avoid this problem. The major diagnostic test used to predict the success of an extubation attempt is a weaning trial. In contrast to the many studies that have evaluated the reliability of diagnostic tests that predict the outcome of a trial of weaning, the diagnostic accuracy of weaning trials in predicting the outcome of a trial of extubation is unknown. Moreover, the accuracy is impossible to determine, because the experiments necessary to measure the sensitivity and specificity of a weaning trial (for predicting extubation outcome) are unethical.

CONCLUSION Since the previous edition of this textbook, we have gained a better understanding of the pathophysiology associated with

Principles of Mechanical Ventilation

unsuccessful weaning and have learned how to wean patients more efficiently. We have also learned how ventilator settings influence survival in patients with ARDS. Less progress has been made in determining how the ventilator can best be used to achieve maximal respiratory muscle rest, which is the most common reason for providing mechanical ventilation.

SUGGESTED READING The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000.

Amato MB, Barbas CS, Medeiros DM, et al: Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347–354, 1998.

Brochard L, Rauss A, Benito S, et al: Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care Med 150:896–903, 1994.

Brochard L, Roudot-Thoraval F, Roupie E, et al: Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:1831–1838, 1998.

Brower RG, Shanholtz CB, Fessler HE, et al: Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 27:1492– 1498, 1999.

Deans KJ, Minneci PC, Cui X, et al: Mechanical ventilation in ARDS: One size does not fit all. Crit Care Med 33:1141– 1143, 2005.

Dhand R, Duarte AG, Jubran A, et al: Dose-response to bronchodilator delivered by metered-dose inhaler in ventilatorsupported patients. Am J Respir Crit Care Med 154:388– 393, 1996.

Dhand R, Tobin MJ: Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 156:3–10, 1997.

Eichacker PQ, Gerstenberger EP, Banks SM, et al: Metaanalysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 166:1510–1514, 2002.

Esteban A, Alia I, Tobin MJ, et al: Effect of spontaneous breathing trial duration on outcome of attempts to discontinue mechanical ventilation. Spanish Lung Failure Collaborative Group. Am J Respir Crit Care Med 159:512–518, 1999.

Esteban A, Frutos F, Tobin MJ, et al: A comparison of four methods of weaning patients from mechanical ventilation.

Spanish Lung Failure Collaborative Group. N Engl J Med 332:345–350, 1995.

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Gattinoni L, Pelosi P, Suter PM, et al: Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 158:3–11, 1998.

Imsand C, Feihl F, Perret C, et al: Regulation of inspiratory neuromuscular output during synchronized intermittent mechanical ventilation. Anesthesiology 80:13–22, 1994.

Jubran A, Mathru M, Dries D, et al: Continuous recordings of mixed venous oxygen saturation during weaning from mechanical ventilation and the ramifications thereof. Am J Respir Crit Care Med 158:1763–1769, 1998.

Jubran A, Tobin MJ: Pathophysiologic basis of acute respiratory distress in patients who fail a trial of weaning from mechanical ventilation. Am J Respir Crit Care Med 155:906– 915, 1997.

Jubran A, Van de Graaff WB, Tobin MJ: Variability of patientventilator interaction with pressure support ventilation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152:129–136, 1995.

Laghi F, Segal J, Choe WK, et al: Effect of imposed inflation time on respiratory frequency and hyperinflation in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:1365–1370, 2001.

Laghi F, Tobin MJ: Disorders of the respiratory muscles. Am J Respir Crit Care Med 168:10–48, 2003.

Leung P, Jubran A, Tobin MJ: Comparison of assisted ventilator modes on triggering, patient effort, and dyspnea. Am J Respir Crit Care Med 155:1940–1948, 1997.

Marini JJ, Capps JS, Culver BH: The inspiratory work of breathing during assisted mechanical ventilation. Chest 87:612–618, 1985.

Marini JJ, Smith TC, Lamb VJ: External work output and force generation during synchronized intermittent mechanical ventilation. Effect of machine assistance on breathing effort. Am Rev Respir Dis 138:1169–1179, 1988.

Parthasarathy S, Jubran A, Tobin MJ: Cycling of inspiratory and expiratory muscle groups with the ventilator in airflow limitation. Am J Respir Crit Care Med 158:1471–1478, 1998.

Rouby JJ, Lu Q, Goldstein I: Selecting the right level of positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 165:1182– 1186, 2002.

Stewart TE, Meade MO, Cook DJ, et al: Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med 338:355–361, 1998.

Straus C, Louis B, Isabey D, et al: Contribution of the endotracheal tube and the upper airway to breathing workload.

Am J Respir Crit Care Med 157:23–30, 1998.

Tobin MJ: Advances in mechanical ventilation. N Engl J Med 344:1986–1996, 2001.

Tobin MJ: Mechanical ventilation. N Engl J Med 330:1056– 1061, 1994.

Tobin MJ (ed): Principles and Practice of Intensive Care Monitoring. New York, McGraw-Hill, 1998.

Tobin MJ (ed): Principles and Practice of Mechanical Ventilation, 2nd ed. New York, McGraw-Hill, 2006.

Tobin MJ, Jubran A: Pathophysiology of failure to wean from mechanical ventilation. Schweiz Med Wochenschr 124:2138–2145, 1994.

Tobin MJ, Jubran A, Laghi F: Patient-ventilator interaction.

Am J Respir Crit Care Med 163:1059–1063, 2001.

Tobin MJ, Perez W, Guenther SM, et al: The pattern of breathing during successful and unsuccessful trials of weaning from mechanical ventilation. Am Rev Respir Dis 134:1111– 1118, 1986.

Yang KL, Tobin MJ: A prospective study of indexes predicting the outcome of trials of weaning from mechanical ventilation. N Engl J Med 324:1445–1450, 1991.

154 Nutrition in Acute Respiratory Failure Lisa M. Bellini

I. OVERVIEW OF MALNUTRITION Incidence of Malnutrition in the Intensive Care Unit Incidence of Malnutrition in Advanced Lung Disease II. EFFECTS OF MALNUTRITION Pathophysiology and Complications of Malnutrition Protein Calorie Malnutrition and Critical Illness Effects of Nutritional Supplementation in Acute Respiratory Failure III. ASSESSMENT OF NUTRITIONAL STATUS Functional Assessment Metabolic Assessment IV. INDICATIONS FOR NUTRITIONAL SUPPORT

VII. BASIC NUTRITIONAL PRESCRIPTION Energy Requirements Glucose Requirements Protein Requirements Fat Requirements Micronutrients Immunonutrition VIII. MONITORING Nitrogen Balance Glucose Control Other Monitoring IX. SPECIAL CONSIDERATIONS IN PATIENTS WITH ADVANCED LUNG DISEASE

V. GOALS OF NUTRITIONAL SUPPORT VI. ROUTE OF ADMINISTRATION AND COMPLICATIONS Enteral Parenteral

OVERVIEW OF MALNUTRITION Malnutrition is a disorder of body composition in which nutritional intake is less than required, resulting in reduced organ function, abnormalities in blood chemistry, reduced body mass, and worsened clinical outcomes. Malnutrition in the setting of acute respiratory failure (ARF) may be a preexisting condition due to underlying advanced lung disease, such as chronic obstructive pulmonary disease (COPD) (see Chapters 41 and 42); alternatively, it may develop during the course of acute illnesses that promote hypermetabolism, as occurs in acute respiratory distress syndrome (ARDS) (see Chapter 145). Regardless of the starting point, ARF results in alterations in substrate metabolism that are manifest as nutritional deficiencies and altered body composition. As the body tries to conserve protein, fat is metabolized as a prin-

cipal source of energy. When fat stores are depleted, visceral and muscle protein catabolism and gluconeogenesis become the main processes for generating energy. Nutritional assessment in these settings is critical. Evaluation usually consists of determination of clinical, anthropometric, chemical, and immunologic parameters that reflect altered body composition. The assessment must be considered in light of the patientâ&#x20AC;&#x2122;s underlying condition, as no single test is diagnostic of malnutrition.

Incidence of Malnutrition in the Intensive Care Unit Physicians may contribute to malnutrition in the hospital setting by failing to recognize it as a complication of illness or injury and addressing it inadequately. Recognition of malnutrition does not insure that adequate nutrition repletion will

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occur. When enteral feeding is undertaken in the intensive care unit (ICU), inadequate nutrition is frequently delivered because of underestimation of patients’ nutritional needs and inappropriate cessation of feedings. A prospective study of patients requiring enteral feedings in an ICU found that physician prescriptions provided a mean of only 66 percent of goal caloric requirements; furthermore, a mean of only 78 percent of the ordered volume was actually infused. Cessation of enteral feeds was judged avoidable in 66 percent of cases, including circumstances when feeding was discontinued at midnight for a procedure on the following day, or was stopped for simple bedside tasks, such as bathing the patient or placement of intravenous lines. An additional study of patients with COPD presenting with ARF (with slightly over one-half requiring mechanical ventilation) revealed malnutrition in 60 percent. Malnutrition was more frequent in those that required mechanical ventilation (74 percent versus 43 percent).

In 1997, the American College of Chest Physicians (ACCP) published a consensus statement on nutrition in the ICU, aimed at guiding patient selection, timing and route of administration, nutrient use, and monitoring of nutrition support. In a study of over 1500 critically ill medical patients who had an ICU length of stay greater than 96 h, cumulative caloric intake reached only about 50 percent of ACCPrecommended guidelines. Notably, patients receiving 33 to 65 percent of recommended caloric targets were more likely to achieve spontaneous ventilation prior to discharge from the ICU, while those receiving more than 65 percent of targets were less likely to be weaned or to be discharged alive from the hospital. The findings suggest that current caloric targets may overestimate patient needs, since moderate caloric intake was associated with a better outcome.

Incidence of Malnutrition in Advanced Lung Disease The finding that patients with advanced lung disease suffer from changes in body composition manifest by progressive weight loss has long been recognized. Thirty to seventy percent of patients with COPD have clinical evidence of malnutrition. Malnutrition associated with advanced lung disease, so-called “pulmonary cachexia syndrome,” has been associated with increased mortality and decline in functional status. Although COPD has been best studied, current thinking is that all advanced lung diseases are characterized by progressive reduction in lean body mass, which is a function of many variables, including aging, exercise, metabolism, tissue hypoxia, inflammation, and use of certain medications. Importantly, basal metabolism in patients with advanced lung disease does not follow the expected normal age-related decline. Many patients are hypermetabolic, presumably secondary to an increased work of breathing. In fact, patients with COPD have a 10-fold increase in daily energy expenditure over the normal baseline of 36 to 72 calories per day.

EFFECTS OF MALNUTRITION The effects of malnutrition may be considered with respect to the underlying pathophysiology, consequences of malnutrition during critical illness, and effects of nutritional supplementation.

Pathophysiology and Complications of Malnutrition A reduction in food intake results in loss of fat, muscle, skin, and, ultimately, bone and viscera. Body mass declines and extracellular fluid volume increases. Nutritional requirements fall as an individual’s body mass decreases, probably reflecting more efficient utilization of ingested food and a reduction in work capacity at the cellular level. However, the combination of decreased tissue mass and reduction in work capacity impedes homeostatic responses to stressors, such as acute respiratory failure.

Malnutrition causes a number of deleterious consequences, including increased susceptibility to infection, poor wound healing, increased frequency of decubitus ulcers, overgrowth of bacteria in the gastrointestinal tract, and abnormal nutrient losses in stool. These alterations result in increased morbidity and mortality in malnourished, hospitalized patients. One study of over 2000 hospitalized veterans found a 30-day mortality rate of 62 percent among those whose serum albumin concentrations fell below 2.0 g/dl. A study of over 4300 patients in ICUs revealed that those with a low body mass index (BMI) on admission (due to preexisting malnutrition) were at increased risk of death during hospitalization and at 6 mo following BMI measurement. A BMI on admission below the 15th percentile was associated with a 23 percent increase in 6-mo mortality.

Adequate nutrition is essential for reversing the physiological derangements described and for recovery from ARF. Supplemental nutrition has been demonstrated to improve morbidity and mortality in certain groups of patients, likely related to contraction of previously expanded extracellular fluid volume and repletion of protein reserves.

Protein Calorie Malnutrition and Critical Illness Metabolic derangements are amplified during periods of critical illness, including ARF; protein calorie malnutrition is particularly detrimental in this situation. The stress of critical illness inhibits the body’s natural conservation responses to malnutrition; aggressive nutritional support instituted early during a critical illness may be protective.

Hypermetabolism associated with critical illness causes a redistribution of macronutrients (fat, protein, and glycogen) from the labile reserves of adipose tissue and skeletal muscle to more metabolically active tissues, such as bone, liver, and other viscera. Within a few days, this response may lead to the onset of protein calorie malnutrition, defined as

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a negative balance of 100 g of nitrogen and 10,000 kcal. The rate of development of malnutrition in critically ill patients is a function of preexisting nutritional status and degree of hypermetabolism.

In the 1940s, Cuthbertson described two phases of the metabolic response to shock: (a) an initial “ebb” phase, and (b) a later, hypercatabolic “flow” phase. The initial “ebb” phase lasts 12 to 24 h and is characterized by fever, increased oxygen consumption, decreased body temperature, and vasoconstriction. These adaptive changes reflect activation of the sympathetic nervous system and pituitary-adrenal axis, reflected in rapid rises in plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone, growth hormone, cortisol, and other corticosteroids. The “flow” phase, which lasts for the remainder of the acute illness, is marked by hypercatabolism and is mediated primarily by catecholamines. The hypercatabolism exceeds anabolism, resulting in net negative nitrogen balance and a shift to utilization of fat as the major fuel source. Subsequent to Cuthbertson’s description, a third or “anabolic” phase was described, beginning with the onset of recovery and characterized by normalization of vital signs, improved appetite, and diuresis.

The difference between the last two phases relates primarily to the level of energy expenditure.

Effects of Nutritional Supplementation in Acute Respiratory Failure Supplemental nutrition may improve respiratory muscle strength and restore ventilatory drive and altered lung defenses. Patients with advanced lung disease often have increased ventilatory drive with a blunted response to hypoxemia. Supplemental nutrition in malnourished patients with advanced lung disease may help restore ventilatory drive, increasing the chances for successful weaning. Malnutrition in advanced lung disease may also increase the risk of infection through a detrimental effect on cell-mediated immunity and reduced cellular resistance of respiratory mucosa to bacterial infection. Introduction of an endotracheal tube may exacerbate the latter effect.

Several retrospective studies suggest that supplemental nutrition may facilitate weaning from mechanical ventilation.

Although a randomized, prospective controlled trial on the effects of supplemental nutrition on weaning has yet to be done, current evidence supports the notion that nutritional support is an important determinant of weaning success.

ASSESSMENT OF NUTRITIONAL STATUS Early detection of malnutrition in ARF enables prompt and aggressive intervention using supplemental nutrition. No single measurement or assessment tool can adequately characterize nutritional status, and the diagnosis of malnutrition remains somewhat subjective. However, both functional and biochemical parameters should be examined to identify

Nutrition in Acute Respiratory Failure

patients at increased risk for developing malnutrition and its complications.

Functional Assessment Functional nutritional assessment consists of a medical history, physical examination, and appraisal of muscle and organ function. Identification of preexisting malnutrition (i.e., malnutrition occurring prior to the onset of respiratory failure) is made by careful attention to the history of present illness and relevant past medical and surgical history, a focused dietary history, and review of the patient’s medications and social habits. This information usually needs to be obtained from the patient’s family. The degree to which the patient’s usual weight deviates from estimated ideal body weight should be considered; the period of time over which the weight has changed is important in evaluating the severity of weight loss.

Historical data should be used to estimate the nutritional consequences of the current hospitalization. Prehospitalization weights should be documented, and any weight changes since hospitalization should be noted and evaluated in the context of concomitant diuresis or fluid supplementation.

Physical examination may suggest the presence of nutritional and metabolic deficiencies. Temporal muscle wasting, sunken supraclavicular fossae, and decreased adipose stores are easily recognized signs of starvation. Careful inspection of the hair, skin, eyes, mouth, and extremities may reveal additional stigmata of protein calorie malnutrition or vitamin and mineral deficiencies.

An assessment of muscle mass and function may yield information about a patient’s protein reserves and overall nutritional status. Estimation of muscle mass and fat stores can be obtained from anthropometric measurements, such as arm circumference or triceps skin fold measurements. These methods are simple, safe, cost effective, and standardized; however, interpretation of results remains controversial, limiting their use in the intensive care setting.

Cardiovascular, respiratory, and gastrointestinal functions should be evaluated with regard to both evidence of malnutrition-related dysfunction and the ability of the patient to tolerate nutritional supplementation. Administration of large fluid volumes associated with parenteral nutrition may be limited by impaired cardiovascular function. Abdominal distention may make use of enteral supplementation difficult.

Newer methods of nutritional assessment that have not been well studied to date include magnetic resonance imaging (MRI), whole body conductance and impedance, and neutron activation.

Metabolic Assessment Information from select laboratory tests may complement the functional assessment and should be evaluated in every patient during the standard nutritional evaluation.

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Serum albumin concentration is the most frequently used laboratory measure of nutritional status; values less than 2.2 g/dl generally reflect severe malnutrition. Although serum albumin is used popularly as an indicator of nutritional status, its value as a surrogate for visceral protein status is limited. Because albumin has a long half-life of 14 to 20 d, its serum level does not accurately reflect acute changes in nutritional status. Furthermore, serum albumin concentration rises rapidly in response to exogenously administered albumin and fluctuates in conditions such as dehydration, sepsis, trauma, and liver disease, irrespective of nutritional status.

Prealbumin (transthyretin) is a more reliable indicator of nutritional status than is albumin because its halflife of 24 to 48 h makes its plasma concentration more reflective of current nutritional state. However, as is the case with albumin, the concentration of prealbumin is diminished in renal and liver disease. Transferrin, with a half-life of 9 d, makes it intermediate between prealbumin and albumin with regard to its sensitivity for identifying incipient malnutrition.

Although serum chemistry values are important in determining the specifics of nutritional support, they do not directly reflect nutritional status. Serum sodium, potassium, chloride, total carbon dioxide, blood urea nitrogen, glucose, iron, magnesium, calcium, and phosphate, as well as prothrombin and partial thromboplastin times, should be measured on admission and rechecked periodically.

Adequacy of cellular immunity may be estimated by measuring total lymphocyte count (TLC) and delayed-type hypersensitivity testing using a series of common antigens (e.g., Candida, Trichophyton, tuberculin, diphtheria, and a glycerin control). Compromise of cell-mediated immunity due to malnutrition is suggested by a TLC less than or equal to 1000/mm3 or lack of skin test induration greater than 5 mm above the glycerin control at 48 h (unless another cause of lymphocyte dysfunction is present). Delayed-type hypersensitivity testing is least useful during an acute illness, because cell-mediated immunity may be depressed in this setting, even in the absence of malnutrition. Furthermore, technical application and interpretation are variable.

INDICATIONS FOR NUTRITIONAL SUPPORT Adequate nutrition is essential for recovery from ARF. Indications for enteral or parenteral nutritional support include preexisting nutritional deprivation, anticipated or actual inadequate oral caloric intake, and significant multiorgan system disease (Table 154-1).

Although supplemental nutrition is a lower priority during the resuscitative phase of respiratory failure, it’s use becomes increasingly important once a patient is stabilized and should be initiated as soon as feasible. Critically ill patients should not be allowed to remain in a state of unopposed starvation because this increases morbidity and

Table 154-1 Indications for Nutritional Support Preexisting malnutrition (i.e., BMI <19) Anticipated inadequate oral intake Significant multiorgan system disease

mortality, particularly in the setting of multisystem organ failure. Several studies support early initiation of nutritional support in the ICU. A randomized multicenter trial of almost 500 critically ill patients found that early initiation of nutritional support reduced duration of hospitalization from 35 to 25 d; a trend toward reduced mortality was also noted.

A related study of medical patients admitted to the ICU indicated that low caloric intake was independently associated with nosocomial blood stream infection.

GOALS OF NUTRITIONAL SUPPORT The goals of nutritional support are different in the different phases of critical illness, which are distinguished on the basis on energy expenditure. In the first several days of critical illness (the “ebb” and “flow” nutritional phases described previously), hypercatabolism exceeds anabolism, resulting in net negative nitrogen balance and a shift to utilization of fat as the major fuel source. During this time, the goal of metabolic support is to maintain vital organ structure and function and attenuate the complications of sepsis, shock, and multisystem organ failure. Metabolic support can blunt the negative nitrogen balance and minimize further protein wasting.

However, such support cannot reverse the negative nitrogen balance entirely until patients enter the third, or anabolic, phase of critical illness. At this point, nutritional goals shift to achieving a positive nitrogen balance and repleting protein stores.

ROUTE OF ADMINISTRATION AND COMPLICATIONS Nutritional support may be administered enterally or parenterally. Clinical circumstances dictate which method is employed.

Enteral Enteral nutrition is preferred over parenteral nutrition because of its lower cost, fewer and less severe complications, lower rates of infection, better rates of wound healing, and association with lower gut mucosal permeability. Enteral feeding requires adequate gastric motility. Impaired gastric

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Table 154-2 Complications of Nutritional Support Enteral

Parenteral

Mechanical

Aspiration Pharyngitis Otitis Sinusitis Airway occlusion

Bleeding Pneumothorax Infection Thromboembolism

Metabolic

Hyperglycemia Hyper-, hypophosphatemia Hyper-, hypokalamia Hyper-, hyponatremia Hyper-, hypocalcemia Hyper-, hypomagnesemia

Hyperglycemia Hyper-, hypophosphatemia Hyper-, hypokalemia Hyper-, hyponatremia Hyper-, hypocalcemia Hyper-, hypomagnesemia Metabolic acidosis Azotemia Elevated liverâ&#x20AC;&#x201C;associated enzymes

Gastrointestinal

Diarrhea Bowel/abdominal distention Vomiting Constipation

emptying can be assessed by checking gastric residual volumes of the tube feedings. Volumes greater than 150 ml should prompt consideration of decreasing the infusion rate, alternative use of intravenous nutritional supplementation, or small bowel feeds. The efficacy of gastric motility agents has not been proved.

Complications of enteral feeding fall into three categories: mechanical, gastrointestinal and metabolic (Table 154-2). The most common complication of enteral feeding is diarrhea, the cause of which may be difficult to discern in the critical care setting, when patients are receiving multiple medications that may be responsible. Evaluation of enteral feeding as the cause of diarrhea begins with adjustment of a single parameter at a time, e.g., infusion volume, rate, or osmolality.

Persistent diarrhea despite use of a low infusion volume infusion of a neutral formula should prompt investigation of other causes and, when appropriate and not contraindicated, use of antimotility agents.

Parenteral Although parenteral nutrition is presumed to be preferable to no nutrition in patients who cannot tolerate enteral feedings, this hypothesis has not been rigorously tested. In fact, a meta-analysis of 26 studies that enrolled over 2200 patients did not demonstrate a decrease in mortality or complications in those receiving total parenteral nutrition (TPN) compared with those receiving standard care with intravenous dex-

trose until able to receive an oral diet. The parenteral route is recommended for those patients in whom enteral nutrition is not possible or is insufficient for meeting nutritional goals.

Complications of parental nutrition can be divided into mechanical and metabolic categories (Table 154-2). Most mechanical complications are related to establishing access for the infusion. Infection is a primary concern. Metabolic complications include the same as with enteral feeding, as well as metabolic acidosis, azotemia, and an increase in liverassociated enzymes.

BASIC NUTRITIONAL PRESCRIPTION The initial parental nutrition regimen for patients with ARF, but without underlying lung disease, centers around administration of a concentrated, low-volume solution to replete electrolytes and address acid-base issues. Thereafter, caloric and protein content (and hence, volume) are increased over several days, progressing over a period of days (Table 154-3).

Enteral regimens typically begin with the agent at full concentration, delivered at a rate of 10 to 20 ml per h. The rate can be increased by 10 to 20 ml every 12 to 24 h until the goal rate is reached. This process should take no more than 4 d.

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Table 154-3 Basic Nutrition Prescription Calculate caloric need based on BEE: BEE (men) = 66.5 + 13.7W + 5H − 6.8A BEE (women) = 655.1 + 9.6W + 1.8H − 4.7A where W = weight, kg H = height, cm A = age, years Multiply total caloric need by stress factor, if applicable: Stress Mild Moderate Severe

Examples Multiplier Stable postoperative state 1.0–1.25 Pneumonia, peritonitis 1.25–1.5 Sepsis, burn, cancer, 1.5–2.5 BMI <19 Administer total calories in a volume consistent with the total fluid needs of the patient. One ml of water is necessary for each kcal administered.

Consider recommended distribution of macronutrients: Macronutrient % Total Calories Glucose 30–70% Fat 15–30% Protein 15–20% Consider recommended micronutrients and electrolytes, as necessary: Micronutrient Dose Frequency of Administration Multivitamin 1 unit Weekly Vitamin K 10 mg Weekly Mineral aliquot Premixed Daily Iron 2 mg Daily Zinc 5–10 mg Daily

A patient’s fluid and electrolyte status must not be compromised by use of nutritional supplementation. The initial volume of the supplement must be based upon careful assessment of the patient’s volume. Electrolyte balance is restored and maintained through daily assessment of losses and requirements. Simultaneously, glycemic control is achieved by balancing glucose and insulin requirements. Once these metabolic parameters are stabilized, attention centers on insuring that protein and calorie needs are met (see below).

Vitamins, trace elements, and lipids are added to complete the nutrition prescription. Despite the association of low albumin with severe malnutrition, administration of supplemental albumin does not improve morbidity or mortality.

Energy Requirements Energy needs are calculated on the basis of basal energy expenditure (BEE). BEE is the amount of energy required to perform metabolic functions at rest; it is influenced by both body size and illness. BEE is estimated using the Harris-Benedict equations (1) and (2):

For men: BEE = 66.5 + (13.7 × weight) + (5 × height) − (6.8 × age)

(1)

For women: BEE = 655.1 + (9.6 × weight) + (1.8 × height) −(4.7 × age)

(2)

where weight is expressed in kg, height in cm, and age in years In using these equations, weight is the usual or actual weight of the patient for those without significant weight loss; for those with significant weight loss, current weight is used; for obese patients, ideal body weight is used.

Traditionally, use of BEE measurements in critical illness has involved multiplication by a “stress factor” of 0.5 to 2.5. Application of the stress factor may result in overfeeding and may predispose the patient to liver steatosis, hyperglycemia, electrolyte imbalances, respiratory compromise due to increased CO2 production, and macrophage

2697 Chapter 154

dysfunction. Use of the standard Harris-Benedict equation (without the stress factor) in determining the BEE of critically ill patients yields an average estimate of 25 kcal/kg body weight per day. Evidence suggests that total energy expenditure is maximal during the second week of critical illness, at which time it may reach 50 to 60 kcal/kg per day.

Glucose Requirements Glucose administration may provide 30 to 70 percent of total daily calories. The amount is adjusted based on serum glucose measurements, aiming to keep levels less than 144 mg/dl.

Administration of insulin may be required.

Protein Requirements The patient’s protein requirements depend upon the degree of metabolic stress to which he or she is exposed. Generally, 15 to 20 percent of daily calories may be administered as protein or amino acids. Importantly, mild or moderately stressed underweight patients have the protein requirements as severely stressed normal or obese patients (2 to 2.5 g/kg/day). Based upon periodic metabolic monitoring, formula protein content should be adjusted to promote positive nitrogen balance and support synthetic function.

Fat Requirements Fat is added to the formula to prevent essential fatty acid deficiency. In general, 15 to 30 percent of calories should be administered as polyunsaturated fatty acids.

Nutrition in Acute Respiratory Failure

testinal mucosal healing after damage by radiotherapy or chemotherapy. Possible benefits of glutamine supplementation have been evaluated in more than 30 controlled trials, most of which, unfortunately, have significant methodologic problems or are too small to permit definitive conclusions. A meta-analysis of 14 randomized trials found that glutamine, especially when given parenterally and at high doses, may improve outcome in postoperative and critically ill patients.

However, at present, identification of indications for glutamine supplementation awaits the results of larger clinical trials.

Arginine and Omega-3 Fatty Acids Arginine is an amino acid with important roles in nitrogen and ammonia metabolism and in the generation of nitric oxide. Animals subjected to wounds or fractures demonstrate improved rates of wound healing, nitrogen retention, and growth when given supplemented dietary arginine. In addition, rats administered arginine-supplemented parenteral nutrition show increased ability to synthesize acute phase proteins when challenged with sepsis. Fatty acids of the omega-3 series have profound effects upon cell membrane fluidity and stability, receptor expression and function, and activation of intracellular signaling pathways.

Multiple randomized trials of “immunonutritional” formulations have been undertaken, primarily in the setting of critical medical illness or routine postoperative recovery. Results have been mixed: Immunostimulation may help counteract the immunosuppressive effects of surgery, but they also may aggravate the systemic inflammatory response in patients with critical illness.

Micronutrients Phosphate, magnesium, potassium and zinc should be administered in amounts necessary to keep serum levels normal. Consensus on the administration of vitamins, minerals, or trace elements is currently lacking.

Immunonutrition Interest is growing in assessment of specific enteral formulations, particularly those with high concentrations of arginine, glutamine, nucleotides, or omega-3 fatty acids, to improve patient mortality and decrease infectious complications. In addition to providing nutritional support, these formulations appear to offer beneficial effects on immunologic and inflammatory responses to critical illness. However, results from randomized trials and systematic reviews have yielded equivocal results.

Glutamine Glutamine is a precursor for nucleotide synthesis and an important fuel source for rapidly dividing cells, such as gastrointestinal epithelia. Animal experiments have shown that glutamine supplementation can prevent or ameliorate the gastrointestinal mucosal atrophy seen during prolonged parenteral nutrition. Glutamine may facilitate gastroin-

MONITORING The most important goal of monitoring nutrition supplementation is avoidance of overfeeding and metabolic derangements.

Nitrogen Balance Monitoring of nitrogen balance is the best method of assessing effectiveness of supplemental nutritional therapy. Nitrogen balance is determined by measuring concurrent protein intake and urinary excretion of urea nitrogen (UUN) over 12 or 24 h. Urea nitrogen is a waste product of protein metabolism that is minimally resorbed by the kidney. Nitrogen balance is the difference between the intake and loss of nitrogen. A positive or negative protein balance is used to determine the adequacy of protein intake. Nitrogen balance is calculated using the following equation: Nitrogen balance = (protein intake/6.25) − (UUN + 4) (3) where protein intake and UUN are each expressed in grams

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The factor 6.25 is based on dietary protein containing 16 percent nitrogen. The factor 4 accounts for the obligatory, nonurea nitrogen losses in skin and feces. The current recommendation is to monitor nitrogen balance every 5 to 6 d.

In the initial stages of critical illness, the goal of nutritional therapy is to maintain a nitrogen balance of zero. A negative balance of 0 to 5 represents moderate stress, while a negative balance greater than 5 represents severe stress. Once the anabolic or recovery phase is entered, the goal is to maintain a positive nitrogen balance to allow for repletion of protein stores.

recommended. Worsening prerenal azotemia may be related to protein administration and should prompt re-evaluation of the protein contribution to total calories. Triglyceride monitoring should be performed weekly. If triglyceride levels are greater than 500 mg/dl, total calories, percent of calories derived from fatty acids, or both, should be reduced. Visceral protein levels (serum prealbumin and transferrin) should be monitored weekly, recognizing that their levels may not represent a response to feeding. Liver-associated enzymes should be assessed weekly. Mild elevations should not prompt a change to liver-specific formulas (see Table 154-2).

Glucose Control Hyperglycemia and insulin resistance are common in critically ill patients, even in the absence of a history of diabetes mellitus. These problems are often compounded by initiation of parenteral or enteral feeding. The general approach to managing such patients traditionally has focused on keeping blood glucose levels under 200 mg/dl (11.1 mmol/L).

A prospective, controlled trial of over 1500 mechanically ventilated patients in surgical ICUs suggested that tighter blood glucose control may have a profound effect on mortality.

Patients were assigned randomly to intensive insulin therapy (target blood glucose of 80 to 100 mg/dl [4.4 to 5.6 mmol/L]) or standard care (target blood glucose of 180 to 200 mg/dl [10 to 11.1 mmol/L]). Mortality while in the ICU and overall in-hospital mortality were lower in the more rigorously controlled group (4.6 versus 8 percent and 7.2 versus 10.9 percent, respectively). Over 97 percent of patients in the rigorously controlled group received intravenous insulin, compared with 33 percent in the control group. Episodes of hypoglycemia (glucose less than 40 mg/dl [2.2 mmol/L]) were more common in the rigorously controlled group (5 versus 0.7 percent); however, no episodes of hemodynamic instability or seizures were observed in association with hypoglycemia.

In addition, retrospective analysis of the data noted that glycemic control, rather than cumulative insulin dose, was more closely associated with improvements in outcome, including mortality, bacteremia, and development of critical illness, polyneuropathy. In-hospital mortality was significantly higher in patients whose mean blood glucose was 110 to 150 mg/dL (6.1 and 8.3 mmol/L) versus those with a mean level under 110 mg/dl (6.1 mmol/L).

In a subsequent, prospective, observational study of 523 adult critically ill patients, survival also correlated with glucose control, rather than cumulative insulin dose. The authors of this study suggested that a slightly higher target serum glucose (less than 144 mg/dl, rather than 110 mg/dl) might optimize survival and decrease the risk of iatrogenic hypoglycemia.

Other Monitoring Daily monitoring of potassium, sodium, BUN, calcium, magnesium, phosphate, and zinc concentrations is usually

SPECIAL CONSIDERATIONS IN PATIENTS WITH ADVANCED LUNG DISEASE Several issues are unique in regard to nutritional support of patients with advanced lung disease who have ARF. Supplemental nutrition is associated with an obligate increase in basal metabolic rate and has a profound effect on gas exchange. Since the breakdown of nutrition products consumes oxygen and generates carbon dioxide, supplemental nutrition increases ventilatory demand. Patients with advanced lung disease have limited ability to respond to increases in ventilatory demand, making difficult ventilatory management and weaning. The desire to limit carbon dioxide production in mechanically ventilated patients has led to a number of studies exploring use of varying nutrient compositions on this metabolic parameter. Comparison of isocaloric formulas containing pure carbohydrates with those containing a mixture of carbohydrates and lipids has demonstrated that the mixtures generally produce lower rates of carbon dioxide production. In fact, excessive carbon dioxide production is well documented when carbohydrate intake is greater than energy demand (i.e., one and one-half times or more the resting energy expenditure). Utilization of exogenous protein as a substrate for anabolism requires nonprotein calories, such as carbohydrates or fat. Thus, increasing protein intake beyond what is appropriate for critical illness is unlikely to play a major role in regulating ventilatory demand.

Administration of lipids intravenously may adversely impact oxygenation in certain situations. Lipid infusions have been associated with transient reductions in diffusion capacity in noncritically ill patients. Although results of studies of lipid infusions in critically ill patients are conflicting, a mechanism for reduced oxygenation appears to be related to modulation of lung prostaglandins levels. Changes in gas exchange typically are clinically insignificant and are eliminated with infusions under 4 to 8 h in duration.

Current recommendations call for patients with advanced lung disease to receive mixed carbohydrate-fat diets in which the fat compromises 20 to 40 percent of total calories. The increase in carbon dioxide production using a mixed carbohydrate-fat diet is minimal; furthermore, if calories provided match energy expenditure, consequences

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should be of little clinical significance. Use of very high fat (providing more than 40 percent of calories) or very low fat (providing fewer than 15 percent of calories) diets is not recommended. The former may reduce carbon dioxide production, but are usually poorly tolerated and result in diarrhea and abdominal discomfort. The latter do not deliver enough essential fatty acids in critically ill, stressed patients and usually increase carbon dioxide production.

SUGGESTED READING Cerra FB, Benitez MR, Blackburn GL, et al: Applied nutrition in ICU patients. A consensus statement of the American College of Chest Physicians. Chest 111:769, 1997.

Cuthbertson DP: Post-shock metabolic response. Lancet 1:443, 1942.

Finney SJ, Zekveld C, Elia A, et al: Glucose control and mortality in critically ill patients. JAMA 290:2041, 2003.

Galanos AN, Pieper CF, Kussin PS, et al: Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. Crit Care Med 25:1962, 1997.

Gianino S, St. John RE: Nutritional assessment of the patient in the intensive care unit. Crit Care Nurs Clin North Am 5:1, 1993.

Herrmann FR, Safran C, Levkoff SE, et al: Serum albumin level on admission as a predictor of death, length of stay, and readmission. Arch Intern Med 152:125, 1992.

Heyland DK: Nutritional support in the critically ill: A critical review of the evidence. Crit Care Clin 14:423, 1998.

Heyland DK, MacDonald S, Keefe L, et al: Total parenteral nutrition in the critically ill. A meta-analysis. JAMA 280:2013, 1998.

Heyland DK, Novak F, Drover JW, et al: Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 286:944, 2001.

Hoffer LJ: Protein and energy provision in critical illness. Am J Clin Nutr 78:906â&#x20AC;&#x201C;911, 2003.

Nutrition in Acute Respiratory Failure

Krinsley JS: Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 78:1471, 2003.

Krishnan JA, Parce PB, Martinez A, et al: Caloric intake in medical ICU patients: Consistency of care with guidelines and relationship to clinical outcomes. Chest 124:297, 2005.

Laaban J, Kouchakji B, Dore M, et al: Nutritional status of patients with chronic obstructive pulmonary disease and acute respiratory failure. Chest 103:1362, 1993.

Mainous MR, Deitch EA: Nutrition and infection. Surg Clin North Am 74:659, 1994.

Martin CM, Doig GS, Heyland DK, et al: Multicentre, clusterrandomized clinical trial of algorithms for critical-care enteral and parenteral therapy (ACCEPT). CMAJ 170:197, 2004.

McClave SA, Sexton LK, Spain DA, et al: Enteral tube feeding in the intensive care unit: Factors impeding adequate delivery. Crit Care Med 27:1252, 1999.

Montori VM, Bistrian BR, McMahon MM: Hyperglycemia in acutely ill patients. JAMA 288:2167, 2002.

Novak, F, Heyland, DK, Avenell, A, et al. Glutamine supplementation in serious illness: A systematic review of the evidence. Crit Care Med 30:2022, 2002.

Reinhardt GF, Myscofski JW, Wilkens DB, et al: Incidence and mortality of hypoalbuminemic patients in hospitalized veterans. JPEN J Parenter Enteral Nutr 4:357, 1980.

Rubinson L, Diette GB, Song X, et al: Low caloric intake is associated with nosocomial bloodstream infections in patients in the medical intensive care unit. Crit Care Med 32:350, 2004.

Santos JI: Nutrition, infection and immunocompetence. Infect Dis Clin North Am 8:243, 1994.

Souba W: Nutritional support. N Engl J Med 336:41, 1997.

Thomsen C: Nutritional support in advanced pulmonary disease. Respir Med 91:249, 1997.

Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the surgical intensive care unit. N Engl J Med 345:1359, 2001.

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155 Treatment of Agitation in the Intensive Care Unit John P. Kress

Jesse B. Hall

I. SEDATION Indications Assessing Adequacy of Sedation Selection of Agent Benzodiazepines Propofol Butyrophenones Dexmedetomidine Ketamine Barbiturates Inhalational Anesthetics

Critically ill patients often require sedatives and analgesics, especially when mechanical ventilation is necessary. Most patients with respiratory failure experience a subjective sense of respiratory distress; furthermore, endotracheal intubation and positive pressure ventilation are uncomfortable for most patients in the intensive care unit (ICU). Patients in the ICU frequently experience pain. As a result, most receive analgesics along with sedatives while undergoing mechanical ventilation. Indeed, a recent multicenter international cohort study reported that 68 percent of mechanically ventilated patients received sedation for a median number of 3 days; 13 percent of mechanically ventilated patients received neuromuscular blocking agents at some point during mechanical ventilation.

Many sedative and analgesic drugs are available for managing agitation in the ICU. Recent studies reporting outcomes of critically ill patients have advanced our understanding of sedative and analgesic pharmacology in this setting.

Drugs used for treatment of agitation in the ICU are extremely potent. A growing awareness of their enduring effects when the agents are used without discretion has dramatically impacted strategies for their administration.

II. ANALGESIA Indications Selection of Agent Opiates Opiate Toxicities III. STRATEGIES FOR USE OF SEDATIVES AND ANALGESICS IN THE INTENSIVE CARE UNIT IV. CONCLUSIONS

SEDATION Sedation is an important part of the management plan for many patients in critical care units. This section focuses on indications for use of sedative drugs, assessment of their efficacy, and clinical use of the most commonly employed agents.

Indications Sedation requirements vary widely in mechanically ventilated patients. Although nonpharmacologic approaches, such as comfortable positioning in bed and verbal reassurance, are reasonable initial considerations, treatment using pharmacologic agents is frequently needed. Effective prescribing of sedatives in critically ill patients begins with an understanding of indications for their use.

Anxiety occurs frequently in patients undergoing mechanical ventilation and is one of the most common indications for sedation. Anxiety may result from uncomfortable experiences, such as the presence of an endotracheal tube; uncertainty of oneâ&#x20AC;&#x2122;s surroundings, diagnosis or prognosis; or isolation from family and friends. In addition, anxiety

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frequently occurs in conjunction with pain, and analgesia should be considered concurrently with sedation; this topic is discussed in detail in a subsequent section.

Dyspnea is common in mechanically ventilated patients and may be a source of distress requiring sedation. Excessive coughing may contribute to patient-ventilator dyssynchrony in some patients. Many patients requiring mechanical ventilation suffer from cardiopulmonary instability and impaired gas exchange. Sedatives may be required to facilitate routine nursing care, particularly in mechanically ventilated patients. Procedures such as endotracheal suctioning, dressing changes, and repositioning often elicit distress requiring sedatives.

Autonomic instability and elevated endogenous catecholamine activity are common in mechanically ventilated patients and may lead to hemodynamic changes (e.g., tachycardia, hypertension) that may elicit myocardial ischemia, particularly in patients at risk for coronary artery disease.

Sedatives may be administered to counter such autonomic hyperactivity. Elevations in oxygen consumption (Vo2 ) and carbon dioxide production (Vco2 ) may compromise patients. Reduction of oxygen consumption can stabilize the balance between oxygen supply and demand by reducing Vo2 . The reduction may be critical in mechanically ventilated patients with shock or severe hypoxemic respiratory failure.

Amnesia is often cited as an indication for sedation of mechanically ventilated patients. For those mechanically ventilated during surgical procedures, the importance of amnesia is indisputable. In contrast, for patients mechanically ventilated during critical illness, the necessity of continuous amnesia is far less certain. Although amnesia for certain periods during the course of a critical illness requiring mechanical ventilation is logical (e.g., with performance of invasive procedures), complete amnesia for extended periods in the ICU does not appear to be beneficial. In fact, recent findings suggest that prolonged amnesia in the ICU may be detrimental to long-term neuropsychiatric recovery from critical illness.

One circumstance in which amnesia is mandatory is during administration of neuromuscular blocking drugs.

The relationship between delirium and sedation is well established. Deliriumâ&#x20AC;&#x201D;defined as an acutely changing or fluctuating mental status, inattention, disorganized thinking, and an altered level of consciousness that may or may not be accompanied by agitationâ&#x20AC;&#x201D;occurs in most critically ill patients. Hyperactive or agitated delirium may occur with anxiety, as well as sepsis, fever, encephalopathy (e.g., hepatic or renal), withdrawal syndromes (e.g., alcohol, tobacco, or illicit drugs) or use of certain medications. Hyperactive delirium is frequently treated with neuroleptic medications, such as haloperidol.

A much greater percentage of mechanically ventilated patients exhibit a hypoactive form of delirium. Whether hypoactive delirium responds to pharmacologic therapy is unclear. Available evidence suggests that sedative medications are more likely to exacerbate, rather than alleviate, hypoactive delirium.

Assessing Adequacy of Sedation Assessment of the adequacy of sedation requires awareness and consideration of its indications. A reliable instrument for categorizing the level of sedation is necessary, and several sedation scales are currently available for use in the ICU. The Ramsay scale is the most frequently utilized in clinical investigations of sedation. While it offers the benefit of simplicity, the Ramsay scale does not effectively measure quality or degree of sedation with regard to the indications outlined above. In addition, the scale has not been validated objectively.

More recently, other sedation scales, such as the Sedation Agitation Scale (SAS) and the Richmond AgitationSedation Scale (RASS) have been examined thoroughly for validity and reliability. The RASS is, perhaps, the most extensively evaluated scale. The scaleâ&#x20AC;&#x2122;s utility in detecting changes in sedation status over consecutive days of critical care and against constructs of level of consciousness and delirium have been validated. Furthermore, the RASS has been shown to correlate with doses of sedative and analgesic medications administered to critically ill patients. Because of their more rigorous scientific validation, the RASS and SAS are preferable to the Ramsay Scale.

Assessment of sedation adequacy is performed at the bedside. Guidance from nurses is useful, as changes in level of sedation are typically noticed first by the bedside nurse. In practice, protocols for sedative administration must take into account that, most often, drug administration is titrated by the nurse. Theoretically, optimal sedation results in a state in which all indications for sedation are addressed while the patient is fully communicative with caregivers. Although a communicative state of wakefulness during sedative administration is ideal and achievable, for many patients, the stresses of mechanical ventilation do not permit its attainment. Instead, many mechanically ventilated patients require sedation to a point at which constant communication is impossible.

An automated electronic device to monitor the sedation level would be useful in the care of mechanically ventilated patients. One such device, the bispectral index monitor, has been shown to track the level of consciousness under general anesthesia. The monitor is based on processing of raw EEG signals into a discrete, scaled number from 0 to 100, which reflects the level of cortical activity (0 indicating absence of cortical activity and 100 indicating full wakefulness). Preliminary data suggest a good correlation between the bispectral index and the SAS and RASS. However, the device has not been thoroughly evaluated in the ICU and awaits more extensive validation before its role in the critical care setting is established.

Selection of Agent Once an indication for sedation is established, the clinician must choose one or more drugs. The use of commonly employed agents and their pharmacologic properties are outlined below.

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Benzodiazepines Benzodiazepines potentiate gamma-aminobutyric acid (GABA) receptor-mediated inhibition of the central nervous system (CNS). The GABA receptor complex regulates a cell membrane chloride channel by increasing intracellular flow of chloride ions. This activity causes hyperpolarization of neurons, raising their excitability threshold. The GABA receptor can be competitively antagonized using the synthetic agent, flumazenil, thereby reversing the pharmacologic effects of benzodiazepines. Midazolam, lorazepam, and diazepam are the three available parenteral benzodiazepines.

The onset of action of midazolam is rapid (0.5 to 5 min), and the duration of action following a single dose is short (approximately 2 h). All parenteral benzodiazepines are lipid soluble and have a large volume of distribution; therefore, they are widely distributed throughout body tissues. The duration of action following a single bolus of a parenterally administered benzodiazepine is dependent mainly on the rate of redistribution to peripheral tissues, especially adipose tissue.

Midazolam undergoes hepatic metabolism and renal excretion. Alpha hydroxyl midazolam is a pharmacologically active metabolite that may accumulate in patients with impaired renal function. When midazolam is administered to critically ill patients by continuous infusion over extended periods, accumulation of the drug in peripheral tissues can occur, leading to prolonged clinical effects. Obese patients with larger volumes of distribution, and elderly patients with decreased hepatic and renal function, may be even more prone to prolonged effects.

Parenteral lorazepam has a somewhat slower onset of action (5 min) compared to midazolam due to lower lipid solubility and resultant reduced ability to cross the bloodbrain barrier. The duration of action following a single dose is longer than that of midazolam (typically 6 to 10 h), depending on the dose given. Critically ill patients requiring mechanical ventilation may show a wide range of responses to the drug.

Parenteral diazepam has a rapid onset of action (1 to 3 min) and a limited duration of action (30 to 60 min) following a single dose, due to high lipid solubility. However, once peripheral tissues become saturated, recovery from the drugâ&#x20AC;&#x2122;s effects can be prolonged for days. Diazepam has several active metabolites that may impair recovery time. Because of the tendency for drug accumulation with diazepam, it is rarely used in patients in the ICU. Pharmacodynamic effects of all three of the benzodiazepines described are similar. All cause a dose-dependent suppression of awareness along a spectrum from mild reduction in responsiveness to obtundation. They are potent anxiolytic drugs and reliably produce amnesia. All benzodiazepines have anticonvulsant properties; lorazepam is the preferred agent for treatment of generalized seizures.

Rarely, paradoxical agitation may occur in patients given benzodiazepines; the agitation may accelerate with additional doses and is more frequently observed in elderly patients.

Treatment of Agitation in the Intensive Care Unit

All benzodiazepines induce a dose-dependent depression of respiratory drive. Benzodiazepine-induced depression of ventilation is less extreme than that seen with opiates; however, concurrent use of both agents may have a synergistic effect. Distinguishing benzodiazepine- from opiate-induced respiratory depression may be difficult. A pattern of reduced tidal volume and slightly increased respiratory rate is more characteristic of a benzodiazepineâ&#x20AC;&#x2122;s effect, while opiates tend to produce slow, deep breathing.

Benzodiazepines have minimal cardiovascular effects in euvolemic patients; a slight decrease in blood pressure without a significant change in heart rate may be observed. Effects are potentiated in the presence of hypovolemia. For patients with elevated endogenous sympathetic drive, more profound decreases in blood pressure may be seen.

Table 155-1 summarizes the pharmacologic properties of the parenteral benzodiazepines. Dependence and withdrawal can be seen in patients receiving benzodiazepines for extended periods after the drugs are discontinued. Benzodiazepine withdrawal may be difficult to detect, since the signs (e.g., autonomic hyperactivity) are relatively nonspecific, particularly in critically ill patients. Accordingly, a high index of suspicion is necessary, especially for patients who have received these drugs for a protracted period.

Propofol Propofol appears to act on the GABA receptor, although not at the same site as do the benzodiazepines. The drug is hydrophobic and must be prepared for administration as a lipid emulsion. The lipid solubility leads to rapid onset of sedation, since time required to cross the blood-brain barrier is short. High lipid solubility also permits rapid redistribution of propofol to peripheral tissues; therefore, the duration of effect is typically measured in minutes. With prolonged, continuous infusions, the duration of effect may be increased slightly, but rarely does it last beyond 60 min from the time the infusion is discontinued. When a propofol infusion is stopped, the drug is slowly redistributed back to the plasma from peripheral tissue stores; however, the redistribution is usually not clinically significant because of the drugâ&#x20AC;&#x2122;s high lipid affinity. Propofol is ultimately metabolized primarily in the liver. The elimination half-life is 4 to 7 h and there are no active metabolites.

Propofol has predictable pharmacodynamic effects on the CNS, acting as a hypnotic agent and causing dosedependent depression of responsiveness and awareness. The drug is also a potent anxiolytic and amnestic agent. Indeed, at high infusion rates, propofol is commonly used for general anesthesia. In addition, propofol is currently viewed by most authorities as an effective anticonvulsant, although preliminary reports of its impact on seizure threshold were conflicting. Propofol has no detectable analgesic activity and is not recommended as the sedative in management of mechanically ventilated patients, since pain control is important in this setting.

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Table 155-1 Properties of Commonly Used Benzodiazepines Midazolam

Lorazepam

Diazepam

Typical starting dose

1–2 mg

0.5–1 mg

5–10 mg

Onset of action

0.5–2 min

3–5 min

1–3 min

Duration of action after single dose

2h

6–10 h

1–6 h

Metabolism

Hepatic

Hepatic (less influenced by age and liver disease)

Hepatic

Elimination

Renal

Renal

Renal

Anxiolysis

4+

4+

4+

Analgesia

No effect

No effect

No effect

Hypnosis

4+

4+

4+

Amnesia

4+

4+

4+

Anticonvulsant activity

3+

4+

3+

Effectiveness in reducing dyspnea

1+

1+

1+

Cardiovascular effect

Venodilation

Venodilation

Venodilation

Respiratory effect

Hypcventilation

Hypoventilation

Hypoventilation

Common side effects

Paradoxical agitation

Paradoxical agitation

Paradoxical agitation

1+ = minimal effect; 2+ = mild effect; 3+ = moderate effect; 4+ = large effect.

Propofol causes ventilatory depression and even apnea in some patients. Because propofol-induced apnea is unpredictable and not always dose dependent, the drug should not be used in settings in which the airway can not be readily secured. Typically, the respiratory pattern seen with propofol is characterized by a decrease in tidal volume and slight increase in respiratory rate.

Propofol may cause significant decreases in blood pressure, especially in patients with hypovolemia. Venodilation and mild myocardial depression are observed. The hemodynamic effects of propofol generally are more pronounced than those of the benzodiazepines. The drug should be administered cautiously in patients with cardiac disease.

Development of hyperlipidemia is a well described complication of propofol. As described previously, the drug is delivered in an intralipid carrier. A 1 percent solution of propofol provides 1.1 kcal/ml; consequently, parenteral lipid feedings must be adjusted accordingly when a propofol infusion is given. Serum triglyceride levels should be checked frequently and the propofol stopped if hypertriglyceridemia is noted.

Propofol can support growth of bacteria and fungi; therefore, strict aseptic technique and frequent replacement of infusion tubing are essential to prevent blood stream infection.

Finally, the “propofol infusion syndrome,” which manifests as dysrhythmias, heart failure, metabolic acidosis, hyperkalemia, and rhabdomyolysis is a rare complication of propofol use. The syndrome appears more likely to occur when high doses (greater than 80 µg/kg/min) and or high concentrations (2 versus 1 percent) of the drug are used. An unpublished, randomized, controlled trial of propofol in pediatric patients reported a drug concentration-dependent increase in 28-d mortality in propofol-treated patients (8 percent with 1 percent propofol; 11 percent with 2 percent propofol) compared with those given other sedatives (4 percent).

Butyrophenones Butyrophenones, such as haloperidol, are sometimes used for sedation of mechanically ventilated patients. These drugs induce a state of tranquility, and patients often demonstrate

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a detached affect. Butyrophenones appear to antagonize dopamine, especially in the basal ganglia, although their exact site of action is not known.

The time of onset of the effect of intravenously administered haloperidol is 2 to 5 min; the half-life is 2 h. Starting doses of 1 to 10 mg are used typically, and the dose is titrated depending on desired endpoint. Haloperidol is metabolized in the liver.

As noted, patients receiving haloperidol appear calm and detached. Consequently, the butyrophenones are typically reserved for acutely agitated or hyperactive patients.

Patients may appear indifferent to their surroundings; occasionally, a state of cataleptic immobility is seen.

Haloperidol provides no amnesia, has no effect on seizure activity, and has minimal analgesic properties.

Haloperidol and other butyrophenones are the drugs of choice for agitated delirium.

Recent data suggest reduced mortality in mechanically ventilated patients treated with haloperidol. However, the findings are preliminary and retrospective in nature. Nevertheless, such reports have created an interest in use of the drug as a sedative in the ICU. More studies are needed to validate these preliminary findings.

When used as a single agent, haloperidol has no significant respiratory depressant activity; there is little attenuation of respiratory depression when used in conjunction with opiates. Hypoxic pulmonary drive is maintained. Reliable maintenance of respiratory function is an attractive feature of haloperidol, since most sedative or analgesic drugs cause respiratory depression.

Concern over adverse cardiovascular effects has limited use of haloperidol as a sedative in critically ill patients.

Haloperidol is known to prolong the QT interval in some patients; although rare, torsade de pointes has been noted in patients receiving the drug. The drug also mildly antagonizes the α1 receptor and may decrease the neurotransmitter function of dopamine, resulting in mild hypotension.

Extrapyramidal effects are occasionally seen with haloperidol, but they are much less common with intravenous, than oral, butyrophenones. When these complications occur, treatment with diphenhydramine or benztropine may be necessary. The neuroleptic malignant syndrome (NMS) is another extremely rare problem thought to result from central dopaminergic blockade, leading to extrapyramidal side effects, muscle rigidity, and excess heat generation. NMS is a life-threatening complication manifested by “lead pipe” muscle rigidity, fever, and mental status changes.

Bromocriptine, dantrolene, and pancuronium have all been used to successfully treat NMS.

Dexmedetomidine Dexmedetomidine is a selective α2 agonist with both sedative and analgesic properties. Patients receiving this drug appear to be sedated when undisturbed, but they are easily aroused with minimal stimulation. Dexmedetomidine is unique in that patients treated with the agent may transition between sedate and awake states quickly and easily without discon-

Treatment of Agitation in the Intensive Care Unit

tinuing the infusion. Consequently, frequent neurological examinations can be performed. The drug is approved for short-term use (less than 24 h) in patients initially receiving mechanical ventilation.

Dexmedetomidine has been shown to be analgesicsparing in postoperative patients. The drug causes no respiratory depression; therefore, it can be continued after discontinuation of mechanical ventilation and extubation. Side effects include bradycardia and hypotension, especially with hypovolemia or high endogenous sympathetic tone. Vasoconstriction and hypertension with increasing doses of dexmedetomidine also have been described. To date, the majority of studies of dexmedetomidine have evaluated postoperative patients in the ICU. Unfortunately, dexmedetomidine has not been extensively studied as an agent for long-term administration in critically ill, mechanically ventilated patients.

Table 155-2 summarizes the pharmacologic properties of propofol, haloperidol, and dexmedetomidine.

Ketamine Ketamine is a so-called “dissociative” anesthetic with a molecular structure similar to phencyclidine. Patients receiving the drug experience a state of mind in which perception is separated from sensation; i.e., patients feel detached from their surroundings (“dissociative state”). While patients appear unaware of their environment, they keep their eyes open and are able to maintain a protective cough reflex. In addition, they may demonstrate coordinated movements that appear without purpose.

Ketamine has profound analgesic properties, but it does not produce respiratory depression. Hypertension and tachycardia may be observed and reflect increased activity of the sympathetic nervous system. Some, but not all, patients experience amnesia. The common side effects of emergence delirium and severe hallucinations greatly limit use of the drug in mechanically ventilated patients. As a phencyclidine derivative, ketamine recently has gained popularity as an illicit drug. Benzodiazepines may reduce the incidence and severity of ketamine-related hallucinations.

Barbiturates Barbiturates, such as thiopental and pentobarbital, are potent agents that cause amnesia and unconsciousness. They have no role as sedatives in mechanically ventilated patients because of their propensity to cause hemodynamic instability and exert prolonged effects due to accumulation in peripheral tissues because of high lipid solubility. Thiopental is sometimes used to induce anesthesia in facilitating endotracheal intubation.

These drugs may be used to induce a pharmacologic coma in patients with severe brain injury.

Inhalational Anesthetics Inhalational anesthetics are used widely in the operating room to maintain general anesthesia in mechanically ventilated patients. The exhaled anesthetics must be effectively scavenged to prevent pollution of the ICU environment, since the agents

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Table 155-2 Properties of Other Sedative Agents Propofol

Haloperidol

Dexmedetomidine

Typical starting dose

1–2 mg/kg

0.5–1 mg

0.5–1.0 µg/kg over 10 min; 0.2–0.7 µg/kg/h infusion

Onset of action

0.5–1 min

2–5 min

5–10 min

Duration of action after single dose

2–8 min

2h

30–60 min

Metabolism

Hepatic, renal, pulmonary?

Hepatic

Hepatic

Elimination

Renal

Renal

Renal

Anxiolysis

4+

3+

3+

Analgesia

No effect

No effect

2+

Hypnosis

4+

2+

3+

Amnesia

4+

No effect

1+

Anticonvulsant activity

3+

No effect

No effect

Effectiveness in reducing dyspnea

1+

No effect

No effect

Cardiovascular effect

Venodilation, arteriolar dilation, myocardial depression

Venodilation, arteriolar dilation

Venodilation, arteriolar dilation, bradycardia, occasional hypertension

Respiratory effect

Hypoventilation

No effect

No effect

Common side effects

Increased triglycerides

Neuroleptic malignant syndrome (rare), extrapyramidal effects (rare)

Hypotension, bradycardia

1+ = minimal effect; 2+ = mild effect; 3+ = moderate effect; 4+ = large effect

are not metabolized to any significant degree. Delivery and scavenging of inhalational anesthetics is technically challenging and has limited use of these agents outside the operating room. However, some studies have reported successful use of these drugs in mechanically ventilated, critically ill patients.

For example, isoflurane, which has analgesic, amnestic, and hypnotic properties, has been described as an effective single agent for mechanically ventilated patients in the ICU.

ANALGESIA The observations that most mechanically ventilated patients experience some level of discomfort and have limited ability

to communicate fully mandates an aggressive, pre-emptive strategy for use of analgesia. Failure to achieve adequate analgesia may result in a mechanically ventilated patient developing agitation that is inadequately treated with sedatives alone.

As a result, inappropriate escalation of sedative doses may result in excessive administration of the drug.

Indications Pain from surgical incisions or trauma is usually obvious, but other indications for pain control in the ICU are often covert. These include endotracheal suctioning or placement of invasive catheters, such as arterial or venous lines. For many patients, the mere presence of an endotracheal tube is painful. Preexisting problems, such as skeletal fractures from

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metastatic cancer or prolonged immobility during bed rest, may also be sources of pain. If all potential causes of pain are not recognized and addressed, discomfort and agitation often persist.

Pain in critically ill, mechanically ventilated patients can increase endogenous catecholamine activity and cause myocardial ischemia, hypercoagulability, a hypermetabolic state, sleep deprivation, anxiety, or delirium. These problems are diminished by adequate treatment.

Because failure to recognize pain as a cause of agitation may lead to inappropriate administration of nonanalgesic sedatives, an aggressive approach to managing pain in mechanically ventilated patients has been strongly recommended by consensus groups. Clinicians should actively search for sources of pain. Ability to discern its presence may be difficult because of impaired communication with mechanically ventilated patients. Furthermore, clinical parameters, such as changes in vital signs, are often not reliable indicators. Therefore, a high level of vigilance toward a need for analgesia is essential in critically ill patients, especially those undergoing mechanical ventilation.

Despite consensus recommendations, management of pain in the ICU is often inadequate. Ineffective communication and delirium may contribute to the problem. Concern over addiction to opiates is not a valid reason for inadequate analgesia in critically ill patients. In addition, an arbitrary limit should not be placed on drug doses.

For most patients, intravenous administration of opiate analgesics is preferred. Intramuscular injections are not recommended because of injection-related pain and unpredictable drug absorption in critically ill patients. Dosing strategies for intravenous administration of opiates include continuous infusions and intermittent dosing.

Intermittent opiate dosing regimens can be divided into scheduled administration, administration on an as-needed (prn) basis, and patient-controlled analgesia (PCA). Strategies employing an as-needed basis may lead to fluctuations between inadequate and excessive analgesia. Patients alert enough to respond to their own pain needs may benefit from a PCA-based regimen, although the majority of mechanically ventilated patients are not alert enough to utilize a PCA device.

Transdermal opiates may be continued in patients who are treated chronically with these medications; however, transcutaneous absorption is unpredictable during critical illness. Certainly, this route should not be used for treating acute pain in mechanically ventilated patients.

Use of clinical tools to categorize pain, such as scales or scoring systems, may be helpful. In general, simpler scales are more effective, since communication for many mechanically ventilated patients is limited. Although it has not been evaluated in critically ill, mechanically ventilated patients, the visual analogue scale (VAS) has excellent reliability and validity.

The VAS uses a self-reported measure of pain intensity that consists of a 10 cm line inscribed on paper; verbal anchors—“no pain” and “severe pain”—define the ends of

Treatment of Agitation in the Intensive Care Unit

the scale. The scale may provide useful information in patients alert enough to respond. A similar scale is the numeric rating scale. This scale also consists of a horizontal line with numeric markings: 1 and 10 anchoring the extremes of the pain intensity scale. The numeric rating scale may be preferred because it can be completed by writing, speaking, or using hand gestures. In addition, it may demonstrate better performance across various age groups.

Selection of Agent Nonpharmacologic analgesic strategies are occasionally helpful and should be considered. For example, malpositioning of invasive catheters (e.g., an endotracheal tube impinging on the main carina) is a problem that may be easily remedied. Likewise, optimal patient positioning in the bed may at least partially relieve low back pain, pain from chest tubes and surgical incisions, etc. However, in spite of attention to these issues, most patients require administration of pharmacologic agents. Opiates are the most commonly used analgesic agents for critically ill patients.

Opiates Opiate receptors are found in both the central nervous system and peripheral tissues. The two most clinically important opiate receptors are the mu and kappa types. Mu receptors include two subtypes: µ1 , which mediate analgesia, and µ2 , which mediate respiratory depression, nausea, vomiting, constipation, and euphoria. Kappa receptors mediate other effects, including sedation, miosis, and spinal analgesia. Opiates may have some anxiolytic properties, but they do not provide reliable amnesia. Commonly utilized opiates are discussed in detail below.

Morphine is the most commonly used opiate and is the standard against which all other opiates are compared.

When given intravenously, morphine has a relatively slow onset of action (typically, 5 to 10 min) due to its low lipid solubility. As a result, movement of the drug across the bloodbrain barrier is delayed. The duration of action after a single dose is approximately 4 h. However, when the drug is given repeatedly, drug accumulation and a prolonged effect are the rule.

Morphine is metabolized in the liver through glucuronide conjugation; an active metabolite (morphine-6glucuronide) is generated that may accumulate, especially in renal failure. Drug elimination occurs in the kidney.

Fentanyl is a highly lipid-soluble, synthetic opiate. Its lipid solubility allows rapid movement across the blood-brain barrier and a quick onset of action. Redistribution of fentanyl into peripheral tissues leads to a short duration of action after a single dose (0.5 to 1 h). However, when fentanyl is given repeatedly, tissue stores become saturated and the clinical effect can be prolonged. Fentanyl has no active metabolites and does not release histamine.

Hydromorphone is similar to morphine with regard to its onset of action. However, since hydromorphone has

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no active metabolites, the drugâ&#x20AC;&#x2122;s duration of action following long periods of administration may be less than that of morphine.

Meperidine is a lipid-soluble opiate that moves rapidly across the blood-brain barrier and has a rapid onset of action (3 to 5 min). The higher lipid solubility leads to peripheral redistribution, so that duration of action after a single dose may be shorter than that of morphine (1 to 4 h). Meperidine undergoes hepatic metabolism and renal elimination. Metabolites of meperidine may accumulate and lead to neurotoxic effects, including seizures. Because many other opiates with better safety profiles are available, this drug probably should not be used in the ICU. Remifentanil is another synthetic, lipid-soluble drug with a rapid onset of action. The drug is unique because of its rapid metabolism via hydrolysis by nonspecific blood and tissue esterases. Consequently, the pharmacokinetic profile of remifentanil is not affected by hepatic or renal insufficiency.

The drug must be given by continuous infusion because of its rapid metabolism and quick recovery time.

To date, remifentanil has not been studied extensively for long-term use in the critical care setting. Most studies report experiences with short-term use in neurosurgical and cardiothoracic surgical units. Some studies suggest that when remifentanil is used during general anesthesia, the incidence of postoperative respiratory failure may be reduced, presumably because patients wake up more rapidly. As a result, extubation in the operating room may reduce the need for routine postoperative care in the ICU.

Opiate Toxicities All opiates cause centrally mediated, dose-dependent respiratory depression mediated by Âľ2 receptors in the medulla. The typical breathing pattern seen with opiates is a reduced respiratory rate with preservation of tidal volume. The response to hypercapnia is decreased and the ventilatory response to hypoxia is obliterated. The respiratory depressive properties of opiates are frequently exploited in mechanically ventilated patients suffering from dyspnea or coughing.

The hemodynamic effects of opiates are less profound than are the respiratory effects. Hypovolemic patients whose blood pressure is sustained by sympathetic hyperactivity may become hypotensive following administration of opiates. Most opiates cause a decrease in heart rate because of decreased sympathetic activity. The histamine release caused by morphine rarely leads to hemodynamic compromise.

Meperidine is unique in that it may cause tachycardia, perhaps through an anticholinergic mechanism. Remifentanil may cause bradycardia and hypotension, particularly when administered concurrently with drugs having vasodilating properties, such as propofol. Hypertension after remifentanil dosing, although described, is uncommon.

Gastrointestinal dysfunction, including drug-related ileus, is seen frequently in mechanically ventilated patients receiving opiates. Methylnaltrexone, a specific antagonist of Âľ2 receptors in the gut, has been reported to attenuate opiate-

induced ileus in humans. However, use of methylnaltrexone in critically ill, mechanically ventilated patients has not been studied.

The neurotoxic effects of meperidine, including seizures, have been discussed previously.

Muscle rigidity occasionally occurs with use of synthetic opiates, such as fentanyl and remifentanil; however, it is not observed with naturally occurring opiates like morphine. The finding may be seen when high doses of the drugs are injected rapidly. The mechanism of opiate-induced skeletal muscle rigidity, although not fully understood, is thought to involve supraspinal activity of the drugs in the striata and substantia nigra. In the most extreme cases, chest wall muscle rigidity may make ventilation impossible. Neuromuscular blockade (e.g., using succinylcholine) is necessary to reverse the rigidity.

Fortunately, the problem is extremely rare with the doses of opiates used in management of mechanically ventilated patients.

Findings of drug dependence and withdrawal may be seen in patients receiving opiates for extended periods. Patients who abuse opiates are at risk when hospitalized for a critical illness. Signs and symptoms are nonspecific and include: pupillary dilation, sweating, lacrimation, rhinorrhea, piloerection, tachycardia, vomiting, diarrhea, hypertension, yawning, fever, tachypnea, restlessness, irritability, increased sensitivity to pain, nausea, cramps, muscle aches, dysphoria, insomnia, symptoms of opioid craving, and anxiety. Patients without prior illicit drug use may also experience opiate withdrawal when pharmacologically administered opiates are stopped suddenly. Whether any pre-emptive strategies, such as downward dose titration or regular interruption of dosing, can attenuate or prevent opiate withdrawal is not known.

In one study of trauma patients in a surgical ICU, a high incidence of withdrawal was noted in those receiving opiates or sedatives for more than 1 week. Patients manifesting withdrawal findings received higher doses of opiates and benzodiazepines than did those not experiencing withdrawal.

A potential role for long-acting opiates, such as methadone, in overcoming this problem is logical, although it has not been studied. Table 155-3 summarizes the pharmacologic properties of commonly used opiates.

STRATEGIES FOR USE OF SEDATIVES AND ANALGESICS IN THE INTENSIVE CARE UNIT Since no single drug can achieve all of the indications for sedation and pain control in the ICU, a combination of drugs, each titrated to specific end points, may be a more effective strategy. The strategy may permit use of lower doses of individual drugs, thereby reducing problems of drug accumulation.

In the ICU, sedatives and analgesics are almost always administered intravenously. Administration by continuous infusion or intermittent boluses has been advocated. Intermittent administration may lead to fluctuations in level of

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Treatment of Agitation in the Intensive Care Unit

Table 155-3 Properties of Commonly Used Opiates Morphine

Meperidine

Fentanyl

Methadone

Usual starting dose

2–5 mg

20–50 mg

25–50 µg

5–10 mg

Onset of action

10 min

3–5 min

0.5–1 min

10–20 min

Duration of action after single dose

4h

1–4 h

0.5–1 h

6–24 h

Metabolism

Hepatic

Hepatic

Hepatic

Hepatic

Elimination

Renal

Renal

Renal

Renal

Anxiolysis

1+

2+

2+

1+

Analgesia

4+

4+

4+

4+

Hypnosis

No reliable effect

No reliable effect

No reliable effect

No reliable effect

Amnesia

No reliable effect

No reliable effect

No reliable effect

No reliable effect

Seizure threshold

No effect

May decrease

No effect

No effect

Effectiveness in reducing dyspnea

4+

4+

4+

4+

Cardiovascular effect

Venodilation

Venodilation

Venodilation

Venodilation

Respiratory effect

Hypoventilation

Hypoventilation

Hypoventilation

Hypoventilation

Common side effects

N/V, ileus, itching

N/V, seizure, ileus, itching

N/V, ileus, itching

N/V, ileus, itching

1+ = minimal effect; 2+ = mild effect; 3+ = moderate effect; 4+ = large effect.

N/V = nausea and vomiting.

sedation and increase demands on nursing time, potentially diverting attention from other aspects of patient care. The perceived benefits of continuous infusions include a more consistent level of sedation and better patient comfort. The convenience of the continuous infusion strategy for both patients and caregivers is likely the greatest reason for its popularity.

Ideally, strategies for sedation and analgesia in critically ill patients should be based upon pharmacokinetic and pharmacodynamic principles. Unfortunately, patients in the ICU frequently exhibit unpredictable alterations in pharmacodynamics, making establishment of precise guidelines for drug administration impossible. For instance, when “shortacting” benzodiazepines, such as midazolam and lorazepam, are administered in the ICU, the drugs accumulate in tissue stores and produce prolonged clinical effects. Other circumstances that confound prediction of pharmacologic behavior of sedatives and analgesics include altered hepatic or re-

nal function, complex drug-drug interactions, altered protein binding, and circulatory instability. The multicompartmental pharmacokinetics typical of critically ill patients defy simple bedside pharmacokinetic profiling. Consequently, clinicians must titrate sedatives and analgesics against discernible clinical end points. Indeed, some critically ill patients require extraordinarily high doses of sedatives; such doses may be much greater than those described in the literature or recommended by the drug manufacturer.

Since oversedated patients are easier to manage than undersedated patients, clinicians are usually very aggressive in using sedation in the ICU. This is appropriate during the state of agitation that is often seen early during critical illness. However, maintenance of deep sedation after agitation resolves may lead to the problems described previously.

Recent clinical studies in critical care have led to evidence-based treatment strategies for many common conditions. For example, over the last decade improved outcomes

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for critically ill patients with ARDS, sepsis, acute renal failure, status asthmaticus, and cancer have been reported. As sicker patients survive the acute phases of critical illness, more aggressive levels of sedation and analgesia may be necessary.

This is especially true for those managed using unconventional ventilator strategies (e.g., permissive hypercapnia, low stretch, prone positioning, and pressure-controlled ventilation), since these modalities may be inherently distressing to many patients.

Although it is not without problems, deep sedation may be the only realistic option for some patients. Ideally, a head-to-toe daily assessment for the presence of organ failure should be routine for every critically ill patient. This is particularly true during the resuscitative phases of ICU care, when assessment of the adequacy of end-organ perfusion and organ function is vital, including neurological assessment.

The mental status examination is an important gauge of brain perfusion. Since brain injury is a devastating complication of critical illness, acute cerebral dysfunction must be detected quickly and corrected, if possible, before permanent injury arises. A thorough neurological examination, including assessment of mental status, may detect problems early and obviate the need for urgent diagnostic studies or therapeutic interventions. However, use of sedatives may limit a clinician’s ability to serially follow a patient’s neurological status.

A protocol-driven approach to sedation has been shown to alleviate many of the problems noted previously. A protocol directed by bedside nurses can shorten the duration of mechanical ventilation, ICU and hospital lengths of stay, and need for tracheostomy. Protocols may help assure adequate analgesia and sedation, based on frequent patient assessment and goal-directed titration of drugs.

A daily respite from sedatives may eliminate the tendency of clinicians to “lock in” to a high sedative infusion rate, which—while appropriate early in ICU care—may be unnecessary on subsequent days. Recently, the practice of routine daily interruption of continuous sedative infusions has been shown to reduce sedation-related complications, duration of mechanical ventilation, and ICU length of stay. The strategy allows patients to remain awake and interactive, thereby potentially reducing the amount of sedatives and opiates given and need for diagnostic studies to evaluate unexplained alterations in mental status. Although interruption of sedative infusions may lead to abrupt awakening and agitation, anticipation of these developments by the ICU team can reduce the incidence of complications, such as self-extubation.

Literature evaluating long-term consequences of recovery from respiratory failure and sedation is limited. Available data suggest that post-ICU depression is common in those who require mechanical ventilation during critical illness.

Posttraumatic stress disorder (PTSD) following recovery has been reported, as well. As noted previously, studies suggest that lack of awareness related to sedation or underlying illness is associated with development of PTSD and that preservation of awareness during mechanical ventilation may reduce the risk.

CONCLUSIONS Critically ill patients frequently exhibit agitated behavior. Sedation and pain control are important components of treatment, especially in those requiring mechanical ventilation.

Treatment of agitation should be directed to specific, individualized goals.

All currently available drugs used to treat agitation have limitations. Complications related to use of these agents are common. Rather than seeking an ideal drug, clinicians should employ strategies of drug administration that are based upon principles of sedative pharmacology in critical illness. When sedative drugs are administered, recognition of specific goals allows rational management strategies to be implemented, leading to improved short- and long-term outcomes.

SUGGESTED READING Bernard GR, Vincent JL, Laterre PF, et al: Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709, 2001.

Brook AD, Ahrens TS, Schaiff R, et al: Effect of a nursingimplemented sedation protocol on the duration of mechanical ventilation. Crit Care Med 27:2609–2615, 1999.

Byatt CM, Lewis LD, Dawling S, et al: Accumulation of midazolam after repeated dosage in patients receiving mechanical ventilation in an intensive care unit. Br Med J 289:799–800, 1984.

Cammarano WB, Pittet JF, Weitz S, et al: Acute withdrawal syndrome related to the administration of analgesic and sedative medications in adult intensive care unit patients.

Crit Care Med 26:676–684, 1998.

Cremer OL, Moons KGM, Bouman EAC, et al: Long-term propofol infusion and cardiac failure in adult head-injured patients. Lancet 357:117–118, 2001.

Desbiens NA, Wu AW, Broste SK, et al: Pain and satisfaction with pain control in seriously ill hospitalized adults: Findings from the SUPPORT research investigators. Crit Care Med 24:1953–1961, 1996.

Ely EW, Baker AM, Dunagan DP, et al: Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 335:1864–1869, 1996.

Ely EW, Shintani A, Truman B, et al: Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA 291:1753–1762, 2004.

Jacobi J, Fraser GL, Coursin DB, et al: Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 30:119–141, 2002.

Jones C, Griffiths RD: Disturbed memory and amnesia related to intensive care. Memory 8:79–94, 2000.

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Jones C, Griffiths RD, Humphris G, et al: Memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Crit Care Med 29:573–580, 2001.

Kollef MH, Levy NT, Ahrens TS, et al: The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest 114:541–548, 1998.

Kress JP, Lacy M, Pliskin N, et al: The long term psychological effects of daily sedative interruption in critically ill patients.

Am J Respir Crit Care Med 168:1457–1461, 2003.

Kress JP, Pohlman A, O’Connor MF, et al: Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 342:1471–1477, 2000.

Marik PE, Varon J: The management of status epilepticus.

Chest 126:582–591, 2004.

Millbrandt EB, Kersten A, Kong L, et al: Haloperidol use is associated with lower hospital mortality in mechanically ventilated patients. Crit Care Med 33:226–230, 2005.

Park GR, Evans TN, Hutchins J, et al: Reducing the demand for admission to intensive care after major abdominal surgery by a change in anesthetic practice and the use of remifentanil. Eur J Anesthesiol 17:111–119, 2000.

Ramsey MAE, Savege TM, Simpson BRJ, et al: Controlled sedation with alphaxalone-alphadolone. Br Med J 2:256– 259, 1974.

Treatment of Agitation in the Intensive Care Unit

Riker RR, Picard JT, Fraser GL: Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients.

Crit Care Med 27:1325–1329, 1999.

Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377, 2001.

Sessler CN, Gosnell MS, Grap MJ, et al: The Richmond Agitation-Sedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166:1338–1344, 2002.

Shelly MP, Mendel L, Park GR: Failure of critically ill patients to metabolise midazolam. Anaesthesia 42:619–626, 1987.

The Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301–1308, 2000.

Venn RM, Newman PJ, Grounds RM: A phase II study to evaluate the efficacy of dexmedetomidine for sedation in the medical intensive care unit. Int Care Med 29(2):201– 207, 2003.

Wagner BKJ, O’Hara DA: Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet 33:426– 453, 1997.

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156 Decision Making in the Intensive Care Unit Bruno DiGiovine Mark A. Kelley

I. OUTCOMES OF MEDICAL CONDITIONS COMMONLY SEEN IN THE INTENSIVE CARE UNIT Respiratory Failure Chronic Obstructive Pulmonary Disease Sepsis and the Systemic Inflammatory Response Syndrome Nontraumatic Coma Malignancy Cardiopulmonary Resuscitation Age Acquired Immunodeficiency Syndrome

Meth ods Employed in Developing Severity-Scoring Systems Acute Physiology, Age, and Chronic Health Evaluation Scoring System Simplified Acute Physiological Score Mortality Prediction Model III. USE OF SEVERITY SCORES IN THE INTENSIVE CARE UNIT Allocation of Resources Quality Management Clinical Decision Making

II. SEVERITY OF ILLNESS SCORING SYSTEMS AND MORTALITY PREDICTION

Care of the critically ill patient is a complex interplay of science, health care economics, ethics, and the art of medicine.

In the intensive care unit (ICU), the health care team utilizes costly technology to rescue patients from the extremes of illness. This struggle places emotional strain on patients, their families, and health care professionals as they balance the desire for cure with concerns for dignity, comfort, and patient autonomy. In this difficult scenario, the physician must provide facts to patients and their families about the severity of illness and prognosis. The prognostic information should include not only predictions about risk of death, but also likely outcomes in terms of quality of life if the patient survives. A description of the objective information available on the outcome of critically ill patients is provided later in this chapter.

Critical care in the United States utilizes expensive health care technology. Recently, general health costs have escalated to approximately 15 percent of the U.S. gross national product, and critical care accounts for as much as

10 percent of the health-related costs. Whether this investment in critical care results in improved health for the nation has been questioned, as has whether most patients even desire this type of treatment. Consequently, considerable research has been performed in defining the prognosis of critically ill patients, through both historical case series and objectively derived predictive instruments.

This chapter focuses on three specific areas. First is a description of the prognosis of patients with the most common conditions found in the medical ICU, such as respiratory failure and sepsis. A discussion of what is known about quality of life after recovery from these conditions is included. The second area is an overview of the outcome instruments that have been developed to predict mortality in the ICU, while the third covers social issues in critical care, such as expectations of patients and their families, advanced directives, and stratification of critically ill patients by resource utilization.

The last section also addresses the ways in which access to prognostic information affects practitioners.

Copyright Š 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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OUTCOMES OF MEDICAL CONDITIONS COMMONLY SEEN IN THE INTENSIVE CARE UNIT Much has been written about the prognosis of certain syndromes and diagnoses prompting admission to the ICU. In general, diagnoses can be divided into two categories. The first is the group of disorders that result in critical illness in the course of chronic illnesses, such as chronic obstructive pulmonary disease (COPD) or cancer. In these disorders, the prognosis depends on the status of the underlying disease.

The second category is an acute illness, such as acute respiratory distress syndrome (ARDS) or severe sepsis. Although the mortality for patients with these diagnoses is certainly affected by underlying disease, many of the prognostic factors measured in the ICU have a direct impact on the prognosis.

Consideration of quality of life after surviving these illnesses is important, since families often make decisions based mainly upon issues surrounding quality of life. This is most obvious if one considers a patient in a coma in whom the prognosis of eventual neurological recovery impacts decision making much more than the likelihood of the patient surviving into the immediate future.

Respiratory Failure Acute respiratory failure (ARF) has been one of the most widely studied critical conditions. Studies have focused on three disorders: COPD, status asthmaticus, and ARDS.

Chronic Obstructive Pulmonary Disease Acute hypercapnic respiratory failure in COPD is usually defined as the presence of an arterial CO2 tension (Paco2 ) that exceeds 50 mmHg, or an increase of 10 mmHg or more from baseline. Recently, a reduction in the hospital mortality of this condition has been improved through use of noninvasive positive pressure ventilation (NPPV). In controlled trials of NPPV (as reviewed by the Cochrane Airways group), the overall hospital mortality in the treatment group was half of that in the usual care group (11 versus 22 percent). However, little evidence exists for an improved prognosis in the era of of NPPV for patients who are intubated. This has been confirmed by recent studies showing that patients who require critical care have hospital mortalities of 20 to 25 percent.

Nevertheless, the long-term prognosis of patients with COPD who are hospitalized remains quite guarded. A prospective study of 17,440 patients admitted to the ICU for acute respiratory failure from COPD demonstrated a 1-year mortality of 59 percent. Long-term mortality was similar for patients who received mechanical ventilation as for those who did not. Indeed, this observation recently has been reinforced by a study addressing the long-term outcomes of patients who received NPPV for COPD-related acute respiratory failure in which the 1-year mortality was 49 percent.

These studies point out that long-term survival in COPD is a function of the underlying severity of the patient’s

disease, rather than the severity of the exacerbation. Indeed, a recently published metric that incorporates measures of body mass index, airflow obstruction, dyspnea, and exercise capacity (as determined using the 6-minute walk test)—the so-called “BODE index”—is an accurate predictor of longterm mortality. This, or other validated prognostic metrics, may prove useful in determining prognosis in the ICU. Based on these observations, a reasonable conclusion is that patients with COPD admitted to the ICU for acute respiratory failure have a hospital survival rate that exceeds 70 percent. Hospital survival for these patients is influenced by the overall severity of illness, rather than degree of respiratory failure, whether acute or chronic. However, survival at 2 years is less than 50 percent and is influenced by severity of the lung disease.

Status Asthmaticus Previously reported hospital mortality rates for patients with status asthmaticus requiring mechanical ventilation ranged from 10 to 38 percent. Subsequent studies report fatality rates of 3 to 8 percent. Possible explanations for the improved outcome are the conservative use of mechanical ventilation to avoid barotrauma and the aggressive use of bronchodilators.

Women have a higher risk than men of fatal asthma.

Patients with near-fatal asthma, when followed prospectively, have an alarming mortality. The mortality rate of near-fatal asthma is 10 percent at 1 year of follow-up, 14 percent at 3 years, and up to 25 perecent at 6 years. Anoxia and prehospital asphyxiation are typical presentations. The statistics emphasize that the critically ill patient with asthma may require special follow-up after discharge in order to prevent recurrence of near-fatal asthma.

Acute Rsepiratory Distress Syndrome ARDS is a common cause of hypoxic respiratory failure that frequently accompanies such conditions as sepsis, shock, and transfusion of blood products (see Chapter 145). Mortality in ARDS is often analyzed by dividing deaths into early (less than 72 hours after ARDS onset) and late groups. Early deaths are thought to be related to the presenting illness or injury, while late deaths are presumably due to complications arising after onset of ARDS. Prognosis and mortality late in the illness appear more dependent on the presence of infection and failure of other organs, particularly the liver, kidney, and central nervous system.

In recent years, survival has improved for patients with ARDS. Two NIH-sponsored trials of controlled ventilation in ARDS have demonstrated that, in specialized centers, hospital mortality ranges from 25 to 31 percent. Reasons for the improvement are unclear, but a study at one referral center showed that the improved mortality appears limited to certain underlying diagnoses. In particular, investigators have found that the case-fatality for sepsis-related ARDS has remained at about 55 percent since 1981, while that related to trauma and other risk factors has dropped from approximately 65 to 25 percent.

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Multiple organ failure is a strong prognostic factor in the outcome of ARDS. Mortality approaches 80 percent with failure of two or more organs (brain, liver, lung, heart, kidney) and reaches 90 percent with failure of three or more. In a report examining prognostic factors among patients with ARDS, the initial ratio of Pao2 to inspired oxygen fraction (Pao2 /Fio2 ) had only a modest influence on mortality. More important were the presence of multiorgan failure, primary ICU diagnosis, and treatment location before ICU admission.

Hence, although the magnitude of initial hypoxemia reflects the severity of ARDS, outcome is determined by the interplay of mutliple organ systems.

For patients with ARDS, considerable information exists regarding quality of life in survivors. In many, quality of life, as measured by the SF-36 and other tools, appears to be reduced for up to 2 years. At 2 years, almost a quarter of survivors report moderate to severe depression, and a similar fraction report moderate to severe anxiety; almost half (47 percent) demonstrate neurocognitive impairment.

Recent studies have demonstrated that an important factor affecting quality of life after ARDS is decreased pulmonary function. Pulmonary function testing reveals diminished function in a large number of survivors. As many as 80 percent of patients have decreased diffusion, although impairment is mild in the majority. In addition, 20 to 50 percent have a restrictive pattern, while 20 percent also have an obstructive component. Notably, one study found that over 30 percent of ARDS survivors were less than fully ambulatory at 1 year.

Persistent symptoms one year after recovery correlate with the duration of mechanical ventilation, the lowest recorded lung compliance, and the requirement of an Fio2 greater than 0.6 for more than 24 hours. No link between choice of ventilatory strategy and long-term outcome has as yet been demonstrated.

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decades. Average mortality from sepsis was 27.8 percent from 1979 though 1984 and 17.9 percent from 1995 through 2000.

Despite the decrease, overall sepsis-related mortality in the population has increased because of an increased incidence of sepsis in elderly persons. Studies have highlighted the importance of organ failure in predicting mortality; patients with three or more failing organs have a mortality rate of approximately 70 percent.

Nontraumatic Coma The prognosis of patients with nontraumatic coma has been the subject of several prospective studies. In such patients, neurologic observations must be made in the absence of central nervous system (CNS) depressant drugs or status epilepticus. Patients without brain stem function (e.g., as indicated by the absence of corneal reflexes) within the first 12 hours, or without pupillary reflexes within the first 72 hours after the onset of coma, have little chance of meaningful neurological recovery. Although nontraumatic coma is frequently encountered in patients in whom cerebral hypoxia has resulted from cardiopulmonary resuscitation, the prognosis of nontraumatic coma is independent of etiology.

Prognostic information exists not only for neurological recovery, but also for mortality. When patients are assessed on day 3 of coma, five independent risk factors for death at 2 months can be identified: (a) age greater than or equal to 70 years; (b) abnormal brain stem response; (c) absent verbal response; (d) absent withdrawal to pain; and (e) level of creatinine in blood greater than or equal to 1.5 mg/dl. When none of these factors are present, mortality is 20 percent; with one factor, 33 percent; with two factors, 60 percent; with three factors, 94 percent; with four factors, 96 percent; and with all five factors, 100 percent. For patients with three or more risk factors, aggressive care beyond 3 days does not improve outcome and comes at a very high economic cost.

Sepsis and the Systemic Inflammatory Response Syndrome

Malignancy

Based on a consensus conference held jointly in 1992 by the American College of Chest Physicians and the Society of Critical Care Medicine, sepsis is defined as a combination of the systemic inflammatory response syndrome (SIRS) and confirmed or suspected infection. SIRS is defined clinically as the presence of two or more of the following: (a) body temperature greater than 38â&#x2014;Ś C or less than 36â&#x2014;Ś C; (b) heart rate greater than 90 beats/min; (c) respiratory rate greater than 20 breaths/min or Paco2 less than 32 mmHg; (d) WBC greater than 12,000 cells/mm3 or less than 4000 cells/mm3 or greater than10 percent immature (band) forms. Severe sepsis is defined as sepsis that occurs in association with organ failure.

When hypotension is present also, the patient is said to have septic shock.

The epidemiology of sepsis has been elucidated in recent years using ICD-9 codes to evaluate the disorderâ&#x20AC;&#x2122;s national impact and outcome. Studies have pointed to a reduction in hospital mortality from sepsis over the last two

Continuous improvements in oncologic treatment make mortality predictions for care in the ICU difficult. For example, studies published prior to 2000 cited a 50 percent in-hospital mortality for cancer patients entering the ICU for nonoperative care; if mechanical ventilation was required, mortality exceeded 70 percent. However, in a study published in 2005, patients with cancer who underwent mechanical ventilation had a mortality rate of 50 percent. Predictors of a poor outcome included older age, poor performance status, recurrent or progressive cancer, or presence of organ failure.

Similar improved outcomes appear to be the case for bone marrow transplant (BMT) recipients. Previous studies showed a very poor prognosis, with in-hospital mortality exceeding 70 percent; patients who required ventilatory support had an in-hospital mortality in excess of 95 percent. However, recent reports of patients who have undergone stem cell BMT have been more optimistic: when admitted to the ICU for any cause, patients had a 50 percent in-hospital mortality.

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Cardiopulmonary Resuscitation The outcome of cardiopulmonary resuscitation (CPR) is influenced by the setting in which it is performed (in hospital versus out of hospital), age of the patient, and underlying diseases. When discussing goals for patient care in the ICU, physicians may attempt to offer a prognosis on outcome if the patient should experience a cardiopulmonary arrest. Recent data from the Cleveland Clinic demonstrated a 23 percent survival to hospital discharge in patients experiencing cardiopulmonary arrestâ&#x20AC;&#x201D;a rate that compares favorably to pooled analyses of worldwide data, in which survival rate to hospital discharge was 15 percent. Long-term outcome of discharged patients appears favorable, with nearly three-quarters surviving for 1 year.

Finally, cardiopulmonary arrests due to ventricular tachycardia or ventricular fibrillation are associated with better survival rates than those caused by asystole or pulseless electrical activity. Similarly, witnessed arrest, arrest in an ICU, respiratory arrest, short duration of CPR, and absence of comorbidities are associated with better chances of survival.

Age Controversy exists over whether age is an independent predictor of mortality in critically ill patients. Approximately half of all patients in the United States admitted to the ICU are over 65 years of age. The percentages are much lower in other western countries. Past reports suggested a correlation between increasing age and hospital mortality. However, more recent investigations using prognostic scoring systems have found that age is a weak variable in portending the likelihood of death. More predictive power rests with such factors as underlying disease, previous functional status, and number of failing organs. Nonetheless, older age is associated with a greater likelihood of disease and poor functional status; no large studies have compared patients in different age groups who have similar severity of disease.

Two other elements that have been examined in relation to patient age and critical care include utilization of ICU resources and the cost and quality of life. About 10 percent of critically ill patients consume about 50 percent of ICU costs.

Although one might envision that the elderly compose a large fraction of these high-resource patients, this is not the case.

Functional assessment of quality of life in the elderly following critical care has yielded mixed results. Some studies find no differences in functional outcome between elderly and young patients; others suggest that the elderly are more impaired after critical care. The studies have not been stratified for severity of illness, making comparisons between the two age groups difficult.

Two studies have shown improvement in prognosis for patients with AIDS treated in the ICU in the era of HAART compared with prior times, with survival rates increasing from 50 to 60 percent to 70 to 75 percent. The improvement is related to a change in the general epidemiology of critical care for affected patients; in particular, fewer admissions to the ICU during the HAART era are for respiratory failure.

HIV-infected patients entering the ICU are more likely to be black, less likely to be homosexual, and more likely to be users of injection drugs.

SEVERITY OF ILLNESS SCORING SYSTEMS AND MORTALITY PREDICTION The complexity of critically ill patients has exposed the limitations of historical methods of prognostication, such as case studies and clinical judgment. From the time of Socrates, physicians have accurately predicted outcome in patients at the extreme ends of the spectrum of disease severity. For example, even inexperienced clinicians can predict the high likelihood of death in a patient with multiple organ failure and shock. Similarly, clinicians can correctly judge that patients admitted to the ICU only for monitoring of an arrhythmia have an excellent prognosis.

The challenge in formulating a prognosis is that most patients entering the ICU fall somewhere between the two ends of the spectrum, and the outcome of most patients cannot be accurately assessed by simple application of clinical judgment. A patient presenting with sepsis and hypotension might have a predicted mortality ranging from 15 to 40 percent, depending on underlying diseases, source of the infection, and other organ system dysfunction.

A number of compelling reasons exist for defining the severity of disease and prognosis in all patients in the ICU. Furthermore, assessment of quality of ICU care is difficult without a means to compare severity of disease among different ICUs. In an era of public accountability, critical care physicians must ensure that patients are provided the best possible care. Objectively measuring the severity and prognosis of the disease enables a rational description of patients in the ICU and lays the foundation for quality assessment.

In addition, utilization of severity scoring systems provides a stable platform for research in critical care therapeutics and economics. An objective scoring system stratifies patients by disease severity, thereby permitting measurement of therapeutic effects and economic consequences. Finally, scoring systems of severity may be useful in clinical decision making, especially in mapping the trajectory of the patientâ&#x20AC;&#x2122;s critical illness.

Acquired Immunodeficiency Syndrome The natural history of HIV infection changed dramatically after the introduction of highly active antiretroviral therapy (HAART). The change has also affected the prognosis of HIVinfected patients in the ICU.

Methods Employed in Developing Severity-Scoring Systems Severity-scoring systems utilized in critical care settings assign numeric values to various degrees of illness. The scores

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are then applied in a mathematical formula to calculate predicted mortality. To a great extent, the ultimate importance of the severity score is its power to predict mortality. Two characteristics are essential in judging predictive instruments: discrimination and calibration.

Discrimination is the ability of a predictive model or scoring system to discriminate between patients who ultimately die and those who ultimately live. Typically, predictive models are based upon sensitivies and specificities for various levels of probability of death. A graphed compilation of sensitivities and specificities across different probability cutoffs results in generation of a receiver operating characteristic (ROC) curve, the area under which is a measure of the discriminative ability of the model. In effect, the curve provides a measure of how well the scoring system works over a range of predictions, but it does not assess how well the model works at any specific probability.

Calibration describes how well the prediction model performs at each specific probability cutoff. For example, a group of patients may have a predicted probability of death of 0.1. Data analysis would include determination of whether 10 percent of this group actually died. Similar analyses could be performed for other probabilities (e.g., 0.2, 0.3, etc.). For all groups, a determination can then be made with regard to how well the resultant curve predicts actual mortality. Overall assessment of the relationship of observed to predicted mortality is a measure of calibration. As noted previously, although the time-honored method of outcome prediction using clinical judgment tends to be highly discriminatory at extremes of probability, the method tends to be poorly calibrated.

Characteristics of discrimination and calibration are depicted in Fig. 156-1. A predictive instrument with perfect calibration and discrimination has predicted mortalities identical to observed mortalities over the complete range of mortality prediction. This corresponds to the line of identity seen on the graph. A poorly calibrated instrument has wide variability around the line of identity and a well calibrated instrument less variability. Therefore, the ideal prediction instrument has minimal variability and comes as close as possible to the line of identity.

Several steps are used in developing ICU severityscoring systems. The first is to assess a representative patient population from a variety of ICUs. The key clinical characteristics of the patients are then analyzed statistically using methods of multivariate analysis and logistic regression. Variables with the most discriminatory power for predicting mortality are then tested and validated in another patient population.

Based on this process, severity-scoring system and mortality prediction algorithms are derived.

A number of important features characterize currently available instruments for assessing outcome: (a) They measure an outcome of clinical significance. Most critical careâ&#x20AC;&#x201C; based severity-scoring systems have focused on in-hospital mortality but interest is increasing in tools to assess postdischarge mortality and functional status. (b) The instruments are easy to use. Data collection on critically ill patients

Decision Making in the Intensive Care Unit

Figure 156-1 Calibration curves for two hypothetical scoring instruments. Perfect calibration is described by the line of identity.

Instrument (A) has a wide variation around the identity line. Instrument (B ) has less variability and therefore is better calibrated across the range of death rates. (Data from Cowen J, Kelley M: Predicting intensive care unit outcome: Errors and bias in using predictive scoring systems. Crit Care Clin 1053-1072, 1994.)

can be time consuming and costly. Therefore, outcome instruments focus on data that are simple to record and reproduce. (c) The instruments have limitations in their application. Notably, they do not accurately predict outcome for populations that are not included in their sets of derivation data. For example, ICU severity-scoring systems are not applicable to all hospitalized patients. Understanding these limitations is important in preventing misuse of the instruments.

Acute Physiology, Age, and Chronic Health Evaluation Scoring System The Acute Physiology, Age, and Chronic Health Evaluation (APACHE) scoring system has two versions (II and III) that are widely used in the United States. APACHE II was derived from studies in 13 hospitals, based on approximately 6000 patients. The instrument assigns points for age, underlying disease, and several other elements of chronic health status; it adds points for physiological variables measured in the first 24 h of ICU admission. The total severity score is entered into a logistic regression equation, which provides a predicted mortality.

APACHE II has excellent calibration and discrimination, but it has several flaws. The first is that the instrument is not as accurate when applied to patients in the ICU who are transferred from other inpatient facilities. The mortality of these patients is generally underestimated by APACHE II as a result of an effect known as â&#x20AC;&#x153;lead time bias.â&#x20AC;? A similar phenomenon has been recognized to affect prediction using the updated version of APACHE, i.e. the APACHE III. The

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second flaw is that the derivation database is not powerful enough to allow stratification of patients by certain disease categories, such as liver failure, respiratory failure, etc. Therefore, APACHE II cannot accurately predict outcome for any specific patient subgroup. Nevertheless, some have suggested that it can be used to decide whether to use certain medical therapies in patients with severe sepsis.

The updated version of APACHE II, called APACHE III, addresses these problems. APACHE III was derived from 40 representative hospitals and more than 17,000 patients.

This instrument includes many of the variables in APACHE II but adds the location of prior treatment and the disease that required admission to the ICU. APACHE III also updates prognosis daily, based on newly measured physiological variables.

The APACHE instruments have been published widely and studied internationally. Their discrimination and calibration have been well validated; flaws in older versions have been corrected. However, the APACHE scores require a great deal of data collection and an investment in expensive proprietary computer technology. In addition, whether specific disease subgroups can be assessed, even using the expanded APACHE III database, remains unclear.

Development of reliable severity scoring systems in critical care has opened the field to a wide range of opportunities in health care management and research. Severity-scoring systems can be considered with regard to their potential uses in resource allocation, quality management, and clinical decision making.

Simplified Acute Physiological Score

Allocation of Resources

The simplified acute physiological score (SAPS) was developed as an alternative tool to the data-intensive APACHE instrument. SAPS provides a summary score after 24 h of ICU admission. It concentrates on physiological variables, as well as such elements as type of admission and underlying diseases.

SAPS II uses 17 variables: 12 physiological variables, age, type of admission, and three underlying disease variables (AIDS, metastatic cancer, hematologic malignancy). The scoring system was derived from 8500 patients and validated on a sample of 4500 patients. The model provides a score that is entered into a mathematical formula the solution of which provides a prediction of in-hospital mortality. SAPS II does not require a principal ICU diagnosis, which is mandated with APACHE III. Based on published data, SAPS II has excellent discrimination and calibration.

Allocation of ICU resources is grounded in the fundamental principle of fairness, which itself has several potential interpretations. The first is the concept of equality, which implies that all patients are entitled to the same access and level of ICU care. The second principle is the principle of equity, according to which a patientâ&#x20AC;&#x2122;s level of care does not jeopardize that of others. A third concept, utilitarianism, places the overall benefit to society above that of the individual. The final application of fairness is distribution according to medical need, regardless of social issues (see Chapter 157).

In the United States, medical need has traditionally dictated allocation of critical care resources. Recently, outcomes and outcome prediction in critical care have raised the issue of medical suitability. This concept dictates that outcome of care, as well as medical need, should be used to assess application of ICU resources. The critical care community has summarized these issues in a consensus statement on the triage of critically ill patients. The guiding principles in this statement are patient advocacy, equitable distribution of care, and provision of care on the basis of expected benefit.

Outcome instruments have been useful in management of hospital resources. Severity scores have been used to identify patients who no longer need intensive nursing and who can be placed in lower-cost settings. Physician and nursing staffs can be queried with respect to the patientâ&#x20AC;&#x2122;s need for the ICU and appropriate adjustments made. These analyses may extend beyond the hospital walls to include a regional approach to critical care. Like trauma patients, critically ill patients may be triaged by severity of illness, so that the most complex cases are treated in larger ICUs.

Mortality Prediction Model Like SAPS, the mortality prediction model (MPM) was developed to simplify the scoring of severity in critically ill patients.

MPM was originally developed in one hospital, but its second version (MPM II) had a derivation database of 12,610 patients from many hospitals. MPM requires that patients be placed in categories that correspond to certain scores. The categories are based on several physiological assessments, chronic diagnoses, acute diagnoses, and other characteristics, such as type of admission, age, and use of CPR or mechanical ventilation. The total score is derived from 15 easily obtainable variables.

The MPM score is determined immediately upon ICU admission (MPM 0) but can be updated after 24 h (MPM 24).

The update contains five of the admission variables and eight additional variables, such as arterial blood gases, creatinine, prothrombin time, urine output, etc. Like SAPS II, MPM II has excellent calibration and discrimination. Since MPM 0 utilizes measurements that are made immediately upon ICU admission, the measurement time may define a patient population that is different from that assessed 24 h after treatment and after the evolution of other diagnoses. Only the MPM 24 can be compared to SAPS and APACHE, since all three instruments use measurements performed within the first 24 h of admission.

USE OF SEVERITY SCORES IN THE INTENSIVE CARE UNIT

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Quality Management Because of the rising costs of health care, patients and insurers have sought methods to compare the value of choosing certain providers. This “health care value” has been defined conceptually as quality divided by cost. While the economic side of this equation is straightforward to measure, quantifying the quality of care is more elusive.

In critical care, severity-scoring instruments have been useful in assessing quality of ICU care. Some uncontrolled studies using predictive scoring instruments suggest that patient outcome is better in ICUs staffed by trained intensivists.

Interhospital comparisons of hospital mortality have been widely published, since several states have mandated outcome measurements in all hospitals.

Institutional comparisons using predictive instruments may be misleading. Two studies using APACHE II demonstrated that previous site of treatment can influence the accuracy of APACHE II. In the first report, APACHE II underestimated mortality in an ICU that accepted transfers from other institutions. In the second, APACHE II underestimated mortality for patients previously treated in the hospital but overestimated mortality for patients admitted from the emergency room. As previously described, this phenomenon, called “lead-time bias,” has been adjusted in APACHE III. Nevertheless, investigators have shown that patients accepted in transfer have a worse prognosis than expected based upon their APACHE III score. These examples demonstrate that even well-designed instruments, such as APACHE II and III, can have unanticipated problems, making institutional comparisons challenging.

Controversies abound concerning the accuracy and relevance of measuring quality of care. The critical care arena offers several advantages over the general health care setting in assessing quality of care: (a) The patient population in ICUs is well defined, and the provision of care is well circumscribed; (b) substantial evidence exists that the degree of illness in the ICU is the major determinant of patients’ hospital mortality; (c) the predictive instruments described have considerable power to risk-adjust ICU populations and to permit evaluation of ICU effectiveness and efficiency. Therefore, severityscoring systems provide a foundation for assessing quality of critical care.

Clinical Decision Making Severity-scoring systems can be helpful in predicting outcome across the entire range of prognosis. However, in assessing an individual patient in the ICU, only the extremes of probability are of practical importance. For purpose of triage, patients who are clearly terminal, or who do not require intensive care, should be identified. For such assessment, clinical judgment, often based on historical case series, is as accurate as any outcome instrument. Patients in between the extremes of prognosis are usually eligible for critical care.

A concept of continuous prognostication has been introduced into the APACHE III instrument. Using this technology, disease severity and prognosis can be updated con-

Decision Making in the Intensive Care Unit

tinuously to plot the trajectory of the patient’s illness. The updated severity score may have more predictive power than that obtained in the first 24 h of ICU admission. The implication is that continuous monitoring of disease severity may assist in critical decisions, such as limiting or withdrawing therapy. This idea has evolved into the concept of “potentially ineffective care” that categorizes patients with a poor prognosis who consume an inordinate amount of resources.

The challenge is that there may be a substantial disparity between how health care workers use prognostic information and how patients and their families use this information. In Canada, a survey demonstrated that health care workers could not even agree among themselves on criteria for withdrawing life support. Two studies have documented that do-not-resuscitate orders are increasingly common in ICUs. However, one of these reports indicated that patients and their families did not always participate in this process.

Given these considerations, one might ask whether having reliable prognostic information actually influences physician behavior. The question was answered by The Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment (SUPPORT).

SUPPORT consisted of an observational period that, in addition to measuring prognosis, demonstrated significant differences in the outcome expectations of health care workers, patients, and families. The intervention component of the study attempted to bridge the communication gap by sharing updated prognoses and establishing better methods of communication among the health care providers, patients, and families. Surprisingly, the study showed that this intervention had no measurable effect on clinical decision making. The ICU teams continued to emphasize the technological quest for cure, rather than concentrating on the patients’ desires to avoid suffering and prolonged, painful dying. The investigators concluded that, at least in the five tertiary academic centers that were part of the study, critical care providers appear to be insensitive to the needs and expectations of patients.

SUPPORT pointed out that simply providing prognostic information will not, by itself, change decision making in the ICU. The reasons for this are likely multiple, but all revolve around the need for better communication among physicians, patients, and their families. Studies have shown that even when physicians are confident about prognosis, they share their assessment with the patient only 37 percent of the time, perhaps, stemming from a belief that physicians must not extinguish patient hope.

However, methods exist for providing honest prognosis while allowing patients to continue to hope for the best outcome. In fact, SUPPORT suggests that patients may have more limited and realistic expectations of high technology than do critical care physicians. Further training on how to best to negotiate issues of trust, uncertainty, and affect in dealing with end-of-life are of benefit to all health care professionals. With such training, physicians will be able to use prognostic information from severity-scoring systems to facilitate

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doctor-patient communication and support rationale decision making about the level of care.

SUGGESTED READING Afessa B, Morales I, Cury J: Clinical course and outcome of patients admitted to an ICU for status asthmaticus. Chest 120:1616, 2001.

Ai-Ping C, Lee KH, Lim TK: In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: A retrospective study. Chest 128:518–524, 2005.

Angus DC, Linde-Zwirble WT, Lidicker J, et al: Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310, 2001.

Asch D, Hansen-Flaschen J, Lanken PN: Decisions to limit or continue life-sustaining treatment by critical care physicians in the United States: Conflicts between physicians’ practices ad patients’ wishes. Am J Respir Crit Care Med 151:288–292, 1995.

Braman S, Kaemmerlen J: Intensive care of status asthmaticus: A 10-year experience. JAMA 264:366, 1990.

Castella X, Artigas A, Bion J, et al: The European/North American Severity Study Group: A comparison of severity of illness scoring systems for intensive care unit patients: Results of a multicenter, multinational study. Crit Care Med 23:1327–1335, 1995.

Chelluri L, Grenvik A, Silverman M: Intensive care for critically ill elderly: Mortality, costs, and quality of life. Arch Intern Med 155:1013–1022, 1995.

Cooper A, Ferguson N, Hanly P, et al: Long-term followup of survivors of acute lung injury: Lack of effect of a ventilation strategy to prevent barotrauma. Crit Care Med 27:2616, 1999.

Cowen J, Kelley M: Predicting intensive care unit outcome: Errors and bias in using predictive scoring systems. Crit Care Clin 10:53–72, 1994.

Dumot JA, Burval DJ, Sprung J, et al: Outcome of adult cardiopulmonary resuscitations at a tertiary referral center including results of “limited” resuscitations. Arch Intern Med161:1751–1758, 2001.

Edgren E, Hedstrand U, Kelsey S, et al: Assessment of neurologic prognosis in comatose survivors of cardiac arrest.

Lancet 343:1055, 1994.

Escarce J, Kelley M: Admission source to the medical intensive care unit predicts hospital death independent of APACHE II score. JAMA 264:2389–2394v, 1990.

Hamel MB, Phillips R, Teno J, et al: Cost effectiveness of aggressive care for patients with nontraumatic coma. Crit Care Med30:1191–1196, 2002.

Hopkins RO, Weaver LK, Orme JF Jr, et al: Two-year cognitive, emotional, and quality-of-life outcomes in acute respiratory distress syndrome. Am J Respir Crit Care Med 172:786–787, 2005.

Knaus W, Wagner D, Draper E, et al: The APACHE III prognostic system: Risk prediction of hospital mortality for critically ill hospitalized adults. Chest 100:1619–1636, 1991.

Le Gall J-R, Lemeshow S, Saulnier F: A new simplified acute physiology score (SAPS II) based on a European/North American multicenter study. JAMA 270:2957–2963, 1993.

Lemeshow S, Teres D, Klar J, et al: Mortality probability models (MPM II) based on an international cohort of intensive care unit patients. JAMA 270:2478–2486, 1993.

Martin GS, Mannino DM, Eaton S, et al: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 348:1546–1554, 2003.

Milberg J, Davis D, Steinberg K, et al: Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 273:306, 1995.

Morris A, Creasman J, Turner J, et al: Intensive care of human immunodeficiency virus-infected patients during the era of highly active antiretroviral therapy. Am J Respir Crit Care Med 166:262–267, 2002.

Portier F, Defouilloy C, Muir J, et al: Determinants of immediate survival among chronic respiratory insufficiency patients admitted to an intensive care unit for acute respiratory failure. A multicenter study. The French Task Group for Acute Respiratory Failure in Chronic Respiratory Insufficiency. Chest 101:204, 1992.

Soares M, Salluh JI, Spector N, et al: Characteristics and outcomes of cancer patients requiring mechanical ventilatory support for >24 hrs. Crit Care Med 33:520–526, 2005.

Stapleton RD, Wang BM, Hudson LD, et al: Causes and timing of death in patients with ARDS. Chest 128:525–532, 2005.

Tulsky JA: Beyond advance directives. Importance of communication skills at the end of life. JAMA 294:359–365, 2005.

Westerman D, Benatar S, Potgieter P, et al: Identification of the high-risk asthmatic patient: Experience with 39 patients undergoing ventilation for status asthmaticus. Am J Med 66:565, 1979.

157 Ethics in the Intensive Care Unit Paul N. Lanken

I. FUNDAMENTAL PRINCIPLES OF BIOETHICS Overview Beneficence and Nonmaleficence Respect for Patient Autonomy Distributive Justice Egalitarian Theory Utilitarian Theory Libertarian Theory Deontological Theories II. RELATIONSHIP BETWEEN HEALTH CARE LAW AND ETHICS III. PRINCIPLES REGARDING END-OF-LIFE ISSUES IN THE INTENSIVE CARE UNIT Principle 1 Principle 2 Principle 3 Legal Standards for Surrogate Decision Makers Principle 4 Principle 5 Principle 6 IV. ETHICS RELATED TO FUTILE MEDICAL INTERVENTIONS Principle 7

Patient care in a modern intensive care unit (ICU) presents a striking contrast. On the one hand, by definition, the ICU is the health care setting in which depersonalized, “high-tech” medicine is practiced and in which the “technological imperative” is often played out. On the other hand, the ICU also is a health care delivery site in which the deeply humanistic concerns of bioethics are evident on a day-to-day basis. Ethics, in simple terms, is the discipline that concerns itself with defining the right action for the right reasons. Bioethics generically refers to the ethics encompassing health care and health care professionals as well as basic biological and physical scientific research relevant to human health and disease.

V. ETHICAL PRINCIPLES RELATED TO MICROALLOCATION OF ICU RESOURCES Principle 8 Principle 9 Principle 10 Principle 11 VI. SPECIFIC ETHICAL QUESTIONS AND CONSIDERATIONS IN THE ICU VII. ‘‘DO NOT ATTEMPT RESUSCITATION’’ (DNAR) ORDERS IN THE INTENSIVE CARE UNIT DNAR Orders and Terminology When to Discuss Withholding or Withdrawing Life-Sustaining Therapy Assessment of a Patient’s Decision-Making Capacity Identification and Role of Surrogate Decision Makers Deciding on the DNAR Order Carrying Out the DNAR Order VIII. PROVIDING PALLIATIVE CARE TO ICU PATIENTS Resolution of Conflicts IX. CONCLUSION

Many ethical dilemmas in the ICU share common themes. For example, advanced technology and a high level of professional intervention in the ICU can keep patients alive for prolonged periods. However, this same capacity for delivering life-sustaining care often fails to achieve what patients really want and what also has been the traditional goal of critical care medicine: restoring patients to sufficiently good health to permit them to leave the ICU with a good quality of life. Ethical dilemmas that characterize critical care medicine often arise from this interface between the ability to prolong life by expensive and sometimes scarce technology and an inability to cure patients or even restore them to their

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baseline. The relevant ethical question often is whether this technology is being used wisely, i.e., whether the patient’s life should be prolonged. The question becomes even more complex for practitioners and patients’ families when different ethical principles suggest conflicting answers.

Although the practice of critical care medicine encompasses a broad range of bioethical issues, several are particularly common, including end-of-life decision making, medical futility, resource allocation, and “do not attempt resuscitation” (DNAR) orders. These issues are some of the most challenging for ICU practitioners and constitute the focus of this chapter.

FUNDAMENTAL PRINCIPLES OF BIOETHICS Overview These fundamental principles of bioethics are particularly relevant in the ICU: (a) beneficence and nonmaleficence; (b) respect for patient autonomy; and (c) justice. Ethical dilemmas in the ICU arise when two or more of these principles are in conflict (Fig. 157-1) and when health care providers must violate one or more ethical principles to resolve the conflict.

Determining which principle is the overriding one is the goal of ethical analysis applied to such conflicts.

Each of these principles also relates to certain moral entities (Fig. 157-1). The principle of beneficence primarily involves physicians, nurses, other health care providers, and health care institutions, all of which are moral agents, i.e.,

entities with inherent values and moral responsibilities that arise from their established roles and positions in society. Respect for patient autonomy relates to patients, their families, and surrogate decision makers or proxies—i.e., individuals who speak on behalf of those patients who lack the capacity to make medical care decisions.

Justice refers to fairness in the distribution of limited resources, i.e., distributive justice. This principle is usually discussed in terms of two levels of applicability. First, on the level of macroallocation of resources, distributive justice entails governmental and institutional decisions on the relative importance of funding health care among a number of social goods and services, e.g., education and defense. Macroallocation also refers to the distribution of health care resources among various regions and communities, e.g., funding for Medicare, Medicaid, and the Veterans Administration health care system. Second, on the level of microallocation of resources, distributive justice refers to decision making about an individual patient or resource allocation within an individual ICU, hospital, or local health care system.

Beneficence and Nonmaleficence The principle of beneficence refers to the traditional aim of medicine and nursing to provide services that benefit the patient. Beneficence may be broadly interpreted to include the principle of nonmaleficence, i.e., doing no harm to the patient. The Hippocratic maxim primum non nocere, which can be translated as “First of all do no harm,” reflects the fundamental importance of this principle for physicians. These two principles—beneficence and

Figure 157-1 Basic ethical principles and related moral agents commonly involved in intensive care unit ethical dilemmas: respect for patient autonomy, beneficence (which includes the principle of nonmaleficence), and justice.

Opposing arrows represent potential conflicts between principles.

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nonmaleficence—commonly conflict when the patient suffers pain as a consequence of receiving beneficial care, e.g., the discomfort of suctioning while intubated. The bioethical conflict is resolved when it reasonably can be concluded that the discomfort of suctioning is more than balanced by its beneficial effects and that the actions are in accord with the patient’s preferences.

In the Hippocratic tradition of beneficence and nonmaleficence, physicians had not only the responsibility, but also the authority to determine what was best for their patients. This has evolved to the more contemporary notion, especially prominent in the United States, that the patient, rather than the physician, determines what is best for the patient. The U.S. physician’s role has evolved from the traditional authoritarian or paternalistic model to that of someone whose role is to share decision-making responsibility with the patient through educating and making recommendations. In this interpretation, the principles of beneficence and nonmaleficence are congruent with the principle of respect for patient autonomy.

Respect for Patient Autonomy The principle of respect for patient autonomy is embodied by the legal concept of self-determination: A competent adult has a right to determine what will be done to his or her body. This principle also relates closely to the legal principle of an individual’s right to privacy. According to these principles, the patient has the right to decide whether or not to undergo interventions that are available and medically appropriate. It is important to recognize that autonomy is a right to choose, not a right to demand and receive any desired treatment. The principle of respect for autonomy is also the basis for informed consent. Except in emergency circumstances, a competent adult must give informed consent prior to receiving medical care, especially that which involves potentially hazardous interventions. Under emergency conditions, i.e., when the patient’s life, limb, or other vital functions are at risk without the intervention, consent is presumed. In the United States, there is a widespread societal and professional consensus that health care providers should not only respect a patient’s autonomy but also enhance it through shared medical decision making.

Outside of the United States, ICU physicians are much more likely to follow the paternalistic tradition of decision making, i.e., make decisions, including decisions to withhold or withdraw life support, on behalf of their patients.

Distributive Justice In the ICU setting, the principle of justice refers to the principle of distributive justice. As alluded to previously, this principle pertains to defining fairness in allocating resources among individuals when not all can receive the resources. Aristotle stated the concept of distributive justice as the “principle of formal justice,” according to which equals should be treated equally and unequals unequally. Although it appears rather straightforward, this formulation cannot be applied easily,

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because specific criteria need to be identified and agreed upon when judging if two individuals are equal or unequal. When applied to distributive justice, various ethical theories define different values as the most relevant criterion for making such judgments, as described below.

Egalitarian Theory The egalitarian theory of justice holds that all individuals have equal intrinsic worth and therefore distributions should not be made based on perceptions of individuals’ different social worth. One egalitarian strategy for fair allocation of health care resources is that patients having the same medical need should have the same medical resources. An example of this is health care funding in the United States for patients with end-stage renal disease (ESRD), all of whose medical expenses are covered by Medicare. Another egalitarian approach holds that each person should have an equal chance of receiving a scarce resource. Examples include dialysis centers that, prior to Medicare funding, held lotteries to determine who would receive chronic dialysis, and centers that took applicants on a “first come, first served” basis. Although the latter practice resembles a “natural lottery,” it is biased due to unequal access to the health care system by poor (uninsured) and wealthy patients due to financial constraints and timeliness of referrals.

Utilitarian Theory Other theories of ethics are based on different criteria. The utilitarian theory of justice is centered on the principle of utility and contends that a fair decision should maximize utility as its consequence. For example, the maxim “The greatest good for the greatest number” reflects utilitarianism. According to this theory, a country with limited health care resources could justify disproportionate spending on public health interventions benefiting many citizens, rather than on critical care beds that benefit relatively few. In the United States, prior to universal Medicare coverage for chronic dialysis, some centers based treatment access on perceived social worth—a utilitarian schema. Patients were prioritized according to whether they were employed, their type of employment, family status, and other measures of perceived social worth. Not unexpectedly, successful dialysis candidates resembled the white, male, middle-class constituents of the anonymous selection committees (so-called “God Committees” because they made lifeand-death decisions). When this approach was publicized, it was criticized as unfair and discriminatory, and ensuing public outcry was the impetus for universal Medicare funding for patients with ESRD.

Libertarian Theory The libertarian point of view holds that health care resources should be allocated according to one’s own resources and ability to pay for them. Private health insurance in the United States is an example of the libertarian view.

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Deontological Theories Deontological, or duty-based, theories of justice are based on rules that define ethical behavior. One influential deontological theory developed by the philosopher John Rawls relates to social institutions in general. From Rawls’ theory were derived the concepts of provision of fair, decent, minimum health care benefits for all, and fair, equal opportunity. The latter concept supports provision of more than an equal share of resources to those who are disadvantaged in order to promote a basic level of societal functioning. On this basis, health care resources should be allocated according to need of the individual patient in order to preserve or restore a basic level of functioning.

Another deontological principle that affects the distribution of limited resources is the so-called rule of rescue. This principle refers to the duty of society to expend resources to save an identified individual’s life if society has the means to do so. The rule underlies well-publicized rescue efforts for individuals whose lives are in danger. Equally predictable but unidentifiable (i.e., anonymous) statistical deaths are not accorded the same moral obligation. Emphasis on the practice of “rescue-type” medicine in the United States, including the burgeoning of ICUs, has been heavily influenced by the rule of rescue.

RELATIONSHIP BETWEEN HEALTH CARE LAW AND ETHICS Ethical behavior and legal requirements are generally not completely congruous. For example, some argue that the traditional application of the law to health care providers is a type of “minimal morality.” For example, states require that practitioners providing medical or nursing care be licensed. In contrast, the professional ethics of these practitioners represents ideal professional behavior: Care should always be provided in accord with the principle of beneficence. For many clinical issues, the relationship between ethical and legal viewpoints is even more complex.

The legality of what health care professionals do may change, depending on external circumstances. For example, health care law may vary considerably over time between two different jurisdictions. Similarly, what is regarded as ethical or unethical behavior for physicians may change. As an example, consider active euthanasia by physicians. Although controversial, all major U.S. professional medical societies consider the practice of euthanasia as unethical. Furthermore, according to state law, it is illegal in the United States. However, over the past 10 years, euthanasia administered by physicians with certain safeguards has become both legal and professionally accepted in the Netherlands and Belgium.

As these considerations highlight, health care providers should view bioethics not as a fixed body of knowledge, but rather as a continually evolving field similar to clinical medicine.

PRINCIPLES REGARDING END-OF-LIFE CARE IN THE INTENSIVE CARE UNIT During the last three decades a broad societal consensus has developed regarding the ethics of withholding or withdrawing life-sustaining therapies or life support. This consensus was catalyzed, for the most part, by a bioethical foundation developed by the President’s Commission in the early 1980s and a series of precedent-setting judicial decisions, including the 1972 Spence decision in the District of Columbia on informed consent, the 1976 New Jersey Supreme Court decision regarding Karen Ann Quinlan, the 1984 California Supreme Court decision regarding Bartling, and culminating with the 1990 U.S. Supreme Court decision regarding Nancy Cruzan.

Based this consensus, one can derive a number of principles that can guide health care professionals in making decisions related to withholding and withdrawing life-sustaining therapy. These principles are discussed in this and subsequent sections.

Principle 1 Informed adults with adequate decision-making capacity can forgo any life-sustaining medical therapy, even if the action results in their death.

The key words and phrases in Principle 1 are adult, informed, and adequate decision-making capacity. The principle applies only to adults, since children generally lack the personal autonomy required by legal or ethical standards.

An adult must have appropriate information, provided in an understandable manner, in order to arrive at an informed decision. In addition, he or she must have sufficient mental capacity to evaluate the specific decision being considered.

Assessment of adequacy of decision-making capacity is described below.

Principle 2 Forgoing life-sustaining therapy includes not only the withholding of therapy, such as cardiopulmonary resuscitation, but also the withdrawal of interventions, such as mechanical ventilation, artificial nutrition, and hydration. There is no substantive ethical or legal difference between withholding and withdrawing life-sustaining therapy.

Controversy over the moral distinctions between actions and omissions leading to a patient’s death ended when consensus developed that withdrawing care is ethically equivalent to withholding care. Likewise, in general, there are no legal distinctions between withholding and withdrawing.

Nonetheless, patients, families, and health care providers often perceive differences between them and their psychological effects.

The legal issue of whether artificial nutrition and hydration provided by an oral, nasal, or percutaneous feeding tube constitutes medical care was decided when the U.S. Supreme Court deemed it so in its 1990 decision on Nancy Cruzan.

This decision established a constitutionally protected legal

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right to refuse any medical care by competent adults or by appropriate surrogate decision makers acting in accord with the patient’s previously expressed preferences or values.

Principle 3 Surrogate decision makers should decide whether to forgo lifesustaining therapy on behalf of patients who have lost decisionmaking capacity based on knowledge of what the patient would have wanted under similar circumstances. In the absence of such knowledge, decisions should be based on the patient’s best interests.

Surrogate decision makers are commonly one or more members of the patient’s immediate family. However, others may serve in this role under a number of circumstances.

When a patient has legally designated someone as health care proxy by means of a durable power of attorney for health care, the designee must be the surrogate decision maker, even if he or she is not a member of the patient’s family. When the patient has not arranged for a valid durable power of attorney but has otherwise identified someone as health care proxy, either in writing or verbally, his or her choice should be respected. Finally, when the patient has not designated a health care proxy or where state statutes do not specify a formal legal hierarchy that determines the order of selection of a surrogate, the presumption is that a close family member who knows the patient well should be the surrogate decision maker. In these circumstances, the patient’s attending physician, as an advocate for protecting the patient’s interests, has the responsibility for evaluating the appropriateness of a surrogate decision maker.

Legal Standards for Surrogate Decision Makers Surrogate decision makers should use one of these two ethical and legal standards: (a) the substituted judgment standard and (b) the best interests standard.

Under the substituted judgment standard, the surrogate decision maker expresses what the patient would have preferred under the circumstances. The decision maker must have knowledge either about the preferences of the patient, as expressed orally or in writing in an advanced directive, e.g., a living will, or about the patient’s values and life goals, from which valid inferences can be made.

Under the best interests standard, such knowledge is lacking, and the surrogate decision maker along with the caregivers must weigh the benefits of life-sustaining therapy against its burdens. The decision is based on the outcome of the balance. For example, the benefits of life, chance of survival, and chance of full recovery with a high quality of life are weighed against the burdens of pain, additional suffering, and poor eventual quality of life.

Principle 4 When in doubt about a patient’s preferences, health care providers should err on the side of sustaining life.

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Although the essence of Principle 4 is obvious, less obvious is a corollary to the principle: Health care providers who decide to sustain a patient’s life should be willing to stop life-sustaining therapy if it is later determined that the patient would not have wanted it or that it was not in his or her best interests. Consistent with this principle is the concept of a “therapeutic trial of life support.” Despite uncertainty about their effectiveness, life-sustaining therapies may be started in order to determine whether they will benefit the patient. Once therapy is under way, the decision to continue it or not can be made by an objective assessment, rather than a prediction, of its effectiveness.

For example, the question often arises whether a patient with acute respiratory failure complicating severe chronic obstructive pulmonary disease, once intubated and ventilated, can be successfully weaned from mechanical ventilation over a certain period of time that is acceptable to the patient. In many cases, the question can be resolved only by a timelimited therapeutic trial of assisted ventilation. In certain instances, when it can be agreed before the therapeutic trial, the ventilator can be withdrawn and the patient allowed to die if extubation or progress toward extubation is not made after an agreed-upon period. Such a therapeutic trial is preferable to not attempting potentially beneficial therapy because of uncertainty or the patient’s fear that once such therapy is started, the ventilator would be continued indefinitely, even against his or her preferences.

Principle 5 Providing the patient or surrogate decision maker has been informed and consented, it is ethically appropriate to relieve pain and other suffering, such as dyspnea, even if doing so has the potential to hasten the patient’s death Giving medication to relieve pain and suffering that may hasten death as a side effect should not be confused with active euthanasia or assisted suicide. When acting in accord with Principle 5, the health care provider’s intention should be to relieve pain and suffering. This follows from the principle of beneficence. In contrast, the intention when performing active euthanasia or assisted suicide is to cause the patient’s death. Withdrawal of mechanical ventilation to allow patients to die from disease is ethically and legally distinct from active euthanasia or assisted suicide. However, in the past some authors have referred to such withdrawal as passive euthanasia.

Since this term may be confused with active euthanasia, it should be avoided when referring to acts of withholding or withdrawing life support.

Principle 6 It is inappropriate to force physicians or other health care providers to comply with a patient’s request to forgo lifesustaining therapy if compliance violates the health care provider’s personal moral values. Under these circumstances, responsibility for care of the patient should be transferred to another provider who can respect the patient’s request.

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This principle affirms individual values and acknowledges the pluralistic nature of society, especially in the United States. Although the principle respects the right of the health care provider to act in accord with personal values, despite conflict with the patient’s preferences, it continues to support the patient’s autonomy. There may be difficulty in implementing this principle if the health care provider who is in conflict with the patient is uncooperative. For example, if the attending physician refuses to comply with the patient’s or family’s request to withdraw life support because of his or her personal moral values, the family may have to assert themselves in having that physician transfer the patient to another, more supportive, physician.

ETHICS RELATED TO FUTILE MEDICAL INTERVENTIONS The issue of a patient’s family demanding continuation of what health care providers judge as futile interventions remains controversial. While some suggest that there are limits to the respect for patient autonomy and that there is no ethical “right” to receive useless or futile interventions, others argue that the definition of medical futility is so subjective that use of the term, and decision making based upon it, are unjustified.

Principle 7 Health care professionals are not obligated to provide medical interventions that are judged as futile, even if requested by the patient or family. Futile life support may be limited without consent of the patient or surrogate decision maker.

Although Principle 7 lacks the strong consensus that supports the six preceding ethical principles, limiting lifesustaining therapy that has been judged futile has, in one form or another, already been incorporated into clinical practice.

One may ask whether the term futile life support is inherently contradictory. If an intervention supports life, how can it be futile?

First, in response, one should make a distinction between physiological futility and medical futility. An intervention that is judged to be physiologically futile is one that is not expected to or does not achieve the relevant physiological function as an end point. For example, cardiopulmonary resuscitation (CPR) is judged to be physiologically futile at the point when health care providers decide to stop an unsuccessful resuscitation. The CPR has failed in its goal of restoring a spontaneous circulation. In the same sense, CPR may be regarded as physiologically futile in a patient with refractory septic shock who has a cardiac arrest after progressively worse hypotension despite use of maximal vasopressor therapy. Under these circumstances—a cardiac arrest occurring despite maximal medical therapy—the conclusion that CPR would have virtually no chance of being successful (beyond possibly a brief time period) appears reasonable. An attempt at

cardiopulmonary resuscitation would prolong the patient’s dying somewhat but could also do physical harm to the patient, e.g., by fracturing ribs, etc. Prolonging dying is not one of the goals of medicine and, under these circumstances, CPR would violate the principle of nonmaleficence. Arguably, some see forcing health care providers to perform CPR with virtually no prospect of success as violating the ethical integrity of the medical profession.

Although there is modest consensus about physiological futility, medical futility is more difficult to define. Some have suggested that an intervention can be judged to be medically futile if reasoning and experience indicate that the intervention would have a high likelihood of failing to result in “meaningful survival.” In applying this definition, the key words are high likelihood, which acknowledges the uncertainties inherent in clinical decision making, and meaningful survival. Meaningful survival signifies that survival has a quality and duration that are of value to the particular individual. Importantly, quality of life refers to the patient’s point of view, not that of the health care provider. As an extension of this definition, some organizations of critical care specialists have recommended that survival of patients with permanent loss of consciousness, such as those in a persistent vegetative state, should be regarded as meaningless. Using this criterion, a lifesustaining intervention for such patients can be judged to be medically futile and, therefore, not obligatory.

Because application of the concepts of physiological or medical futility as the basis for withholding or withdrawing life-sustaining intervention can be misapplied due to their subjective definitions, appropriate guidelines and safeguards for their application should be incorporated within a health care institution’s written policies. This is especially important to ensure due process for patients and families. Furthermore, appropriate resources, such as institutional ethics committees or consulting bioethicists, should be available to provide consultations to clinicians and families. In contrast to the legacy of high-level, important court decisions affirming a patient’s right to forgo life-sustaining therapy, case law on use of physiological or medical futility as the basis for withdrawal of life support is quite limited and, at present, inconclusive.

ETHICAL PRINCIPLES RELATED TO MICROALLOCATION OF ICU RESOURCES Microallocation includes the process of admitting patients who are competing for a limited number of ICU beds or providing specific scarce resources to patients within the ICU— e.g., use of continuous renal replacement therapy or extracorporeal life support (ECLS). Microallocation encompasses concepts of both triage and rationing. Triage is the system of prioritizing patients according to severity of illness and, under some circumstances (e.g., in combat or disasters with mass casualties), according to the degree of benefit accrued to the patient by access to medical care. It entails consideration

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of the impact of caring for one patient on the system’s capacity to care for others. In the broad sense, rationing is an economic term that refers to the process of deciding among competing goals when resources are limited. In a narrow sense, rationing implies depriving some patients of beneficial care when not all can receive that care. One example is the use of waiting lists for solid organ transplants.

In contrast to the constantly inadequate number of solid organs for transplantation, ICU bed shortages often occur intermittently. Furthermore, in the face of persistent excess demand, ICU shortages can be addressed by spending more money to open more ICU beds, whereas the same does not solve the problem of scarcity of solid organs.

Compared to the obvious impact of an insufficient supply of solid organs on mortality, the impact on patient outcomes of situations when ICU demand exceeds ICU supply is unclear. This may be due to the presence of flexibility in ICU supply and demand compared to the circumstances of shortage of solid organs. Flexibility of supply arises from using “intermediate care” units for patients who do not necessarily need critical care but who still require monitoring and more care than provided on a general inpatient unit.

There is also flexibility in demand since patients who normally would be admitted to an ICU postoperatively often can be held in postanesthesia care units. In response to severe ICU bed shortages, elective surgical cases may be canceled. Finally, emergency departments may be able to function for limited periods in a similar holding capacity in response to ICU bed shortages.

The following principles are derived from fundamental legal and ethical principles and can serve as guides to making microallocation decisions in the ICU despite lack of an explicit societal consensus in how to allocate care and expensive health care resources.

Principle 8 Each individual’s life is equally valuable.

This principle affirms two fundamental concepts: (a) All individuals are equal; and (b) all human life is valuable.

The principle reflects the egalitarian concept that all individuals are equal because of their same intrinsic worth, which in turn arises from their humanity and human dignity. On this basis, each individual should receive respect and equal treatment. According to this principle, access to ICU resources and other services should not be prioritized according to perceptions of relative social worth among individuals. Patients should not be regarded as more or less valuable to society by virtue of their social class, employment status, family status or ethnicity, etc.

The principle has its roots in legal principles derived from concepts of due process in the Constitution of the United States. Although there is no legal right to health care in general for citizens of the United States, there is a legal obligation for health care providers to administer care in emergency situations. Because care in the ICU is similar to emergency care from the perspective of the need to address urgent and of-

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ten life-threatening medical needs, one could argue that for patients in need, ICU care is as much a right as emergency care. Although this remains an unresolved legal issue, external accrediting and state regulatory bodies hold health care institutions accountable to have resources available to meet the medical needs of their patients.

Principle 9 Vulnerable members of the community should be protected.

This principle reiterates Principle 8 that all members of the community should be treated as having equal value.

However, Principle 9 goes beyond a simple sense of equality by highlighting that additional safeguards should be taken to ensure that society’s vulnerable members are treated fairly.

One of these safeguards is protection against potential tyranny of the majority. For example, consider a policy in which the majority of subscribers of a health maintenance organization (HMO) decide to not fund beneficial critical care for premature infants or the elderly in order to make money available for other health care purposes. Such a policy would adversely affect these vulnerable groups, whether or not the majority’s motives were judged to be altruistic (e.g., improving public health programs) or self-serving (e.g., providing free cosmetic surgery).

Historical justifications for this precaution reflect past events when society has restricted access to education, employment, or health care for certain vulnerable groups, such as the poor, the handicapped, or ethnic and racial minorities.

In accord with John Rawls’ principle of fair equality of opportunity, there is an egalitarian duty to provide extra (not equal) resources to those who are disabled or disadvantaged as a means of helping them function effectively in society. For example, education of handicapped children is supplemented by provision of additional resources. The supplementation provides the handicapped with a fair equality of opportunity to achieve a basic level of education. The same rationale justifies provision of additional health care resources, such as critical care, to patients in greater need rather than provision of each person with an equal amount, irrespective of need.

Current legal protections for certain vulnerable groups in the United States also reflect this principle. For example, as potential subjects in clinical research, children and other persons with absent or limited autonomy, such as the mentally retarded or prisoners, are accorded extra protection.

Principle 10 Access to intensive care should be based on the patient’s medical need and the potential benefit of such care; judgments about whether a benefit is worthwhile should reflect not only the values of the patient and health care providers but also the values of the community.

This principle affirms that decisions to admit and care for patients in the ICU should be primarily based on medical appropriateness. In general, this principle holds that patients with the same degree of medical need should be treated

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the same. However, the principle also recognizes that different medical interventions can be used for the same medical need and have a range of potential benefits from minimally (marginally) beneficial to clearly beneficial. On this basis, patients should receive critical care only when they have sufficient medical need and when critical care provides a sufficient degree of potential benefit, i.e., exceeds a certain threshold.

Evaluating the value of receiving critical care is a complicated process that incorporates three points of view: those of the health care provider, patient, and community. The health care provider’s professional knowledge is required for assessing the patient’s medical needs, deciding which interventions can meet those needs, and predicting the likelihood of success. In addition, although medical benefit denotes how well an intervention meets the patient’s needs, only the patient can determine if the potential benefit of an intervention has sufficient personal value to justify receiving it. Finally, the community and health care institution—the parties ultimately paying for the resources—have a legitimate role in deciding whether the potential benefit of a certain intervention has sufficient value to society to make it worth the financial cost. For example, the question of whether a marginally beneficial therapy should be covered by a health care plan needs a societal perspective that extends beyond medical expertise and patient opinion. Denial of care because of very low potential benefit should reflect the community’s values and priorities for using its resources.

Communities and their health care institutions may place different values on the same services. For example, one health care institution may decide that patients in states of permanent unconsciousness should be restricted from care in the ICU. Another may decide the opposite, holding that sanctity of life prevails above all other considerations. A health care system, its members, and its providers might decide not to provide critical care for all patients with irreversibly fatal diseases when death is imminent. In a financially closed system, such as one with full capitation or a global budget, money saved by such a decision could fund a comprehensive hospice home care program for the same category of patients. Involvement of health care providers in decision making provides a safeguard from the tyranny of the majority of the community, whereby vulnerable members are treated unfairly by denying reimbursement for clearly beneficial therapies.

Principle 11 Although health care providers have a primary obligation to benefit their patients, this duty has limits when it unfairly compromises the availability of resources for others.

The primary professional duty of health care providers is to promote their patients’ best interests. This responsibility is derived from the principles of beneficence and fidelity and constitutes the core of the physician-patient relationship.

Some have argued the physician-patient relationship bestows on the physician a fiduciary-like responsibility to his or her patients. Under this responsibility, physicians are obligated

to put their patients’ interests above their own and those of others when providing medical care. This obligation for physicians is needed because of marked inequalities of medical knowledge and experience between health care providers and patients. It also recognizes the patient’s vulnerability and dependency on the health care provider due to sickness and disability.

In a closed system in which physicians put their patients’ interests foremost without regard for limited resources, a situation arises that some have likened to the “tragedy of the commons.” In this analogy, each herdsman is only motivated by self-interest and keeps adding cows to a common grazing area. Overgrazing eventually results in tragic consequences for all of the cows. Likewise, if health care providers keep spending limited health care resources on their own patients without regard for costs or availability of resources for other patients, the resources will be depleted eventually. The result is their unavailability for all. From these considerations arises the need for limits on the physician’s duty. However, limitations cause an inherent tension for physicians between duty to patients and obligation to support a system whose availability of resources could be compromised by unchecked promotion of patient interests (e.g., by expending resources in the pursuit of minimal but expensive marginal benefits).

Even though health care providers should practice costeffective medicine whenever possible—i.e., they should select the less costly of two therapies with equivalent effectiveness— in the absence of a closed system and explicit limits, providers are not obligated to withhold beneficial care from patients solely because of personal concerns over cost.

Allocation rules for the ICU should be made at the institutional level and not at the level of the individual practitioner.

Individual physicians may have subjective biases about issues that constitute worthy bases for allocation decisions. Decision making on an institutional basis provides additional safeguards that the process is fair since institutional policy making is generally an explicit process that has built-in mechanisms for internal review and external scrutiny.

SPECIFIC ETHICAL QUESTIONS AND CONSIDERATIONS IN THE ICU Principles 1 through 11 can be illustrated more fully when applied to a number of important ethical questions commonly arising in the ICU. Can intubated patients in the ICU really express their preferences?

Although communication may be a difficult and slow process, selected patients receiving mechanical ventilation may be quite lucid, especially when not receiving sedation.

At these times, it is not uncommon for health care professionals to communicate with the patient verbally and for the patient to write responses or questions. When the patient cannot write (e.g., due to neuromuscular weakness) more creative means of communication can be tried. Examples include

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having the patient blink in response to yes or no questions and creating controlled leaks around the tracheal cuff to allow patients to phonate during the inspiratory phase of mechanical ventilation.

Should one assume that patients in the ICU are capable of valid decision making?

Under ordinary circumstances in medical practice, one should presume that adult patients have adequate decisionmaking capacity. In fact, the law presumes an adult to be competent until judged by a court to be legally incompetent. However, one can argue that a critically ill patient in an ICU generally lacks decision-making capacity. Many factors may compromise the decision-making capacity of a critically ill patient: effects of the underlying disease; use of sedatives, narcotics, and other mind-altering medications; sleep deprivation; pain; anxiety; disorientation; and fear. Adopting this point of view, health care providers should carefully assess the patient’s decision-making capacity, relying on his or her communication, as discussed below.

What if the family or surrogate decision maker of a critically ill, incapacitated patient overrides the patient’s previously known preferences regarding life-sustaining therapy?

In general, according to the principle of respect for patient autonomy, the patient’s preferences should guide therapy, even if the patient’s family or surrogate decision maker opposes these preferences. However, if the patient’s surrogate has a valid durable power of attorney over the patient’s health care decisions, the surrogate can legally exercise control over decisions—although it should be quite unusual for the person holding a durable power of attorney to ignore a patient’s preferences. Regardless of the legal status of the surrogate, in the event of a conflict, the recommended first step for health care providers is discussion of differences directly with the surrogate. If needed, a request for informal or formal consultation from the hospital’s ethics committee or bioethicist can be taken as the next step. In these circumstances, the principle of beneficence and the health care provider’s fiduciary relationship with the patient obligate the health care provider to act as the patient’s advocate. Only in rare instances should the conflict have to be resolved in a court of law.

What if health care providers do not agree with the patient’s or surrogate’s preferences regarding life support?

When health care providers disagree with patients or their surrogates regarding life support, physicians and nurses have little choice except to transfer care to other health care professionals. (This assumes, of course, that the decisions are made by an informed patient with adequate decision-making capacity or by a surrogate who has a valid durable power of attorney.) A classic example of this type of conflict is refusal of blood products on religious grounds by a Jehovah’s Witness despite the presence of life-threatening gastrointestinal bleeding. In this case, health care providers must respect the patient’s legal and ethical right to refuse the blood, even if such action results in the patient’s death. When conflicting bioethical principles arise (Fig. 157-1), respect for patient autonomy overrides beneficence. Under different circumstances—e.g., if the patient is a child of a Jehovah’s Witness and is a minor—

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health care providers can regularly obtain a court order to give blood products, despite the parents’ opposition.

When preferences are expressed by a surrogate decision maker who lacks a valid durable power of attorney, the strength of the surrogate’s directives is less compelling. If the patient’s health care providers are concerned that the surrogate may not be acting in the patient’s best interests, they should seek consultation with the ethics committee to resolve the conflict.

Is a “slow code” or “Hollywood code” ever ethically acceptable?

A “slow code” occurs when health care providers perform CPR with less than the usual intensity or speed; the intent of such an approach is to allow the patient to die. The premise is that resuscitating the patient is inappropriate. A “Hollywood code” carries the same meaning as “slow code” but includes the pretense that the code is genuine. The deception in both of these practices makes them ethically problematic and unacceptable. These practices may be employed in hospitals that do not have policies allowing DNR orders on the basis of physiological futility when CPR is considered extremely unlikely to be successful for patients. One way to discourage these types of codes is for institutions to support their physicians’ authority to use their professional judgment in not providing inappropriate or ineffective interventions.

If CPR or another life-sustaining intervention is judged to be futile, what should health care providers do? Can they be forced to provide futile interventions?

When health care providers judge that CPR or other life support is futile, they should discuss this with the patient (if possible) or the patient’s surrogate decision maker.

Sometimes the surrogate or family agrees with the physician’s judgment that limitation of life support is appropriate. Some families may even be thankful and relieved that the physician has taken responsibility for the decision to withhold or stop the intervention. If the surrogate opposes withholding CPR or other interventions that are judged futile, attempts to reach agreement through further discussion and consultation with the ethics committee should be made. If these efforts are unsuccessful, attempts should be made to transfer the patient to another physician in the same or another institution for provision of the particular intervention in question. However, patients for whom judgments of futility apply are often too unstable to be moved to another institution. Ultimately, if the patient cannot be transferred and if it is allowed by hospital policy, the physician should write a DNR order on the basis of futility and should inform the surrogate. If such DNR orders are not permitted by hospital policy and if the patient cannot be transferred to another hospital, the physician faces a limited number of alternatives: (a) acquiescence and provision of futile care; (b) resignation from the case by transferring care to another physician in the same institution; or (c) procurement of a court order to limit therapy on the basis of futility.

Is the current system of “first come, first served” regarding ICU admissions fair? Which patients should be discharged from a full ICU in order to make room for new patients?

2730 Part XVII

Acute Respiratory Failure

Whether the admissions policy of an ICU is fair or unfair can be assessed by first considering the policy in relation to this basic principle of distributive justice: Equals should be treated equally and unequals treated unequally. If admission is granted solely on the basis of whether a patient’s severity of illness meets a threshold, and if critical care can provide more than certain minimal threshold of potential benefit, the patient should be admitted to an available bed. This practice constitutes an example of “equals being treated equally,” where the overriding criteria for equality or inequality are a sufficient degree of medical need and the potential for deriving benefit. If policies limit admissions to the ICU based solely on gender, race, ethnicity, or age—even if a patient meets thresholds for severity of illness and derivation of potential benefit—equals are being treated unequally and the decision is considered unfair.

If patients do not meet the thresholds for degree of illness or potential benefit, they should not be admitted, even if requested by the patient or his or her family. This scenario is an example of unequals (i.e., those with lower medical needs) being treated unequally (e.g., not being admitted to the ICU), where a sufficient degree of illness or potential benefit are the determinative criteria. These same considerations should govern not only decisions to admit patients to the ICU, but also decisions to continue care in the ICU. What are the alternatives when a critically ill patient needs admission to a full ICU? Providers could refuse to admit the patient, irrespective of the relative degrees of illness among the new and old patients, assuming all existing ICU patients meet the criteria of sufficient medical need and derivation of potential benefit. This decision is consistent with the “first come, first served” rule. The waiting patient could be admitted to another ICU in the same hospital or stabilized and transferred to another hospital where an ICU bed is available. Alternatively, providers could transfer the least sick patient in the full ICU to another ICU in the same hospital or an intermediate care unit in order to make room for the new patient (assuming the new patient is clinically more in need than the transferred patient). Resources in the intermediate care unit might need to be increased temporarily to care for the transferred patient adequately. In addition, one could discharge the ICU patient with the poorest prognosis in order to make room for the new patient (assuming the new patient had a better prognosis than the one discharged).

Unless differences in prognoses are striking, deciding on the relative benefits of critical care among patients is subject to bias and value judgments—a problematic issue from an ethics standpoint.

Currently available objective estimates of outcome in an ICU may improve decision making regarding resource allocation by decreasing subjectivity (see Chapter 156). However, these estimates can be misleading when used in this regard.

The estimated risk of death assumes that the patient has received critical care; hence, a low predicted risk of death would not constitute firm grounds in excluding a patient from the ICU. It is clear that objective determination about who would do well in an intermediate care unit instead of an ICU would be useful in making these kinds of triage decisions. In ad-

dition, it is unclear how accurate the current generation of objective prognostic systems is in comparing relative risks of survival. For example, is a predicted mortality risk of 40 percent significantly different from a 50 percent risk? Finally, even if these systems predict mortality risks greater than 90 percent, it is unlikely that families of critically ill patients would accept a 5 or 10 percent chance of survival as too low to continue ICU care.

When should an individual patient’s consumption of scarce or expensive resources be limited?

When a provided resource meets a patient’s medical needs, the resource should be limited only if the patient is consuming a disproportionate share; that is, if continued consumption would threaten availability for others. For example, a patient who has persistent variceal hemorrhage, despite all possible therapeutic attempts, may require an almost continuous infusion of blood products to prevent death from exsanguination. When availability of the blood bank’s supply of that type of blood product may be compromised, it is appropriate to stop transfusions. Some would argue that there is an obligation to do so. Such a decision by clinicians and appropriate consultants should be communicated to the family (since the patient is likely to be encephalopathic under these circumstances). However, deciding on the point at which a patient’s share of a resource is disproportionate may be difficult.

With regard to consumption of limited or expensive resources, physicians face an ethical dilemma between two conflicting professional roles: (a) as patient advocate, keeping the patient alive in accord with the principles of beneficence and respect for autonomy; and (b) as a “wise steward” of a health care system’s limited resources. Few guidelines exist that address the tension created by these dual roles. Although the limited resource in the example provided above was blood, the same argument could apply to health care costs. Money is as limited a resource as tangible medical products and interventions in a large health care system that is financially closed. In a closed system, money spent on behalf of one patient decreases funds available for other patients. One important future ethical challenge for health care providers in the ICU is integration of these roles as financial resources become even more constrained.

‘‘DO NOT ATTEMPT RESUSCITATION’’ (DNAR) ORDERS IN THE INTENSIVE CARE UNIT DNAR Orders and Terminology End-of-life decisions have a prominent role in the management of patients in intensive care units. For critically ill patients, DNAR orders are common, and the majority of patients dying in intensive care units have DNAR orders at the time of their death. Clinicians practicing critical care must be familiar with the details of DNAR decision making. Because in-hospital resuscitations are much more likely to fail

2731 Chapter 157

than succeed, many hospitals have changed what was originally written as “Do Not Resuscitate” or DNR orders to the more realistic descriptor, “Do Not Attempt Resuscitation” or DNAR orders.

When to Discuss Withholding or Withdrawing Life-Sustaining Therapy Ideally, a patient’s primary care provider should have discussed the patient’s preferences for withholding or withdrawing life support well before admission to an ICU. If done with medically informed foresight, the primary care provider should have discussed and clarified how use of life support fit into the patient’s overall plan for medical care, in accord with the patient’s life goals and values. At the time of this discussion, the patient should have been encouraged to prepare a written advance directive and designate a surrogate decision maker and preferably a durable power of attorney. Preferences for degrees of medical interventions under various specific scenarios that patients might reasonably encounter should have been discussed. For example, in the case of a patient with severe lung disease who has previously needed mechanical ventilation, what are the patient’s preferences regarding re-intubation and duration of assisted ventilation?

Does the patient want to be intubated again if clinically indicated? What should be done if the patient cannot be weaned after 1 week or after 2 or more weeks?

After a patient is admitted to an ICU, the patient, a family member, surrogate decision maker, or health care provider may initiate discussion about whether continued or new life support is appropriate. If the patient has an advance directive, the patient’s ICU caregivers should explore its meaning and applicability to first clarify why the patient was admitted to the ICU. If the advance directive simply indicates that life support should be withdrawn when there is no reasonable hope for meaningful recovery (a common phrase in many living wills), one needs to understand how to interpret “reasonable” and “meaningful recovery” before being able to offer appropriate recommendations regarding continuing, withholding, or withdrawing life support.

However, if the patient lacks a written advance directive (which is the case in the vast majority of admissions), he or she may have talked to family or friends about preferences regarding life support (e.g., a preference “not to be kept alive by machines”). Alternatively, even if the patient has not expressed anything specifically about life support, family or close friends might agree about what the patient’s preferences would be based on their knowledge of his or her life goals and values.

In circumstances in which a patient’s prognosis is very poor and provision of CPR or other interventions would be futile or highly burdensome, the attending physician should initiate end-of-life discussions with the patient’s family or surrogate decision maker as early as possible. In general, ICU attending physicians should meet with the patient’s family within the first 48 hours of ICU admission specifically to discuss the patient’s condition, prognosis, and what is known

Ethics in the Intensive Care Unit

about the patient’s preferences related to continuing or forgoing life support.

Assessment of a Patient’s Decision-Making Capacity Competency should be distinguished from decision-making capacity. An adult is legally competent until a court of law decides otherwise; children, as minors (unless emancipated by parenthood or marriage), lack legal competency. In contrast, decision-making capacity refers to a patient’s functional ability, which is often determined by the patient’s attending physician. Many legally competent patients lack adequate decision-making capacity when critically ill or heavily sedated. Conversely, a patient who is legally incompetent may retain some decision-making capacity, e.g., a teenager who has opinions about his or her medical care.

If a patient has adequate decision-making capacity in relation to a specific decision, then the patient should be able to demonstrate a set of abilities relating to comprehension, making comparisons, value judgments, and communication (Table 157-1). Adequate decision-making capacity in relation to a specific decision is generally present when the patient demonstrates all of the following: (a) comprehension; (b) comparative judgment; (c) communication; (d) appreciation of consequences; and (e) ability to make a choice. The patient should be able to understand information about his or her medical condition, its prognosis, and treatment alternatives, including having no treatment at all. The patient should also be able to judge and compare the medical alternatives and outcomes relative to personal values and life goals.

Finally, the patient should be able to communicate preferences consistently. One should specify the context of the assessment for decision-making capacity, since in some cases patients may have adequate capacity for certain decisions but not for others.

The attending physician is responsible for assessing the patient’s decision-making capacity. The process includes review of the patient’s medical history, performance of mental status examinations, and consultation with the patient’s

Table 157-1 Standards for Determining Decision-Making Capacity Ability to communicate a choice Ability to make a reasonable treatment choice Ability to appreciate the decision and its consequences Ability to rationally manipulate the information Ability to understand the fundamental meaning of the decision

2732 Part XVII

Acute Respiratory Failure

nurses and family. If doubt or conflict arises about the determination, additional information should be obtained, e.g., by requesting a psychiatric consultation.

Identification and Role of Surrogate Decision Makers As is often the case, when a patient in the ICU lacks decisionmaking capacity, the physician commonly turns to a surrogate decision maker. The choice of proxy may be legally mandated in states that have established a legal hierarchy, e.g., spouse first, parents next, etc. Another legal mandate is an individual having a valid durable power of attorney for health care decisions. In the absence of a legal directive, if the patient has informally designated someone as surrogate decision maker, that choice should be followed with some exceptions. In most cases, the surrogate decision maker will be a close family member. An appropriate surrogate should be willing to serve in that role and to accept responsibility for making the patient’s decisions, preferably based on knowledge of the patient’s preferences, values, and life goals. This knowledge allows the surrogate to act on the basis of a substituted judgment, i.e., what the patient would have wanted under the circumstances.

In unusual cases, no individual who knows the patient or is willing to serve as a surrogate decision maker can be

identified. In such circumstances, it is desirable to find a relatively neutral party (generally not a hospital employee) to act as surrogate—e.g., the chairperson of a hospital’s ethics committee. If this is not possible, prior to their implementation, knowledgeable health care providers who are not involved in the case should review DNAR decisions. The aim of the review is to ensure that the process of determination of DNAR status is sound, i.e., the decision is based on a best interests standard or a futility judgment with appropriate due process.

Deciding on the DNAR Order A DNAR order actually consists of much more than a proscription of CPR. In most hospitals, it also refers to withholding or withdrawing one or more life-sustaining therapies. For a patient in the ICU, these therapies may include antiarrhythmic drugs (chemical cardioversion), intubation, mechanical ventilation, dialysis, blood products, intravenous pressors, antibiotics, and parenteral and enteral nutrition.

How should limitation of certain treatments be decided? One approach is to define the goals of therapy that are applicable to the patient. Once these goals are established, one can decide which therapies are compatible with them. In some institutions, DNAR orders have been classified into three levels, each with a different goal of treatment (Table 157-2).

Table 157-2 Do Not Attempt Resuscitation (DNAR) Orders: Levels of Intervention and Associated Therapeutic Goals Level

Interventions

Goals of Therapy

A

All therapies except cardiopulmonary resuscitation (CPR)

Patient is to receive all medically indicated therapies to preserve life and restore function, including those to prevent cardiac or respiratory arrest. However, if patient suffers cardiopulmonary arrest, no resuscitative attempts will be made unless specified in advance (e.g., only drug therapy permitted). Patient will not be intubated or mechanically ventilated. Restrictions may be temporarily suspended during general anesthesia or other invasive procedures if agreed upon previously. “No ICU transfer” may also be specified.

B

No additional therapy and no CPR

Therapy already under way to be continued as medically indicated, but in general, no additional treatment given except for patient comfort.

Goal is maintenance of status quo while discussions evolve or prognosis becomes more certain. If cardiac or pulmonary arrest occurs, no resuscitative attempts to be made.

C

Palliative care only

Treatment limited to nursing care and therapy whose goal is comfort.

Treatment for relief of pain, anxiety, or dyspnea may be used, even if the treatment worsens cardiac or respiratory function. All life-sustaining interventions, including artificially provided food and water, will be discontinued unless exceptions agreed upon, e.g., continued mechanical ventilation.

2733 Chapter 157

As a first step in the decision-making process, health care providers should meet with the patient’s family or surrogate decision maker to inform them about the current medical situation, review the goals of therapy, and reassess the appropriateness of the level of current treatment in relation to the goals. The discussion should include the patient unless he or she lacks sufficient decision-making capacity. Attendance should include the attending physician, the patient’s primary care physician (if applicable), consultants (when relevant for explanations and discussions of prognosis), house staff, and one or more ICU nurses and respiratory therapists caring for the patient. These meetings promote open communication among parties, help all to feel involved in the decisionmaking process, and facilitate understanding and acceptance of the results. “Family meetings,” in which families have the opportunity to grieve while making DNAR decisions, have become common and a way of life in the practice of critical care medicine.

Carrying Out the DNAR Order After deciding on the limits of therapy, the attending physician should document the meeting’s discussion in the medical record and the justification for the DNAR order. The order should be written in a clearly identifiable location in the record as well as communicated orally to other health care providers. Details of DNAR policies vary among institutions.

For example, in some states, the signature of a capable patient or surrogate decision maker may be required for a DNAR order. In the usual case, just prior to removal from assisted ventilation, bolus intravenous doses of opioids and benzodiazepines should be given pre-emptively to sedate the patient and control anxiety, pain, and dyspnea. After the desired level of sedation has been achieved, the patient is extubated and the dosage of opioids and sedatives is titrated to maintain patient comfort. A physician, nurse, or respiratory therapist may do this. If a staff member is uncomfortable with removal of life support, he or she should be given the option of not participating. Ultimately, the physician who writes the DNAR order must be prepared to extubate or remove the patient from the ventilator if necessary.

PROVIDING PALLIATIVE CARE TO ICU PATIENTS Palliative care aims to restore or maintain quality of life and prevent needless physical or emotional suffering. Titrating opioids and sedatives to prevent the patient from suffering pain, dyspnea, or anxiety is one form of palliative care. Another is addressing the patient’s and family’s needs for relief of spiritual or existential suffering as well as bereavement care.

It is a multidisciplinary process.

After removal from assisted ventilation, ICU patients may be legitimately kept in the ICU for palliative care. Although this may seem paradoxical to some, the patient’s needs

Ethics in the Intensive Care Unit

may demand an intense level of nursing and physician intervention to keep him or her comfortable, e.g., by frequent adjustments of the dose of opioid or sedative. Continued care in the ICU also has the advantage of providing continuity of care by the same physician and nursing team.

However, for patients whose needs for palliative care can be met by a less intense level of nursing and medical care, thought should be given to transferring that patient to another room outside of the ICU, e.g., in a step-down unit. This is especially important if medically needy patients require an ICU and there are no open ICU beds available.

On the one hand, transfer of such patients should be given a higher priority if the demand for ICU beds is high and supply is tight, and if the patient’s post-assisted ventilation course is estimated to be prolonged, i.e., longer than 1 to 2 days. Some hospitals have special palliative care units for such patients with specially trained nursing and medical staff and pleasant and private surroundings for the patient and his or her family.

On the other hand, transfer out of the ICU should be given lower priority if demand for ICU beds is modest and supply of open beds is good, and if the patient’s course is anticipated to be measured in terms of hours. It makes little sense in such situations to transfer a patient out of an ICU bed for him or her to die during transport or several hours later in another unit.

Resolution of Conflicts Good communication during the decision-making process, as a rule, prevents the occurrence of conflicts. However, if communication is poor among physicians and nurses, conflicts are common. Conflicts may also occur between the patient’s family and the health care team. Conflicts may arise when one party favors forgoing life support and the other does not—for example, if the family wants full critical care continued despite pessimism about the patient’s recovery on the part of the health care team. Alternatively, a family may wish to stop life support while the attending physician is reluctant to do so.

Resolution of conflicts begins with open communication among all parties. It may be helpful to consult with the hospital’s ethics committee. Reviewing hospital policy, identifying legal myths or real limits, and getting all parties around the same table for discussion may resolve the conflict. Rarely should conflicts have to be referred for judicial review. If the situation reaches an impasse, it may be prudent to offer to transfer the patient to another attending physician in the same hospital or to another hospital rather than go to court.

CONCLUSION In today’s critical care environment, death in the ICU usually occurs after life-sustaining therapy is withheld or withdrawn.

Many ethical considerations in the ICU arise from the frequency and complexity of this process. Health care providers

2734 Part XVII

Acute Respiratory Failure

face ethical dilemmas in which decisions violate one or more ethical principles in order to respect an overriding ethical principle. Weighing ethical principles in limiting life support is supported by a broad ethical, legal, and professional consensus. As a general rule, the overriding principle is respect for patient autonomy, and hospital policies regarding DNAR orders should reflect this. Despite well-written policies, conflicts still occur, and other resources—e.g., ethics committees or consulting bioethicists—are frequently helpful in their resolution. Only in very rare cases should a conflict have to be resolved in court.

SUGGESTED READING American Medical Association: Medical futility in end-of-life care: Report of the Council on Ethical and Judicial Affairs.

JAMA 281:937, 1999.

American Thoracic Society: Fair allocation of intensive care unit resources. Official statement of the American Thoracic Society. Am J Resp Crit Care Med 156:1282, 1997.

American Thoracic Society: Palliative care for patients with respiratory diseases and critical illnesses: an official American Thoracic Society clinical policy statement. Am J Resp Crit Care Med (in press).

American Thoracic Society: Withholding and withdrawing life-sustaining therapy. Am Rev Respir Dis 144:726, 1991.

Brody H, Campbell ML, Faber-Langendoen K, et al: Withdrawing intensive life-sustaining treatment—recommendations for compassionate clinical management. N Engl J Med 336:652, 1997.

Cohen S, Sprung C, Sjokvist P, et al: Communication of endof-life decisions in European intensive care units. Int Care Med 31:1215, 2005.

Curtis JR, Rubenfeld GD (eds): Managing Death in the Intensive Care Unit: The Transition from Cure to Comfort. New York, Oxford University Press, 2001.

Danis M, Federman D, Fins JJ, et al: Incorporating palliative care into critical care education: Principles, challenges, and opportunities. Crit Care Med 27:2005, 1999.

Faber-Langendoen K, Lanken PN: Dying patients in the intensive care unit: Forgoing treatment, maintaining care.

Ann Intern Med 133:886, 2000.

Hardart GE, Truog RD: Attitudes and preferences of intensivists regarding the role of family interests in medical decision making for incompetent patients. Crit Care Med 31:1895, 2003.

Hodde NM, Engelberg RA, Treece PD, et al: Factors associated with nurse assessment of the quality of dying and death in the intensive care. Crit Care Med 32:1648, 2004.

Lautrette A, Darmon M, Megarbane B, et al: A communica-

tion strategy and brochure for relatives of patients dying in the ICU. N Engl J Med 356:469, 2007.

Lilly CM, De Meo DL, Sonna LA, et al: An intensive communication intervention for the critically ill. Am J Med 109:469, 2000.

Lynn J, Teno JM, Phillips RS, et al: Perceptions by family members of the dying experience of older and seriously ill patients: Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. Ann Intern Med 126:97, 1997.

Meisel A, Snyder L, Quill T: Seven legal barriers to end-of-life care: Myths, realities and grains of truth. JAMA 284:2495, 2000.

Prendergast TJ, Claessens MT, Luce JM: A national survey of end-of-life care for critically ill patients. Am J Respir Crit Care Med 158:1163, 1998.

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Making Health Care Decisions: The Ethical and Legal Implications of Informed Consent in the Patient-Practitioner Relationship. Washington, D.C., U.S. Government Printing Office, 1982.

President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Deciding to Forego Life-Sustaining Treatment: Ethical, Medical and Legal Issues in Treatment Decisions. Washington, D.C., U.S. Government Printing Office, 1983.

Puntillo KA, Benner P, Drought T, et al: End-of-life issues in intensive care units: A national random survey of nurses’ knowledge and beliefs. Am J Crit Care 10:216, 2001.

Schneiderman LJ, Gilmer T, Teetzel HD, et al: Effect of ethics consultations on nonbeneficial life-sustaining treatments in the intensive care setting: A randomized controlled trial.

JAMA 290:1166, 2003.

Selecky PA, Eliasson CA, Hall RI, et al: Palliative and endof-life care for patients with cardiopulmonary diseases: American College of Chest Physicians position statement.

Chest 128:3599, 2005.

Sprung CL, Cohen SL, Sjokvist P, et al: End-of-life practices in European intensive care units: The Ethicus Study. JAMA 290:790, 2003.

Truog RD, Cist AF, Brackett SE, et al: Recommendations for end-of-life care in the intensive care unit: The Ethics Committee of the Society of Critical Care Medicine. Crit Care Med 29:2332, 2001.

Wennberg JE, Fisher ES, Stukel TA, et al: Use of hospitals, physician visits, and hospice care during last six months of life among cohorts loyal to highly respected hospitals in the United States. Br Med J 328:607, 2004.

White DB, Curtis JR: Care near the end-of-life in critically ill patients: A North American perspective. Curr Opin Crit Care 11:610, 2005.

Appendixes

A Normal Values: Typical Values for a 20-Year-Old Seated Man Ventilation (BTPS) Tidal volume (VT ), L Frequency (f), breaths/min Minute volume (VE ), L/min Respiratory dead space (VD ), ml Alveolar ventilation, VA , L/min Lung Volumes and Capacities (BTPS) Inspiratory capacity (IC), L Expiratory reserve volume (ERV), L Vital capacity (VC), L Residual volume (RV), L Functional residual capacity (FRC), L Total lung capacity (TLC), L Residual volume/total lung capacity × 100 (RV/TLC), % Mechanics of Breathing Forced vital capacity (FVC), L Forced expiratory volume, first second (FEV1 ), L Maximum voluntary ventilation (MVV), L/min Forced expiratory volume in 1 s/forced vital capacity × 100 (FEV1 /FVC), % Forced expiratory volume in 3 s/forced vital capacity × 100 (FEV3 /FVC), % Forced expiratory flow during middle half of FVC (FEF25−75 ), L/s Forced inspiratory flow at the middle of FIVC (FIF50 ), L/s

0.6 12 7.2 150 5.4 3.0 1.9 4.9 1.4 3.2 6.3 22

4.9 4.0 170 83 97 4.7 5.0

Static compliance of the lungs (Cst, l), L/cm H2 O Compliance of lungs and thoracic cage (CRS, respiratory system compliance) L/cm H2 O Airway resistance at FRC (Raw), cm H2 O/L/s Pulmonary resistance at FRC, cm H2 O/L/s Airway conductance at FRC (Gaw ), L/s/cm H2 O Specific conductance (Gaw /V1 ) Maximum inspiratory pressure, mmHg Maximum expiratory pressure, mmHg Distribution of Inspired Gas Single-breath N2 test ($N2 from 750 to 1250 ml in expired gas), % N2 Alveolar N2 after 7 min of breathing O2 , % N2 Closing volume (CV), ml CV/VC × 100, % Closing capacity (CC), ml CC/TLC × 100, % Slope of phase III in single-breath N2 test, % N2 /L Gas Exchange O2 consumption at rest (STPD), ml/min CO2 output at rest (STPD), ml/min Respiratory exchange ratio (R), CO2 output/O2 uptake

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

0.2

0.1 1.5 2.0 0.66 0.22 −75 120 <1.5 <2.5 400 8 1900 30 <2

240 192 0.8

2736 Appendix A

alveolar gas PAO2 , mmHg PACO2 , mmHg arterial blood PaO2 , mmHg SaO2 , % pH PaCO2 , mmHg PaO2 , while breathing 100% O2 , mmHg Alveolar Ventilation Alveolar ventilation, L/min Physiological dead space/tidal volume × 100 (VD /VT ), % Alveolar-arterial oxygen-gradient, (A-a) PO2 , mmHg Diffusing Capacity Diffusing capacity at rest for CO, single-breath (DlCOsb ), ml CO/min/mmHg

105 40 95 98 7.41 40 640

Diffusing capacity per unit alveolar volume (Dl/Va) Control of Ventilation Ventilatory response to hypercapnia, L/min/per $ PaCO2 mmHg Ventilatory response to hypoxia, L/min per $SO2 (%) Arterial blood PO2 during moderate exercise, mmHg

Pulmonary Hemodynamics 4.2 Pulmonary blood flow (cardiac output), <30 L/min Pulmonary artery systolic/diastolic pressure, 10 mmHg Pulmonary capillary blood volume, ml 29 Pulmonary “capillary” (wedge) blood pressure, mmHg

4.8

>0.5 >0.2 95

5.4 25/8 100 <10

B Terms and Symbols in Respiratory Physiology GENERAL SYMBOLS

QUALIFYING SYMBOLS

P

Partial pressure in blood or gas.

PO2 = partial pressure of O2

I

¯ X

A bar over the symbol indicates a mean value. P¯ = mean pressure, as distinct from instantaneous pressure

E

X˙

A time derivative (rate) is indicated by a dot above the symbol V˙ O2 = oxygen consumption per minute, ml

A

V˙ CO2 = CO2 production per minute, ml

an p f max

Inspired Vi = inspired volume Expired Ve = expired volume ˙ = expired volume per minute Ve Alveolar Va = alveolar volume V˙ = alveolar ventilation per minute Tidal Vt = tidal volume Dead space Vd = volume of dead space ˙ = dead-space ventilation per minute Vd Barometric Pb = barometric pressure Standard conditions: temperature 0◦ C, pressure 760 mmHg, and dry (0 mmHg water vapor) Body conditions: body temperature and ambient pressure, saturated with water vapor at these conditions Ambient temperature and pressure, dry Ambient temperature and pressure, saturated with water vapor at these conditions Anatomic Physiological Respiratory frequency, per minute Maximum

t

Time

T

%X

Percent sign preceding a symbol indicates percentage of the predicted normal value

D

X/Y%

Percent sign following a symbol indicates a ratio function with the ratio expressed as a percentage. Both components of the ratio must be designated.

B

FEV1 /FVC, % = 100 × FEV1 /FVC Xa, Xa

A small capital letter or a lower-case letter on the same line following a primary symbol is a qualifier to further define the primary symbol. Alternatively, subscript letters may be used.

Xa = XA , Xa = Xa Additional qualifiers of the primary symbol may be identified as shown.

PeCO2 = Pressure of CO2 in the expired air, mmHg

GAS PHASE SYMBOLS Primary Symbols V V˙

Volume of gas Flow of gas

F

Fractional concentration of a gas

STPD

BTPS

ATPD ATPS

BLOOD PHASE SYMBOLS Primary Symbols Q Volume of blood Q˙ Blood flow Q˙ = cardiac output, L/min

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

2738 Appendix B

C

Concentration in the blood phase CO2 = concentration of oxygen in blood, ml of O2 per 100 ml of blood

Lung Capacities∗ IC Inspiratory capacity. The sum of IRV and TV.

S

Saturation in the blood phase SO2 = Saturation of hemoglobin with O2 , percent

IVC

Inspiratory vital capacity. Maximum volume of air inspired from the point of maximum expiration, i.e., from RV

VC

Vital capacity. Maximum volume of air expired from the point of maximum inspiration, i.e., from TLC

FRC

Functional residual capacity. Sum of RV and ERV. FRC is the volume of air remaining in the lungs at the resting end-expiratory position.

TLC

Total lung capacity. Volume of air in the lungs after maximum inspiration. Also, the sum of all volume compartments of the lungs.

RV/TLC,%

Residual volume to total lung capacity ratio, expressed as a percentage.

CC

Closing capacity. Closing volume plus residual volume, may be expressed as a percentage of TLC: CC/TLC, %.

Qualifying Symbols a

Arterial CaO2 = concentration of O2 in arterial blood, ml of O2 per 100 ml of blood

c

Capillary CcO2 = concentration of O2 in capillary blood, ml of O2 per 100 ml of blood

c′

Pulmonary end-capillary Pc′O2 = partial pressure of O2 in end-capillary blood, mmHg

v

Venous CvO2 = concentration of O2 in venous blood, ml of O2 per 100 ml of blood

v¯

Mixed venous C¯vO2 = concentration of O2 in mixed venous blood, ml of O2 per 100 ml of blood

VENTILATION AND LUNG MECHANICS TESTS AND SYMBOLS

Forced Respiratory Maneuvers During Spirometry† FVC Forced vital capacity. The maximum volume of air forcibly expired from total lung capacity.

FIVC

Forced inspiratory vital capacity. Maximum volume of air forcibly inspired starting from residual volume.

FEVt

Timed forced expiratory volume. Volume of air expired in a specified time in the course of the forced vital capacity maneuver.

FEV1 = volume of air expired during the first second of the FVC.

FEVt/FVC, %

Expiratory reserve volume. Maximum volume of air expired from the resting end-expiratory level.

Ratio of time forced expiratory volume to forced vital capacity, expressed as a percentage.

FEFx

Tidal volume. Volume of air inspired or expired with each breath during quiet breathing. When tidal volume is used in gas-exchange formulations, this symbol is used.

Forced expiratory flow, related to some portion of the FVC curve. Modifiers refer to the amount of the FVC that has been expired at the time of measurement.

FEF200−1200

Forced expiratory flow between 200 and 1200 ml of the FVC (formerly called the maximum expiratory flow rate).

FEF25−75

Forced expiratory flow during middle half of the FVC (formerly called the maximum midexpiratory flow rate or MMEF).

Static Lung Volumes∗ Primary Compartments RV

Residual volume. Volume of air remaining in the lungs after maximum expiration.

CV

Closing volume. Volume of air expired from the onset of airways closure to residual volume. May be expressed as a fraction of VC: CV/VC, %.

ERV

Vt

IRV

Inspiratory reserve volume. Maximum volume of air inspired from the end-tidal inspiratory level.

∗ ∗

Expressed as BTPS.

†

Combinations of volumes for practical purposes.

All values at BTPS.

2739 Appendix B

PEF V˙ maxx

FIFx

MVV

PImax

PEmax

Peak expiratory flow. Highest value for expiratory flow.

Maximum flow when x percent of the FVC has been expired.

V˙ max75 = flow (instantaneous) when 75 percent of the FVC has been expired.

Pressure Terms Paw Pressure at any point along the airways Pao

Pressure at the airway opening

Ppl

Pleural pressure

PA

Alveolar pressure

Forced inspiratory flow. As in the case of the FEF, appropriate modifiers designate the volume at which flow is being measured.

Unless otherwise specified, the volume qualifiers indicate the volume inspired from RV at the point of measurement.

FIF25−75 = forced inspiratory flow during the middle half of the FIVC.

Pbs

Pressure at the body surface

Pes

Esophageal pressure: used to estimate Ppl

Pa–Pbs

Transthoracic pressure

Pa–Ppl

Transpulmonary pressure

Ppl–Pbs

Pressure difference across the chest wall

Maximum voluntary ventilation. Volume of air exhaled during maximum breathing efforts within a specified time period. If breathing frequency is set by the examiner, it is indicated by the qualifier.

MVV60 = MVV at a breathing frequency of 60 per minute.

Paw–Ppl

Transbronchial pressure, estimated as difference between airway and pleural pressures.

Maximum inspiratory pressure. The maximum pressure generated during an inspiratory effort.

Maximum expiratory pressure. The maximum pressure generated during an expiratory effort.

Measurements Related to Ventilation V˙ E Expired volume per minute (BTPS) V˙ I

Inspired volume per minute (BTPS)

V˙ CO2

Carbon dioxide production per minute (STPD)

V˙ O2

Oxygen consumption per minute (STPD)

R

Respiratory exchange ratio, the ratio of CO2 output to O2 intake in the lungs

V˙ A V˙ D

Mechanics of Breathing∗

Flow-Pressure Relationships† R

General symbol for frictional resistance, defined as the ratio of pressure difference to flow.

Raw

Airway resistance, calculated from pressure difference between airway opening (Pao ) and alveoli (Pa) divided by the airflow, cmH2 O/L/s.

Rl

Total pulmonary resistance, measured by relating flow-dependent transpulmonary pressure to airflow at the mouth.

Rti

Tissue resistance (viscous resistance of lung tissue), calculated as difference between Rl and Raw.

Rus

Resistance of the airways on the upstream (alveolar) side of the point in the airways where intraluminal pressure equals Ppl, i.e., equal pressure point. Measured during a forced expiration.

Rds

Resistance of the airways on the downstream (mouth) side of the point in the airways where intraluminal pressure equals Ppl, i.e., equal pressure point. Measured during a forced expiration.

Gaw

Airway conductance, reciprocal of Raw.

Gaw/Vl

Specific conductance, airway conductance, expressed per liter of lung volume at which Gaw is measured.

Alveolar ventilation per minute (BTPS) Ventilation per minute of the physiological dead space (BTPS) defined by the equation PaCO2 − PeCO2 V˙ D = V˙ E PaCO2 − PiCO2

VD

Volume of the physiological dead space, calculated as V˙ D /f.

Vd/Vt

Ratio of dead space to tidal volume. The fraction, usually expressed as a percentage, of each breath that does not contribute to CO2 elimination.

∗ All

pressures expressed relative to ambient pressure unless otherwise specified. † Unless otherwise specified, resistance measurements are assumed to be made at FRC.

2740 Appendix B

Volume-Pressure Relationships C

General symbol for compliance of the lungs, chest wall, or total respiratory system.

Volume change per unit change in applied pressure. For the lungs, the applied pressure is the pressure difference across the lungs, or transpulmonary pressure, Pao–Ppl; for the chest wall, the applied pressure is the transthoracic pressure, Ppl–Pbs; for the entire respiratory system, the applied pressure is Pao–Pbs.

Vc

Capillary blood volume. This should be Qc for consistency with other symbols, but Vc is entrenched in the literature. In the equation that follows for 1/Dl, Vc represents the effective pulmonary capillary blood volume, i.e., capillary blood volume in intimate association with alveolar gas.

1/Dl

Total resistance to diffusion, including resistance to diffusion of test gas across the alveolar-capillary membrane, through plasma in the capillary, and across the red blood cell membrane (1/Dm), the resistance to diffusion with the red cell arising from the chemical reaction of the test gas and hemoglobin (1/θVc), according to the formulation

Cl

Lung compliance. Value for the volume change divided by the transpulmonary pressure.

Cw

Chest wall compliance. Value for the volume change divided by the transthoracic pressure.

Cdyn

Dynamic compliance. Value for compliance determined at time of zero gas flow at the mouth during uninterrupted breathing. The respiratory frequency appears as a qualifier.

Cdyn40 = dynamic compliance at a respiratory frequency of 40 per minute.

Dl/Va

Static compliance, value for compliance determined on the basis of measurements made during a period of zero airflow.

BLOOD GAS SYMBOLS

Specific compliance. Compliance divided by the lung volume at which it is determined, usually FRC.

PaCO2

Arterial CO2 tension, mmHg

SaO2

Arterial O2 saturation, percent

CcO2

Oxygen content of pulmonary end-capillary blood, ml of O2 per 100 ml of blood

(A-a)Po2

Alveolar-arterial difference in the partial pressure of O2 , mm Hg

CaO2 –C¯vO2

O2 content difference between arterial and mixed venous blood (arteriovenous O2 difference), ml of O2 per 100 ml of blood

Cst

C/Vl

Pst

Static pulmonary pressure at a specified lung volume.

PstTLC = static recoil pressure of the lung measured at TLC (maximum recoil pressure)

DIFFUSING CAPACITY TESTS AND SYMBOLS Dlx Diffusing capacity of the lung expressed as volume (STPD) of gas (x) uptake per minute per unit alveolar-capillary pressure difference for the gas used. A modifier can be used to designate the technique: DlCO /sb = Single-breath CO diffusing capacity

Dm θ

DlCO /ss = Steady-state CO diffusing capacity Diffusing capacity of the alveolar-capillary membrane (STPD).

Reaction rate coefficient for red blood cells.

Determined as the volume of gas (stpd) that will combine per minute with 1 unit volume of blood per unit of gas tension. If the specific gas is not stated, θ is assumed to refer to CO and is a function of existing O2 tension.

1 1 1 = + DL DM θVc Diffusing capacity per unit of alveolar volume. Dl is expressed STPD, and Va is expressed in liters, BTPS.

Symbols for these values are readily composed by combining general symbols. Some examples include the following:

PULMONARY SHUNT SYMBOLS Q˙ s Flow of blood via shunts. This is usually ˙ determined as percent of cardiac output (Q) while breathing 100% O2 , according to the equation CcO2 − CaO2 Q˙ s = × 100 CcO2 − C¯vO2 Q˙ where CcO2 = O2 content of end-capillary blood CaO2 = O2 content of arterial blood C¯vo 2 = O2 content of mixed venous blood

Index Note: Page numbers followed by f and t indicate figures and tables, respectively.

A Abacavir hypersensitivity, 2260, 2261 in HIV-infected (AIDS) patients, radiographic findings in, 2249t ABCA3, 125, 126f mutations of, disorders associated with, 129f, 130 Abdominal motion, analysis of, 1646 Abdominal muscle(s), 72f, 76–77 Abdominal paradox, 2609 ABPA. See Allergic bronchopulmonary aspergillosis Abscess amebic, 1494–1495, 2398–2400 Bezold’s, 2094, 2094f brain, in neutropenic host and cancer patient, 2217, 2218f cold, in hyperimmunoglobulin E syndrome, 2239 deep neck, 2167 hepatic amebic, 1494–1495, 2398, 2400 and pleural effusion, 1496, 1496f intra-abdominal, and pleural effusion, 1496, 1496f laryngeal, upper-airway obstruction caused by, 848f lung, 1988–1989, 2007, 2099, 2142f acute, 2149 associated conditions, 2153, 2154t chronic, 2149 classification of, 2149 clinical features of, 2149t, 2151–2153 definition of, 2141 diagnosis of, 2154–2156 hemoptysis caused by, 410, 413 historical perspective on, 2142–2143 in hyperimmunoglobulin E syndrome, 2239 image-guided drainage of, 536 location of, 2147

microbiology of, 2144–2146, 2147f, 2153, 2154t mortality from, 2159 nonspecific, 2142 outcomes with, 2159 and parapneumonic effusions, 1488–1489 pathophysiology of, 2146–2149 primary, 2152 putrid, 2149 radiologic diagnosis of, 2153 secondary, 2149, 2152, 2152f as solitary pulmonary nodule, 1817 in surgery and trauma patients, 2199 treatment of, 2141–2142, 2158–2159 failure of, 2155f orbital, 2090, 2090f paravertebral, 1596 peritonsillar, 2086 skin, 390 subperiosteal, 2090, 2090f Absidia infection (incl. pneumonia) epidemiology of, 2317 in neutropenic host and cancer patient, 2217 in invasive fungal sinusitis, 2091 Absidia corymbifera, 2316t, 2317 Acanthamoeba, 1995, 2401 infection (incl. pneumonia) in cancer patients, 2219 in immunocompromised host, 2210 Acanthamoebiasis, 2401 Acebutolol, pulmonary effects of, 1097 Acetaldehyde, in smoke and inhalation injury, 1057 Acetaminophen, dose-related airway response to, in aspirin-sensitive asthmatics, 801 Acetazolamide, 2643 pulmonary effects of, 1093

Acetic acids, and aspirin-induced asthma, 802t Acetylcholine and pulmonary circulation, 1347 pulmonary endothelial response to, 1341, 1342f N-Acetylcysteine, 2641–2642 for cystic fibrosis patient, 876 for idiopathic pulmonary fibrosis, 1157–1158 Acetylsalicylic acid. See also Aspirin and asthma, 802t and interstitial lung disease, 1110t Achalasia, 389f, 1306, 1308f, 1596 pulmonary complications of, 857 Achromobacter xylosoxidans, infection (incl. pneumonia), in cystic fibrosis, 875, 881, 2176 treatment of, 875, 2179 Acid-base balance PCO2 and, 213–214 pH-temperature relationship and, 214 renal contribution to, 208–211 respiratory contribution to, 211 strong ion difference and, 213–214 weak anion concentration and, 213–214 Acid-base disturbances, 207, 208t diagnostic approach to, 214–219 clinical information in, 214–215 mixed approach to patient with, 219 case example, 220–221 ventilatory adaptations to, 167 Acid-base map, 215, 215f Acid-fast stains, 2038–2039, 2462 Acid hydrolase(s), mast cell, 310t, 311 Acid maltase deficiency respiratory abnormalities in, 1659 ventilatory impairment in, 1668t

Copyright © 2008, 1998, 1988, 1980 by The McGraw-Hill Companies, Inc. Click here for terms of use.

I-2 Index Acidosis. See also Metabolic acidosis; Respiratory acidosis and dyspnea, 397 and pulmonary vasomotor control, 1346 Acinetobacter, 1998 in acute mediastinitis, 2166t drug-resistant, 2282 infection (incl. pneumonia), 2008 neonatal nosocomial pneumonia caused by, 2126 nosocomial, 2196, 2279–2280, 2280t, 2282, 2581–2582 treatment of, 2285–2288, 2287t in surgery and trauma patients, 2197 treatment of, 2062 Acinetobacter baumannii, pneumonia, 2009 Acinetobacter calcoaceticus infection (incl. pneumonia), nosocomial, 2281t var. anitratus. See Acinetobacter baumannii Acinic cell tumors, 1925–1926 Acinus (pl., acini), 26, 28f, 29, 47, 48f, 53 airways in branching pattern of, 62, 62f morphometric characteristics of, 62, 63f definition of, 695 design of, and gas exchange, 61–65, 62f gas exchange in, 63–65 involvement in emphysema, 695–696, 695f number of, 51 typical path model for, 62–63, 63f, 64t Acquired immune deficiency syndrome.

See AIDS (acquired immune deficiency syndrome); Human immunodeficiency virus (HIV) Acrokeratosis paraneoplastica, 432, 432f Acrolein, in smoke and inhalation injury, 1054, 1057 source of, 1054t Acromegaly, 1930t, 1934–1935 Acrosclerosis, 429, 429f Acrylonitriles, in smoke and inhalation injury, source of, 1054t Actin, 72 Actinomyces, 1986 in acute mediastinitis, 2166t in empyema, 2144t infection (incl. pneumonia), 2020, 2022, 2156t staining characteristics of, 2035t, 2036–2037, 2039, 2039f Actinomyces israelii, 1999f, 2007 staining characteristics of, 2039f Actinomyces odontolyticus, in empyema, 2144t

Actinomycetes, thermophilic, hypersensitivity pneumonitis caused by, 1163t Actinomycin-D, pulmonary effects of, 1070t, 1073 radiation therapy and, 1181 Actinomycosis, 1990, 2007 cutaneous manifestations of, 430–431 cytopathology of, 518 diagnosis of, 1998, 1999f Activated protein C, recombinant human, for SIRS/MODS, 2570 Activation-induced cytidine deaminase, 324 Acute interstitial pneumonia, 1106t, 1145, 2541t. See also Diffuse alveolar damage clinical features of, 1116t computed tomography of, 1115t, 1116t histology of, 1116t occupational exposures and, 935t in rheumatoid arthritis, 1204 treatment of, 1116t Acute lung injury biologic markers in, 2528–2529 causes of diagnosis of, 2544–2545, 2545f direct, 2527, 2528, 2538, 2538t indirect (systemic), 2527, 2538, 2538t treatment of, 2544–2545, 2545t clinical course of, 2558 clinical presentation of, 2538, 2540 consensus definition of, 2535–2537 definition of, 2524, 2535–2537 diagnosis of, 2540–2544 laboratory studies in, 2536, 2536t, 2542–2543 differential diagnosis of, 2540, 2541t–2542t direct toxicity and, 2528 duration of illness in, 2558 early phase, 2539, 2539f epidemiology of, 2537–2538 fluid management in, 2552–2553, 2553t hemodynamic management in, 2554, 2554t hospital days for, 2537, 2537t ICU days for, 2537, 2537t imaging in, 2673 incidence of, 2537–2538, 2537t infection and, 2527 inflammation and, 2527–2528 late phase, 2539, 2539f long-term sequelae, 2559–2560 lung-protective ventilator strategy for, 2530, 2531t, 2532, 2546–2549, 2547f adjuncts to, 2552–2557 experimental, 2557–2558 mechanisms of, 2525–2529 mediators of, 2525–2527 mortality from

causes of, 2558–2559 factors affecting, 2538 mortality rate for, 2537–2538, 2537t trends in, 2558 neutropenia and, 2528 oxygen supplementation in, failure of, 2539, 2539f pathogenesis of, pathways of, 2529, 2529f pathology of, 2525, 2526f, 2539–2540, 2539f pathophysiology of, 39, 2539–2540, 2539f and postoperative respiratory failure, 2582 prone positioning in, 2554–2555 pulmonary edema in, pathophysiology of, 2523–2525 rescue/salvage interventions for, 2551–2552, 2555–2556, 2558t resolution of, 2530–2532 risk of, factors affecting, 2538 and SIRS/MODS, 2562f, 2564 in surgery and trauma patients, 2198–2199 survivors cognitive/psychological function in, 2559–2560 health-related quality of life of, 2559 neuromuscular function in, 2559 physical impairment in, 2559 pulmonary function in, 2559 transfusion-related and respiratory failure, 2584–2585 treatment of, 2586 treatment of, 2544–2558 goals of, 2544, 2544t lung recruitment maneuvers in, 2555 Acute lupus pneumonitis, 1199, 1199f Acute lymphoblastic (lymphocytic, lymphoid) leukemia (ALL), 2139 Acute necrotizing gingivitis, 2087 Acute physiology and chronic health evaluation system. See APACHE scoring system Acute respiratory distress syndrome, 2444, 2515 in acute oxygen toxicity, 2627–2628 aerobic capacity after, assessment of, cardiopulmonary exercise testing in, 625 blastomycosis and, 2346, 2347f in bone marrow and stem cell transplant recipients, 2226 bronchoalveolar lavage cellular profile in, 1121t causes of diagnosis of, 2544–2545, 2545f direct, 2538, 2538t indirect (systemic), 2538, 2538t treatment of, 2544–2545, 2545t

I-3 Index clinical course of, 2558 clinical presentation of, 2538, 2540 complement in, 349 computed tomography of, 1115t, 2673 consensus definition of, 2535–2537 cytokines in, 336–337 definition of, 2524, 2535–2537 diagnosis of, 2540–2544 laboratory studies in, 2536, 2536t, 2542–2543 differential diagnosis of, 2014, 2540, 2541t–2542t drug-induced, 1091t, 1093 duration of illness in, 2558 epidemiology of, 2537–2538 fibroproliferative phase, 2539–2540 fluid management in, 2552–2553, 2553t hemodynamic management in, 2554, 2554t historical perspective on, 2535 hospital days for, 2537, 2537t ICU days for, 2537, 2537t imaging in, 2673 incidence of, 2537–2538, 2537t inhaled nitric oxide and, 366 long-term sequelae, 2559–2560 lung-protective ventilator strategy for, 2530, 2531t, 2532, 2546–2549, 2547f adjuncts to, 2552–2557 experimental, 2557–2558 in malaria, 2405–2406, 2406f in miliary tuberculosis, 2475 morbidity in, 2519–2520 mortality from, 2519–2520 causes of, 2558–2559 factors affecting, 2538 mortality rate for, 2537–2538, 2537t trends in, 2558 multiple organ failure in, 449–450 outcomes of, 2714–2715 oxygen supplementation in, failure of, 2539, 2539f pathogenesis of, 2523–2532 pathways of, 2529, 2529f pathology of, 2042, 2539–2540, 2539f pathophysiology of, 35, 39, 341, 2539–2540, 2539f in plague, 2431 and postoperative respiratory failure, 2582 in pregnancy, 258–259, 259t prognosis for, 2714–2715 proliferative phase, 2539–2540 prone positioning in, 2554–2555 protein nitration in, 363, 364f pulmonary edema in, radiographic features of, 478f radiation-related, 1891–1892 radiographic features of, 482 rescue/salvage interventions for, 2551–2552, 2555–2556, 2558t

risk factors for, 2582, 2582t risk of, factors affecting, 2538 scintigraphy in, 559 and SIRS/MODS, 2562f, 2564 in surgery and trauma patients, 2198–2199 survivors cognitive/psychological function in, 2559–2560 health-related quality of life of, 2559 neuromuscular function in, 2559 physical impairment in, 2559 pulmonary function in, 2559 time course of evolution, 2539, 2539f toxin exposure and, 996–997, 997f, 1000t in trauma patient, 1765–1766 treatment of, 2544–2558, 2586 goals of, 2544, 2544t lung recruitment maneuvers in, 2555 Acyclovir, indications for, 2375t, 2394 ADA. See Americans with Disabilities Act Adalimumab, pulmonary toxicity of, 440 Adaptation, 229–230 definition of, 229 inherited, 229 limitation of, 230 nonhereditary, 229 optimization of, 230 Adenocarcinoma of lung, 1832t, 1835–1838, 1836f–1837f acinar, 1836 cytopathology of, 529, 529f mixed type, 1836 papillary variant, 1836 solid variant, 1836 solid with mucin production, 1836 presenting as solitary pulmonary nodule, 1816 Adenoid cystic carcinoma, 1845, 1846f, 1925 Adenoma sebaceum, 438 Adenosine, pulmonary effects of, 1091t Adenosquamous carcinoma, of lung, 1832t, 1838 Adenovirus, 1991–1992 and acute bronchitis, 2097 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t assays for, 1989t and bronchiolitis, 896, 898f, 2382 characteristics of, 2375t and common cold, 2085, 2376t and croup, 2087, 2376t, 2379 and diffuse alveolar damage, 2042 infection (incl. pneumonia), 1987, 2019, 2020, 2025 in adults, 2389 in bone marrow and stem cell transplant recipients, 2223, 2223f, 2228

and bronchiectasis, 2186 chemokines in, 355 in children, 2391 cytopathology of, 523, 523f diagnosis of, 1999, 2001, 2002, 2106 in early infancy, 2129 in HIV-infected (AIDS) patients, 2258 radiographic findings in, 2215 in immunocompromised host, 2392 pathology of, 2043, 2045f pleural effusion in, 1494 in severe combined immunodeficiency, 2236 treatment of, 2395 molecular detection of, 2002 and pharyngitis, 2086, 2378 serotypes of, 2374 staining characteristics of, 2035t and tracheobronchitis, 2376t, 2380, 2381 vaccine against, 2073 Adjuvant, definition of, 1895 Adjuvant Navelbine International Trialist Association study, 1869t, 1870–1871 Adrenal insufficiency, in SIRS/MODS, 2570 Adrenergic agonists. See Beta-adrenergic agonists Adrenergic receptors, 2631–2632, 2632t β 2 -, persistent activation, in asthma, 117–118 Adrenocorticotropic hormone (corticotropin, ACTH), ectopic production of, 432–433, 445, 1929, 1930t, 1933–1934 in small cell lung cancer, 1904–1905, 1905t Adriamycin, plus bleomycin, pneumonitis caused by, 2011, 2012t Adult respiratory distress syndrome, surfactant in, 125, 133 Advance directive(s), 2112, 2731 AEC1. See Type I alveolar epithelial cells AEC2. See Type II alveolar epithelial cells AECB. See Bronchitis, chronic, acute exacerbations of AECC. See American European Consensus Conference AEP. See Eosinophilic pneumonia(s), acute AERD. See Aspirin-exacerbated respiratory disease Aerobes in acute mediastinitis, 2166t colonization by, of mouth and upper respiratory tract, 2154–2155, 2156f, 2274 in empyema, 2144, 2144t infection (incl. pneumonia), nosocomial, 2279–2280, 2280t, 2281t

I-4 Index Aerobic capacity, 228, 613 Aerosol, definition of, 994t AFC. See Antibody-forming cell(s) African sleeping sickness, 2409 African trypanosomiasis, 2409 AFS. See Allergic fungal sinusitis Agammaglobulinemia Bruton’s, 2139 X-linked. See X-linked agammaglobulinemia Age of ICU patient, and outcomes, 2716 and postoperative pulmonary complications, 668 and risk of venous thromboembolism, 1426 Aging, and neck motion, 2648 Aging lung, 264 airspace enlargement in, differential diagnosis of, 698–699, 698t Agitation, in ICU patient, 2701–2710 Agranulocytosis, 2138–2139 AHI. See Apne/hypopnea index AIA. See Asthma, aspirin-induced AID. See Activation-induced cytidine deaminase AIDS (acquired immune deficiency syndrome). See also Human immunodeficiency virus (HIV) bronchoalveolar lavage cellular profile in, 1121t in ICU patient outcomes with, 2716 prognosis for, 2716 immunoglobulins in, 330 pleural effusion in, 1502 pneumothorax in, 1523–1524 treatment guidelines for, 1531 AIP. See Acute interstitial pneumonia Air, distribution of, in lungs, radiographic evaluation of, 473–476 Air-blood barrier, 32–33, 51, 51f, 1342f formation of, 97f, 98–99, 99f thick parts of, 33 thin part of, 33 Air bronchogram, 2019–2020 Air-conditioner lung, 2012 Air contrast studies, 469 Air crescent sign, 2024, 2025f, 2308, 2308f Air embolism, 1424, 1443 cerebral, dysbaric, 1047 diving-related, 1045, 1046 dysbaric, 1047 iatrogenic, 1047 in pregnancy, 259t with transthoracic needle aspiration and biopsy, 647 Airflow age-related changes in, 271–272, 272f–274f inspiratory, average rate of, 2592–2593

laminar, 154, 154f, 175, 176f patterns of, 154, 154f transitional, 154, 154f turbulent, 154, 154f, 176 Airflow obstruction causes of, 729–730 in chronic obstructive pulmonary disease, 711–712, 712f, 729–730 definition of, 729 new-onset, in bone marrow and stem cell transplant recipients, 2227–2228 Airflow resistance, calculation of, 155 Air hunger, 394, 404 Air-liquid interface, physical forces at, 125–126, 149–151, 150f, 151f Air-meniscus sign, 1917 Air pollution, 1009–1035 adverse effects of, 1010 clinical concerns about, 1012 principles and concepts relevant to, 1011–1016 public health concerns about, 1012 biologically effective dose in, 1013, 1014f concentration of, 1012–1013, 1014f criteria pollutants in, 1011, 1011t dose of material in, 1013, 1014f epidemiology of, research approaches to, 1015 confounding factors in, 1015 exposure to, 1012–1013, 1014f health risks of, control of, 1033–1035 community-oriented strategies for, 1034–1035 patient-oriented strategies for, 1033–1034 historical perspective on, 1010 indoor, 1020–1032 adverse effects of, 1012, 1013t biologic agents in, 1030–1032, 1030t classification of, 1020 and clinically evident disease, 1013t complaints related to, medical approach to, 1034, 1035f contaminants in, 1020, 1021t–1023t control of, 1010–1011 and exacerbation of disease, 1013t health effects of, 1010 and increased risk for disease, 1013t mass-balance formulation for, 1020 patient education about, 1034, 1034t and perception of exposure to indoor air pollutants, 1013t and perception of unacceptable indoor air quality, 1013t and physiological impairment, 1013t sources of, 1020, 1021t–1023t and symptom responses, 1013t syndromes associated with, 1032 mixed pollutants in, research on, 1015–1016

outdoor, 1016–1020 classification of, 1016 criteria pollutants in, 1011t, 1016 exposures in, 1016–1020 hazardous pollutants in, 1020 health effects of, 1016–1020 photochemical, 1019–1020 sources of, 1016 toxic pollutants in, 1011t, 1016, 1020 research approaches to, 1013–1016 risk assessment with, 1015, 1015t risk management for, 1015 and susceptible populations, 1032–1033, 1032t time-activity patterns and, 1013 total personal exposure in, 1013, 1014f Air Quality Index, 1035 Airspace enlargement differential diagnosis of, 698–699, 698t in infancy, 699 Air trapping, in bronchiolitis, 896, 2381 Air travel atmospheric pressure changes in, and bullae, 917–918 barotrauma in, 918 in chronic obstructive pulmonary disease, 735–736 Airway(s) abnormalities, and respiratory failure, 2514–2515 acinar, 47 branching of, 26, 26f adult, 2646–2647 anatomy of, bronchoscopic assessment of, 632 assessment of rule of threes for, 861 scoring systems for, 861 biology of, 137–140 insights into, from disease states, 144 branching of, 25–26, 25f, 26f, 44, 44f, 173 caliber of, 153 central, extrinsic compression of, 856–857 complications in, in lung transplant recipient, 1789 conducting, 47 age-related changes in, 264, 264t branching of, 26, 26f development of, 108 diameters of, 45–46 in host (immune) defense, 280f, 281–282, 287t mechanical defenses of, 1969–1970, 1971f mucosa of, 279, 280f submucosal structures of, 279, 280f volume of, 46 wall structure of, 27–31, 27f, 28f development of, 92–94, 93t, 94f diameters of

I-5 Index along airway tree, 44–45, 45f bronchial pathway length and, 45–46, 46f generations of branching and, 45–46, 46f difficult, 861, 2648, 2655, 2655t dynamic compression of, 156–157, 157f emergency access to, 861 extrinsic compression of, 856–857 therapeutic bronchoscopy in, 641–642 function, bronchoscopic assessment of, 632 hyperresponsiveness and asthma, 789–790, 791f, 793 and chronic obstructive pulmonary disease, 711 molecular mechanisms of, 117–118, 117f rhinoviruses and, 775 infant, 2646–2647 lumen of, mucosal components of, 279, 280f management of, in respiratory failure, 2515–2516 nasopharyngeal, mechanical defenses of, 1969 number of, and cross-sectional area, by generation, 173, 175f obstruction endoluminal, therapeutic bronchoscopy in, 640–641 and intubation, 2649 management of, algorithm for, 641, 641f peripheral (small), function, testing of, 588–591 in pregnancy, 253–254 responsiveness, 789–790, 791f and asthma, 793 environmental exposures and, 790, 791f viral infection and, 816 rupture, in trauma patient, 1760–1761 secretions, in immune defense, 1970 securing, 861 stents for, 862 in trauma patient, initial management of, 1757–1758 upper. See Upper airway Airway conductance, 584, 584f definition of, 1327, 2739 normal, 1323, 2735 Airway disease cardiopulmonary exercise testing in, 625 drug-induced, 1091t, 1093 occupational, 934, 934t, 981 in rheumatoid arthritis, 1203–1204, 1203f, 1204f in Sj¨ogren’s syndrome, 1210

Airway occlusion pressure(s), responses to hypoxia and hypercapnia, age-related changes in, 269, 269f Airway pressure, assessment of, in acute respiratory failure, 2670–2671, 2670f Airway pressure release ventilation, in ALI/ARDS, 2551 Airway reactivity, 585–588 Airway resistance, 153–155, 583–585, 584f, 585t, 2670, 2670f, 2671 age-related changes in, 272–273 airway diameter and, 45, 45f airway size and, 49 calculation of, 155 in chronic obstructive pulmonary disease, 711 definition of, 1327, 2739 on downstream side, definition of, 1327, 2739 knowledge of, historical perspective on, 12 normal, 1323, 2735 on upstream side, definition of, 1327, 2739 Airway smooth muscle (ASM) anti-inflammatory therapy and, 122–123 in asthma, 116, 118–121, 119f calcium signaling in, 116, 117f cell cycle in, regulation of, signal transduction pathways in, in vitro, 119–120, 120f chemokine release by, 121, 122t cytokine-induced synthetic responses, 122 [cAMP]i mobilizing agents and, 123 cytokine release by, 121, 122t and extracellular matrix, 123 hyperplasia, 118–121, 119f hyperresponsiveness, molecular mechanisms of, 117–118, 117f hypertrophy of, 118–121, 119f immunomodulatory proteins expressed by, 121–122, 122t in lung disease, 115–116, 116f proliferation, in vitro inhibition of, 120–121 mediators of, 118–119 Airway surface liquid, 281 antibacterial activity in, 143 composition of, 140 modification of, 137 production of, 137 regulation, 140 in cystic fibrosis, 2174–2175, 2174f in normal airway, 2174–2175 Airway tree airflow velocity in, 48–49, 48f design of, 44–49, 44f functional zones of, 47

Albendazole for ascariasis, 2418, 2418t for echinococcosis, 2418t for hookworms, 2418, 2418t for Pneumocystis pneumonia, 2370 for strongyloidiasis, 2418t Albumin, serum, in nutritional assessment, 2694 Albuterol adverse effects and side effects of, 824t for asthma, 822, 823t, 824t for chronic obstructive pulmonary disease, 738t, 739 dosage and administration of, 824t dosage forms, 2632t for exercise-induced asthma, 812 receptor activity, 2632t structure-activity relationships, 2632–2633 sustained-release adverse effects and side effects of, 827t for asthma, 823t, 827t dosage and administration of, 827t for ventilated patient, 2685, 2685f Alcoholism, and pneumonia, 2100t Alcohols, in indoor air, sources of, 1023t Aldehydes in indoor air, sources of, 1023t in smoke and inhalation injury, 1054, 1057 ALI. See Acute lung injury Aliphatic hydrocarbons exposure to, 1027t sources of, 1027t Alkalosis, and pulmonary vasomotor control, 1346 Alkanes, in indoor air, sources of, 1023t Alkylating agents mechanism of action of, 1073 pneumonitis caused by, 2011, 2012t pulmonary effects of, 1073–1076, 1074t, 1181 Allergen(s), and risk of asthma, 794, 815 Allergic angiitis and granulomatosis, 2013. See also Churg-Strauss syndrome Allergic bronchopulmonary aspergillosis (ABPA), 837–843, 1222–1223, 1999, 2013, 2291, 2292t, 2294, 2295t acute, 839, 840t and aspergilloma, 841f, 843, 2301 and bronchiectasis, 840f–841f, 841–842, 2185t, 2187, 2190, 2296, 2298f, 2299f, 2301 bronchoalveolar lavage cellular profile in, 1121t clinical features of, 838, 1222, 1223t, 1231t, 2296 clinical staging of, 839–841, 840f–841f, 840t

I-6 Index Allergic bronchopulmonary aspergillosis (ABPA) (Cont.) complications of, 843 in cystic fibrosis, 839, 880, 2176–2177, 2294–2296, 2297, 2300 diagnosis of, 729–730, 1222–1223, 2296–2298, 2299t guidelines for, 838–839 diagnostic criteria for, 838, 839t, 1222, 1222t differential diagnosis of, 839, 1231t epidemiology of, 837 exacerbations, 840, 840t genetics of, 837–838 histopathology of, 842, 2298–2299 historical perspective on, 837 immunopathogenesis of, 838, 2295–2296 mucus plug in, 839, 839t, 2296, 2296f, 2297f pathogenesis of, 837–838 post-transplant recurrence of, 843 prognosis for, 843 pulmonary fibrosis in, 840t, 841, 841f radiographic findings in, 840f–841f, 841–842, 1222, 1224f, 2296, 2298f, 2299f recurrent, 839–840, 840f–841f, 840t remission, 839, 840t risk factors for, 2295–2296 staging, 839–840, 1222, 1223t, 2299, 2300t steroid-dependent asthma in, 840–841, 840t therapeutic bronchoscopy for, 643 treatment of, 842–843, 1223, 2299–2300 advances in (future directions for), 2300 monitoring of, 2300 Allergic bronchopulmonary candidiasis, 2315 Allergic bronchopulmonary mycosis, 837–843, 1222 microbiology of, 837 Allergic fungal sinusitis, 2090–2091 Allergic lung disease, radiographic features of, 483 Allergic rhinitis, 1031 Allergy and asthma, 793 and chronic obstructive pulmonary disease, 711 clinical markers of, 792 definition of, 792 pathophysiology of, 792 TH1-TH2 paradigm of, 792–793, 792f Allergy(ies), 330 IgE-mediated, in IgA deficiency, 332 testing for, 819 Allopurinol pulmonary effects of, 1242 and vasculitis, 1464

All-trans retinoic acid pulmonary effects of, 1081–1082, 1081t, 1294–1295 and vasculitis, 1464 Almitrine, 2643 Alphastat regulation, 214 Alternaria in allergic fungal sinusitis, 2091 hypersensitivity pneumonitis caused by, 1163t in indoor air, 1031 infection (incl. pneumonia), in cancer patients, 2217 staining characteristics of, 2035t Altitude adaptation to, 229–230 and alveolar PO2 , 595t and arterial PO2 , 594–595, 595t for flying, and chronic obstructive pulmonary disease, 735–736 high clinical disorders of, 1040–1043 physiological effects of, 1039–1040 and pulmonary arterial pressure, 1345, 1346f and pulmonary circulation, 1344–1345, 1346f and pulmonary vascular remodeling, 1344–1345 and pulmonary vascular resistance, 1335 and respiration, 1345, 1346f ventilatory adaptations to, 167 Aluminum, occupational lung disease caused by, 935t Aluminum oxide, bronchiolitis caused by, 893t, 895–896 Alveolar-arterial oxygen tension gradient, age-related changes in, 273, 274f Alveolar-capillary membrane diffusion across, measurement of, 196–197 gas exchange across, 192 permeability, scintigraphic assessment of, 558–559 Alveolar cell carcinoma, radiographic features of, 477f, 478, 482, 482f Alveolar disease diffuse, radiographic features of, 477f, 478f, 482–483, 482f, 489f localized, radiographic features of, 477–482, 477f–488f Alveolar duct(s), 26, 26f, 47, 47f, 51, 51f, 53, 175, 695 age-related changes in, 264 Alveolar edema, 1234t Alveolar entrance ring, 41f, 51f, 53 Alveolar filling disease, radiographic features of, 477, 477f–478f Alveolar gas composition, 592 normal values, 1324, 2736

Alveolar hemorrhage syndromes, 1234t, 1237–1242, 1281–1297. See also Diffuse alveolar hemorrhage antiphospholipid antibody and, 1241 collagen vascular disease and, 1241 immune complexes and, 1241 Alveolar hypoventilation and arterial hypoxemia, 2616–2617, 2616t cyanosis in, 415 drug-induced, 1091t generalized, 424 net, 424 oxygen therapy for, 2619 pulmonary hypertension in, 1395, 1396f, 1397f syndromes of, 424 Alveolar microlithiasis, 1234t, 1237, 1238f Alveolar oxygen pressure, age and, 273 Alveolar pressure, 150, 575, 575f during breathing cycle, 148, 148f measurement of, historical perspective on, 12 Alveolar proteinosis, 1234t in cancer patient, 2221 Alveolar sac(s), 26, 26f, 44, 175, 695 Alveolar septa (sing., septum), 41f, 51–52, 51f, 52f fiber system of, 52–53, 52f micromechanics of, 56–57, 56f, 57f Alveolar ventilation normal, 1323, 2735 normal values, 1324, 2736 Alveolar vessels, 1349, 1349f Alveolar volume, and diffusing capacity, 198 Alveoli (sing., alveolus), 47, 47f, 174f, 175.

See also Diffuse alveolar damage abnormalities of, and respiratory failure, 2515 age-related changes in, 264 cells of, 32–41 collateral channels between, 151 defense functions of, structural correlates, 41 formation of, 88 in host (immune) defense, 282–284, 285f, 287t interdependence of, 151 mechanics of, 149–151, 150f, 151f and stabilization of lung structure, 54 number of, 51 in restrictive lung disease, 423–424 Alveolitis, fibrosing, 491f Amantadine, for influenza, 2387–2388, 2387t AMB-D, 2299 for candidiasis, 2315–2316 for fusariosis, 2322 for invasive fungal infections, 2309–2311, 2310t, 2311t, 2312 lipid formulations of

I-7 Index for invasive fungal infections, 2310–2311, 2310t, 2311t, 2312 for zygomycosis, 2320 prophylaxis, 2313 for zygomycosis, 2320 Ambient temperature and pressure, saturated with water, 574, 574t Ambulation, postoperative, early, 673t, 674 Amebiasis, 2397–2401 clinical manifestations of, 2398 diagnosis of, 2400 hemoptysis in, 414 intestinal, 2398 pathology of, 2043t, 2049 pericardial disease, 2400, 2400f pleural effusion in, 1494–1495 pleuropulmonary, 2398–2400, 2398f–2399f treatment of, 2400–2401 Ameboma, 2398 American Conference of Governmental Industrial Hygienists, 941 American European Consensus Conference criteria for acute lung injury, 2535–2537, 2536t criteria for acute respiratory distress syndrome, 2535–2537, 2536t American Medical Association (AMA), guidelines for evaluation of permanent impairment, 681–682, 682t in asthma, 682–683, 683t in berylliosis, 684 in hypersensitivity pneumonitis, 684 in lung cancer, 684 in obstructive sleep apnea, 684 in pneumoconiosis, 684 American Society of Anesthesiologists, clinical classification of health status, 668, 668t Americans with Disabilities Act (ADA), 689–690 American Thoracic Society criteria for evaluation of impairment/disability, 684–685 definition of chronic obstructive pulmonary disease, 707 Shortness of Breath Scale, 397, 398t American Thoracic Society/Division of Lung Diseases, Respiratory Symptoms Questionnaire, 679, 679t American trypanosomiasis, 2407–2409 Amikacin, 2058 adverse effects and side effects of, 2483t, 2503 for hospital-acquired pneumonia, 2061 interactions with immunosuppressive agents, 2503t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t

resistance to, mycobacterial, 2505 for tuberculosis, 2479 dosage and administration of, 2482t Amino acid metabolism, disorders of, 1276 Aminoglycosides aerosolized, 2059, 2061t dosage and administration of, 2054, 2058 for hospital-acquired pneumonia, 2061 interactions with immunosuppressive agents, 2503t mechanism of action of, 2058 nebulized, 2058 organisms susceptible to, 2058 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 pulmonary effects of, 1091t for yersiniosis, 2441 Aminopenicillins, 2056 Aminophylline as respiratory stimulant, 2643 structure-activity relationships, 2636 Aminoquinolines, for Pneumocystis pneumonia, 2370 Aminorex pharmacology of, 1370 pulmonary effects of, 1093, 1347 and pulmonary hypertension, 447, 1382–1383 Amiodarone adverse effects and side effects of, 1094 bronchiolitis associated with, 905–906 and interstitial lung disease, 1110t pneumonitis caused by, 2010, 2012t pulmonary toxicity of, 1088, 1089, 1090t, 1091t, 1093, 1094–1096 clinical presentation of, 1095 diagnostic evaluation for, 1095–1096 laboratory findings in, 1095 radiographic findings in, 1095 risk factors for, 1094–1095 treatment of, 1095–1096 and respiratory failure, 2584 Ammonia bronchiolitis caused by, 893t, 894 inhalation injury caused by, 998, 1000t renal recycling of, 210–211, 210f in smoke and inhalation injury, 1057 source of, 1054t water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995t Ammonium, 210 Amniotic fluid embolism, 259t, 1424, 1444 Amoxicillin, 2056 dosage and administration of, for pneumonia in children, 2131 resistance to, 2131

Amoxicillin/clavulanate, 2056 indications for, 2060, 2157 for melioidosis, 2440 for Moraxella catarrhalis infection, 2445 Amphiregulin, 312 Amphotericin B for acanthamoebiasis, 2401 for blastomycosis, 2348 for coccidioidomycosis, 2345 for cryptococcosis, 2333–2334, 2333t for histoplasmosis, 2340 for leishmaniasis, 2409 pneumonitis caused by, 2012t pulmonary effects of, 1088–1089, 1089, 1090t, 1091t Amphotericin B deoxycholate. See AMB-D Ampicillin, 2056 indications for, 2060 for pasteurellosis, 2429t, 2430 for yersiniosis, 2429t, 2441 Ampicillin/sulbactam, 2056 for hospital-acquired pneumonia, 2061t, 2062 indications for, 2131, 2157 for staphylococcal pneumonia, in children, 2132 Amyl nitrite, for cyanide poisoning, 1057 Amyloid, 1233–1234, 1235f Amyloid light chain, systemic, 1234 Amyloidoma, 1234–1235, 1235f Amyloidosis, 1233–1236, 1234t AA, 1234 computed tomography of, 1115t definition of, 1233 diagnosis of, 1236 diffuse interstitial, 1234, 1235f, 1236 nodular parenchymal, 1234–1235, 1235f, 1951–1952, 1951f presenting as solitary pulmonary nodule, 1817 primary, 1234 pulmonary, 1234–1236, 1235f upper airway obstruction in, 855 sarcoidosis and, 1136t secondary, 1234 senile, 1234 tracheobronchial, 1234, 1236 Amyotrophic lateral sclerosis (ALS), 1668 ventilatory impairment in, 1651–1652 Anaerobes in acute mediastinitis, 2166t acute sinusitis caused by, 2089 in aspiration pneumonia, 2141–2143, 2143t colonization by in children, 2136 of mouth and upper respiratory tract, 2154–2155, 2156f culture of, 2153–2154 and dental hygiene, 2060 in empyema, 2141–2143, 2143t, 2144t

I-8 Index Anaerobes (Cont.) infection (incl. pneumonia), 2099, 2143, 2143t, 2148f bacteriology of, 2153–2154, 2156, 2156t and bronchiectasis, 2189t clinical features of, 2149t conditions underlying, 2145t historical perspective on, 2142–2143 history and physical findings in, 2101t hospitalization rate for, 2105t laboratory diagnosis of, 2153–2154 nosocomial, 2280t, 2281t treatment of, 2285–2288, 2286t prevention of, 2156–2157 radiologic diagnosis of, 2153 treatment of, 2157, 2157t in lung abscess, 2141–2143, 2143t, 2154t in oral cavity, 2086–2087 staining characteristics of, 2153 Anaerobic threshold, 226, 613 in classification of cardiac and circulatory failure, 614–615, 615t determination of, 615 Analgesia for agitated ICU patient, 2706–2708 agent for, selection of, 2707 indications for, 2706–2707 strategies for, 2708–2710 epidural, and postoperative somnolence, 1747 postoperative, 673t, 674 effects on pulmonary function, 2577 inadequate, and risk of pulmonary complications, 670 Anatomy alterations of infections associated with, 1983t, 2210t types of, 1983t, 2210t pathologic, knowledge of, historical perspective on, 5t, 13–14 Ancylostoma, and eosinophilic pneumonia, 1214t, 1215–1216 Ancylostoma brasiliensis, and eosinophilic pneumonia, 1215–1216 Ancylostoma duodenale, 2013, 2414t, 2415, 2416 Anemia in chronic obstructive pulmonary disease, treatment of, 737 dyspnea in, 402–403 physiological, of pregnancy, 256 Anergy, 2043t detection of, 2002 Anesthesia for bronchoscopy, complications of, 643–644

duration of, and postoperative pulmonary complications, 669 effects on pulmonary function, 2576–2577 general, effects on pulmonary function, 2576–2577 neuraxial, effects on pulmonary function, 2577 type of, and postoperative pulmonary complications, 669 Anesthetics, inhalational, for agitated ICU patient, 2705–2706 Aneurysm, Rasmussen’s, 2470 Angioedema causes of, 860 management of, 860 upper airway obstruction in, 860 Angiogenesis, in idiopathic pulmonary fibrosis, 1154–1155 Angiography in bullous disease, 921, 924f CT. See Computed tomographic angiography pulmonary, 459f, 466, 468f arterial anatomy on, 471f of pulmonary embolism, 1436, 1436f therapeutic, 466 venous anatomy on, 471f Angiosarcoma, pleural, 1550–1551 Angiostasis, in idiopathic pulmonary fibrosis, 1154–1155 Angiotensin-converting enzyme (ACE), in Pneumocystis pneumonia, 2361 Angiotensin-converting enzyme (ACE) inhibitors and chronic cough, 410 and interstitial lung disease, 1110t pulmonary toxicity of, 1090t, 1091t, 1096 Angiotensin II, and pulmonary circulation, 1347 Anhydrides and occupational asthma, 985t, 986, 989 occupational lung disease caused by, 934t, 935t Animal allergens lung disease caused by, 934, 934t and occupational asthma, 985t, 986 Animal handlers’ asthma, 988 Anion exchanger 1, 204 Anion gap, 214, 216, 219 plasma, 216 urine, 216–217 Anisakiasis, 2421 ANITA. See Adjuvant Navelbine International Trialist Association study Ankylosing spondylitis. See also Collagen vascular disease clinical features of, 1117t, 1211, 1625 computed tomography of, 1115t, 1117t epidemiology of, 1625

etiology of, 1625 exercise capacity in, 1626 gas exchange in, 1626 histology of, 1117t and neck motion, 2647–2648 pleuropulmonary abnormalities in, 1626–1627 pulmonary complications of, 1194, 1194t, 1211, 1211f pulmonary function testing in, 1620t, 1625–1626 respiratory mechanics in, 1619t, 1625–1626 rib cage in, 1625–1626, 1626f treatment of, 1117t, 1627 Anlage, lung, 92, 94f–95f Anomalous pulmonary venous return, magnetic resonance imaging of, 465f, 466 Anorexia, in pulmonary disease, 452–453 Anorexigens pharmacology of, 1370 and pulmonary circulation, 1347 pulmonary effects of, 1091t, 1093–1094 and pulmonary hypertension, 447, 1093–1094, 1382–1383 Antacid(s), and nosocomial pneumonia, 2277–2278 Anthrax, 2006, 2271, 2435–2437. See also Bacillus anthracis and acute mediastinitis, 2166t as bioweapon, 2428, 2435–2436 clinical features of, 2436 cutaneous, 2435 diagnosis of, 2429t epidemiology of, 1984t, 2428t, 2436 historical perspective on, 2435 inhalation, 2271, 2428t, 2435 diagnosis of, 2437 differential diagnosis of, 2437 epidemiology of, 2436 pathogenesis of, 2436 pathophysiology of, 2436 radiologic features of, 2436–2437 Koch’s work on, 15 mail-room epidemic of, 2435–2437 pathogenesis of, 2040, 2080 prevention of, 2437 radiologic features of, 2436–2437 transmission of, 2436 treatment of, 2429t, 2437 Anthrax mediastinitis, 1563 Antiarrhythmics, pneumonitis caused by, 2010, 2012t Antibiotics active transport of, 2053 for acute exacerbations of chronic obstructive pulmonary disease, 742t, 2118f, 2118t, 2119t, 2120–2121, 2120t, 2121t for acute mediastinitis, 2164t, 2168–2169

I-9 Index adequate therapy with, 2051 adverse effects and side effects of in bone marrow transplant recipient, 2367 in HIV-infected (AIDS) patients, 2367 in organ transplant recipient, 2367 aerosolized, 2058–2059 for cystic fibrosis patient, 875–876, 2178–2179 for anaerobic infections, 2157, 2157t anti-pseudomonal, for cystic fibrosis patient, 875–876, 883–884, 2178–2179 anti-staphylococcal, for cystic fibrosis patient, 875–876, 2178 appropriate therapy with, 2051 bactericidal, 2052, 2054 concentration-dependent killing by, 2054 time-dependent killing by, 2054 bacteriostatic, 2052 combination therapy with, 2108 for community-acquired pneumonia, 2060–2061 for hospital-acquired pneumonia, 2061–2062, 2061t for community-acquired pneumonia, 2108–2110, 2109t for cystic fibrosis patient, 875–876, 2178–2179 cytotoxic, pulmonary effects of, 1069–1073, 1070t empiric therapy with, 2051–2052 in cancer patient, 2220, 2221–2222 for community-acquired pneumonia, 2108, 2109t for febrile cancer patient, 2220 for febrile neutropenic patient, 2220 focused therapy with, 2051 for hospital-acquired pneumonia, 2061–2062, 2061t hydrophilic, 2053 for immunocompromised host, difficulties of, 2204 inactivation of, 2053 initial therapy with, 2051 lipophilic, 2053 MBC of, 2052 mechanism of action of, 2052 MIC of, 2052, 2054 mutant prevention concentration of, 2052 for neonatal nosocomial pneumonia, 2126–2127 penetration into lung, 2053, 2053t inflammation-dependent, 2053, 2053t pharmacodynamics of, 2054–2055 pharmacokinetics of, 2054–2055 for pneumonia, in surgery and trauma patients, 2199–2200

prophylactic, for immunocompromised host, 2208 pulmonary effects of, 1089 resistance to, 2052, 2065 and infection in neutropenic host and cancer patient, 2217 and risk of infection in immunocompromised host, 2207 selective decontamination of digestive tract, in prevention of nosocomial pneumonia, 2289 sensitivity to, 2052 for staphylococcal pneumonia, in children, 2132 use of, principles of, 2052–2055 volume of distribution of, 2053 Antibody(ies), 1978–1979 defects of immunologic work-up of, 2234t pulmonary infection in, 2233–2236 Antibody(ies) (Ab) definition of, 321–322 pulmonary, antigen-specific, 328–329 Antibody-dependent cell-mediated cytotoxicity (ADCC), 1978 Antibody-forming cell(s), 329 Anticholinergics, 2635–2636 adverse effects and side effects of, 826t, 2635, 2636 for asthma, 822, 823t, 826t, 2635–2636 for chronic obstructive pulmonary disease, 737–738, 738t, 739, 2635–2636 for exercise-induced asthma, 811t, 812 long-acting adverse effects and side effects of, 829t for asthma, 829t mechanism of action of, 829t mechanism of action of, 826t pharmacology of, 2635 Anticoagulant(s) and diffuse alveolar hemorrhage, 1295 for idiopathic pulmonary fibrosis, 1158 and interstitial lung disease, 1110t for pulmonary arterial hypertension, 1391 for pulmonary embolism, 1438 duration of therapy with, 1441 in long-term management, 1440–1441 Anticonvulsant(s) pneumonitis caused by, 2010, 2012t pulmonary effects of, 1089, 1092, 1097 Antifungal agent(s) for allergic bronchopulmonary aspergillosis, 842–843, 2299 for blastomycosis, 2348 for coccidioidomycosis, 2345 combination therapy with, for invasive fungal infections, 2312

for cryptococcosis, 2333–2334, 2333t for histoplasmosis, 2340 intracavitary instillation, for aspergilloma, 2303 intracavitary instillation of, for aspergilloma, 536–538 for invasive fungal infections, 2309–2312, 2310t, 2311t prophylaxis with, 2312–2313 therapy with, for zygomycosis, 2320 Antigen(s) asthmatic response to, 774, 774f lymphocyte recognition of, 1974 Antigen inhalation challenge testing, 587 Antigen-presenting cell(s) (APC), 323, 1974, 1975f in allergy, 792, 792f Anti-inflammatory agents, 2637–2641.

See also Corticosteroid(s); Nonsteroidal anti-inflammatory drugs (NSAIDs) for bronchiectasis, 2191 for cystic fibrosis patient, 876–877, 2179 for sarcoidosis, 1140, 1140t Antimetabolites pneumonitis caused by, 2012, 2012t pulmonary effects of, 1076–1078, 1076t Antimicrobial therapy for nosocomial pneumonia, 2009 pneumonitis caused by, 2010, 2011–2012, 2012t pulmonary effects of, 1099–1100 Antineutrophil cytoplasmic antibody (ANCA) characteristics of, 1291–1292, 1291f cytoplasmic (c-ANCA), 1291, 1291f perinuclear (p-ANCA), 1291, 1291f pulmonary renal syndromes associated with, 1288–1290 clinical features of, 1290–1291 pulmonary vasculitis associated with, 1241, 1283, 1288–1290 and vasculitis, 1449–1450, 1450f, 1450t, 1451–1461, 1451f Antinuclear antibody(ies), in coal worker’s pneumoconiosis, 972–973 Antioxidants cellular, 2626 and chronic obstructive pulmonary disease, 716–717, 716f Antiphospholipid antibody and alveolar hemorrhage, 1241 in systemic lupus erythematosus, 1241 Antiphospholipid antibody syndrome, 1463 alveolar hemorrhage in, 1293 Antiphospholipid syndrome, and alveolar hemorrhage, 1241 Antiprotease(s), 1970 in chronic obstructive pulmonary disease, 715–716

I-10 Index Antiretroviral therapy and drug-drug interactions, 2261 for HIV-infected (AIDS) patients, 2244–2245 and tuberculosis treatment, 2482t, 2490 Anti-rheumatic agents, pneumonitis caused by, 2010, 2012t Antithrombin III deficiency, risk of venous thromboembolism in, 1426–1427 α 1 -Antitrypsin, 1970 allelic variants of, 723 deficiency of, 723–726 and chronic obstructive pulmonary disease, 708, 710, 716, 717, 724–725, 731 clinical features of, 723–724 conditions associated with, 731, 732t cutaneous manifestations of, 437 liver disease in, 725–726 lung disease in, 724–725, 725f phenotyping of, 723, 724f genetics of, 723 in lung parenchyma, 721t and neutrophil elastase, 720 nomenclature for, 723 physiological functions of, 723 polymers of, 723, 724f properties of, 723 replacement therapy with, 734, 2642 adverse effects and side effects of, 2642 serum level of, immunoassay for, 723 Antiviral agent(s), 2394–2395 for influenza, 2387–2388, 2387t prophylactic, for influenza, 2388 Anxiety, and chest pain, 420 AOM. See Otitis media, acute Aortic aneurysm, 857 computed tomography of, 466, 470f CT angiography of, 463, 470f hemoptysis from, 414 radiographic evaluation of, 466, 469f radiographic features of, 498, 499f–500f, 503f Aortic arch double, respiratory symptoms caused by, 857 right-sided, respiratory symptoms caused by, 857 Aortic dissection CT angiography of, 462, 503f pain of, 420 radiographic features of, 498, 500f, 503f Aortic ulcer(s), CT angiography of, 463 Aortic valve, disease, cardiopulmonary exercise testing in, 621–622, 621f, 622f Aortography, 466–469

Aortopulmonary window, 1861, 1861f lymph nodes, sampling, VATS technique, 657, 657f visualization of, VATS technique, 657, 657f APACHE scoring system, 2717–2718 Aplastic anemia, and risk of infection, 2306 Apnea, recurrent, pathophysiology of, 170 Apnea/hypopnea index, 1698 Apneustic center, 12 Apophysomyces, infection (incl. pneumonia), epidemiology of, 2317 Apophysomyces elegans, 2316t, 2317 Apoptosis in chronic obstructive pulmonary disease, 716, 717 epithelial cell, 377 and idiopathic pulmonary fibrosis, 1153–1154 APRV. See Airway pressure release ventilation Arachidonic acid metabolism, 350, 350f, 803–804, 803f, 2640 pathways, 1340–1341, 1341f metabolites mast cells and, 310t, 311–312 and pulmonary vasomotor control, 1340–1341, 1341f Arachidonic acid metabolites, 778, 782f Arcanobacterium hemolyticum, pharyngitis caused by, 2086 ARDS. See Acute respiratory distress syndrome; Adult respiratory distress syndrome ARDSNet. See also Fluid and Catheter Treatment Trial ALVEOLI trial, 2548, 2552 ARMA trial, 2546–2548, 2548t, 2550f, 2551f, 2552 Late Steroid Rescue Study, 2555t, 2556, 2557t, 2558 ventilator strategies, 2546–2547, 2548t Area under the curve, 2054 Area under the inhibition curve, 2054 Argatroban, for pulmonary embolism, 1439 Arginine vasopressin (AVP), ectopic production of, 1929, 1930t, 1932–1933 Aristotle, 4, 5t Aromatic hydrocarbons exposure to, 1027t in indoor air, sources of, 1021t, 1023t sources of, 1027t Arrhythmia(s) with cor pulmonale, 1377

in respiratory failure, 2518t, 2519 sleep apnea and, 1712–1713 supraventricular, in chronic obstructive pulmonary disease, 743 Artemisinin derivatives, 2407 Arterial blood oxygen content of, 2614–2615 sampling, technique for, 594 Arterial blood gases abnormalities of, severity of, Social Security Listings for, 686, 687t analysis in acute respiratory failure, 2669 in ALI/ARDS, 2536, 2536t, 2542–2543 in dyspnea, 404–405 in evaluation of impairment/disability, 681 in HIV-infected (AIDS) patients, 2249 in neuromuscular disease, 1642–1643 preoperative, 670 for lung resection, 671 in respiratory failure, 2515, 2516t in asthma, 818 composition of, 594–596 interpretation of, 594–596 temperature and, 594, 595t time and, 594, 595t normal values, 1324, 2736 Arterial carbon dioxide tension, in chronic obstructive pulmonary disease, 712 Arterial gas embolism dysbaric, 1047 hyperbaric oxygen therapy for, 1050–1051, 1050f iatrogenic, 1047 Arterial oxygen content, calculation of, 612t Arterial oxygen tension, in chronic obstructive pulmonary disease, 712 Arterial PCO2 (PaCO2 ), 207, 595–596, 595t Arterial pH, 207, 595–596, 595t ventilatory adaptations to, 167 Arterial PO2 (PaO2 ), 594–595, 595t age-related changes in, 273, 274f Arterial venous CO2 removal, 2556 Arteriography bronchial, 466 systemic, 466–469 Arteriole(s), pulmonary, 32 Arteriovenous fistula hemoptysis from, 414 pulmonary, congenital, 1356–1357, 1357f Arteriovenous malformation hepatic, 1477 pulmonary. See Pulmonary arteriovenous malformation(s)

I-11 Index Arteriovenous oxygen difference calculation of, 612t in exercise, 224 Artery(ies), pulmonary, development of, 94f, 97, 100, 108–110 Artesunate, 2407 Arthralgia, in histoplasmosis, 2337 Arthritis in histoplasmosis, 2337 psoriatic, drug treatment of, pulmonary toxicity of, 440 Arthropods, in indoor air, sources of, 1022t Arylsulfatase(s), 1272–1273 mast cell, 310t, 311 Arylsulfatase A, 1272–1273 Arylsulfatase B, 1272 eosinophil, 314 Arylsulfatase C, 1272 Asbestos, 1010. See also Benign asbestos pleural effusions airborne, 1020 exposure to, 944 levels of, 1029 bronchiolitis caused by, 893t, 895–896 control, 943–944, 957 exposure to, 1029–1030 bystander, 944 and estimated lifetime cancer risks, 1029, 1029t indirect, 944 occupational, 944 pleural effusion caused by, 1498–1499 reduction/limitation of, 957 types of, 944 fiber types, 943 health effects of, 1029–1030, 1029t in indoor air, sources of, 1021t lung disease caused by, 934, 934t, 935t, 943–957. See also Asbestosis nonmalignant, 944–948 physical characteristics of, 943 production of, worldwide, 943–944 in schools, 1010–1011 substitutes for, 1028–1029 use of, historical perspective on, 943–944, 1028 Asbestos bodies, 951–952, 952f Asbestos Hazard Emergency Reduction Act, 1010–1011 Asbestosis, 402f bronchoalveolar lavage in, 949, 952 cellular profile in, 1121t carcinogenesis induced by, mechanisms of, 953–954 chest radiographs in, 938–939, 938f clinical features of, 949–950 computed tomography of, 1115t cytopathology of, 516, 517f diagnosis of, 951–952 epidemiology of, 949

exposures associated with, 1109t gallium-67 citrate imaging in, 949 long-term surveillance for, 950 natural history of, 949 onset of, 422 pathogenesis of, 948–949 pathology of, 948, 948f, 1396f pathophysiology of, 949–950 prognosis for, 952 pulmonary function testing in, 950 radiographic features of, 483, 484–485, 950–951, 951f smoking and, 949 treatment of, 952 Ascariasis, 2414t, 2415–2418 presenting as solitary pulmonary nodule, 1817 treatment of, 2418, 2418t Ascaris and eosinophilic pneumonia, 1214–1215, 1214t infection, 1092 infestation, pathology of, 2045 Ascaris lumbricoides, 1995, 2013, 2414t, 2415–2417, 2416f, 2418t and Loeffler syndrome, 1214–1215 Ascites, in bone marrow and stem cell transplant recipients, 2225 Ash leaf macules, 438 ASL. See Airway surface liquid ASM. See Airway smooth muscle L-Asparaginase, immunologic effects of, 2216 Aspergilloma, 1991, 1994–1995, 2291, 2292t allergic bronchopulmonary aspergillosis and, 841f, 843, 2301 antifungal agents for, intracavitary instillation of, 536–538 clinical features of, 2301–2302 diagnosis of, 2000, 2301–2303 differential diagnosis of, 2303 pathogenesis of, 2301 pathophysiology of, 2301 prognosis for, 2303 radiographic findings with, 2301–2303, 2302f sarcoidosis complicated by, and postoperative pulmonary complications, 667 sinus, 2090–2091 treatment of, 2303 Aspergillosis, 2022. See also Aspergillus; Aspergillus fumigatus allergic bronchopulmonary. See Allergic bronchopulmonary aspergillosis angioinvasive, 2292t imaging of, 2024, 2024f, 2025f bronchial stump, 2292t, 2304 chronic, 2292t, 2293, 2304–2305

cavitary, 2304–2305 fibrotic, 2304–2305 necrotizing, 2292t, 2301, 2304 in chronic granulomatous disease, 2292, 2292t clinical manifestations of, 2294–2313 computed tomography of, 482f in cystic fibrosis, 880 cytopathology of, 519, 519f differential diagnosis of, 2323t in hematopoietic stem cell transplant recipient, 2292, 2292t hemoptysis in, 410, 412f, 413 in HIV-infected (AIDS) patients, 2256–2257, 2292, 2292t radiographic findings in, 2214t immune response to, 2293–2294 in immunocompromised host, 1997, 2292, 2292t invasive, 2291–2292. See also Invasive pulmonary aspergillosis diagnosis of, 2000 differential diagnosis of, 2323t invasive bronchial, 2292t, 2304 pseudomembranous, 2292t, 2304 ulcerative, 2292t, 2304 in leukemia, 2292, 2292t mycology of, 2292–2293 in neutropenic patient, 2292, 2292t nonangioinvasive, 2292t pulmonary, 2291–2313 chronic, 2292t, 2293, 2304–2305 cavitary, 2304–2305 fibrotic, 2304–2305 necrotizing, 2292t, 2301, 2304 epidemiology of, 2291–2292 invasive. See Invasive pulmonary aspergillosis spectrum of, 2291–2292, 2292t pulmonary alveolar proteinosis complicated by, 2014 Aspergillus, 1986, 1991, 1996, 2291 in allergic fungal sinusitis, 2091 colonization by, 2294 diagnosis of, 2000 in empyema, 2144 fungus ball, 2049, 2293 in hospital environment, 2274–2275 hypersensitivity pneumonitis caused by, 1163t identification of, in tissue, 2035, 2038t, 2293 in indoor air, 1031 infection (incl. pneumonia), 1092, 2022, 2024. See also Aspergillosis in bone marrow and stem cell transplant recipients, 2222, 2229 in cancer patients, 2221 cavitation in, 2146 in cell-mediated immunodeficiency, 2236 in Chediak-Higashi syndrome, 2238

I-12 Index Aspergillus, infection (Cont.) in children, immune defects and, 2138 diagnosis of, 1999 differential diagnosis of, 2322 in HIV-infected (AIDS) patients, 2212t, 2245 radiographic findings in, 2215, 2249t hospitalization rate for, 2105t immune defect associated with, 1983t, 2210t in immunocompromised host, 2209 in leukocyte adhesion deficiency, 2239 in neutropenic host and cancer patient, 2217 nosocomial, 2280t, 2281t in organ transplant recipient, 2230, 2231f pathology of, 2045, 2050, 2050f pleural effusion in, 1494 in tuberculosis, 2470 in invasive fungal sinusitis, 2091 in invasive (malignant) otitis externa, 2092 in lung abscess, 2154t molecular detection of, 2002 pathogenicity of, 838 sputum culture for, 2000 staining characteristics of, 2035t, 2038f, 2049f, 2293 virulence factors, 2294 Aspergillus clavatus, hypersensitivity pneumonitis caused by, 1163t Aspergillus flavus, 2292 infection (incl. pneumonia), 2306 Aspergillus fumigatus, 1991, 2292–2293 allergens, 2297 drug-resistant, 2303 fungus ball, 2301 hypersensitivity pneumonitis caused by, 1164t identification of, in tissue, 2049–2050, 2049f immune response to, 343 infection (incl. pneumonia). See also Aspergillosis and bronchiectasis, 2189, 2189t in cancer patients, 2215f diagnosis of, 2297–2298, 2299t in hyperimmunoglobulin E syndrome, 2239f pathology of, 2046f in surgery and trauma patients, 2197 pathogenicity of, 2294 staining characteristics of, 2037f virulence factors, 2294 Aspergillus nidulans, 2292 Aspergillus niger, 2292 fungus ball, 2301 identification of, in tissue, 2050

Aspergillus oryzae, 2309 hypersensitivity pneumonitis caused by, 1164t Aspergillus terreus, 2292 infection (incl. pneumonia), 2306, 2308 staining characteristics of, 2038f Aspiration, 2020 after lung resection, 1747–1748 after swallow, 1306, 1307f and anaerobic pleuropulmonary infections, 2145t in bone marrow and stem cell transplant recipients, 2222, 2225 and bronchiectasis, 2185t, 2186 classification of, 1299 diffuse, 2027 of gastric contents and postoperative respiratory failure, 2582–2584 prevention of, 2583–2584, 2649 in gastroesophageal reflux disease, 1308–1309, 1309f in healthy persons, 2146 iatrogenic mechanisms and, 1310–1312 and lung abscess, 2147 neuromuscular conditions causing, 1305–1309, 1305t of oropharyngeal secretions, and nosocomial pneumonia, 2274 prevention of, 2111 before swallow, 1305–1306, 1306f during swallow, 1306, 1307f Aspiration pneumonia, 389, 389f, 2005t, 2007, 2198 bronchoalveolar lavage cellular profile in, 1121t in children, 2136, 2136f classification of, 2150t clinical features of, 2149–2150, 2149t in collagen vascular disease, 1194t cytopathology of, 524, 524f definition of, 1299, 2141, 2150 diagnosis of, 2153 in elderly, 2007 hospitalization rate for, 2105t imaging of, 2022 microbiology of, 2143, 2143t in mixed connective tissue disease, 1209–1210 pathophysiology of, 2146–2149 in polymyositis-dermatomyositis, 1208 in pregnancy, 259t prevention of, 2156–2157 radiographic features of, 482 risk factors for, 2098 in scleroderma, 1208, 1208f Aspiration pneumonitis, definition of, 1299 Aspirin asthma induced by, 799–807 desensitization, in aspirin-sensitive asthmatics, 806–807, 806f

dyspnea caused by, 403 and interstitial lung disease, 1110t and other NSAIDs, cross-reactivity of, 801–803 pulmonary effects of, 1088, 1090t, 1091t, 1093, 1097 reactions to cutaneous, 799–800 respiratory, 799–801 sensitivity to, and asthma, 816–817 Aspirin challenge, 804–805, 805t Aspirin-exacerbated respiratory disease, 800 Asthma, 398. See also Status asthmaticus age distribution of, 788, 788f air pollution and, 1032–1033, 1032t airspace enlargement in, differential diagnosis of, 698–699, 698t airway inflammation in, 773–774, 783–784, 784f, 815 cellular roles in, 775–777 maskers of, 833–834 airway responsiveness and, 789–790, 791f, 793, 815 airway smooth muscle shortening in, 116, 118–121, 119f allergy and, 793 animal handlers’, 988 anti-inflammatory therapies for, alternatives, 831–832 aspergillosis and, 839, 840–841, 840t, 2291, 2292t, 2294–2295, 2295t aspirin-induced, 313, 799–807 clinical presentation of, 799–801, 800f diagnosis of, 804–805, 805t genetics of, 801 history-taking in, 816–817 pathogenesis of, 803–804 treatment of, 805–807, 806f aspirin-intolerant, 800 atopic, 330 bakers’, 988–989 biologic enzyme–induced, 989 bronchoalveolar lavage cellular profile in, 1121t candidiasis and, 2315 cardiac, 402, 421 causes of, 395 chemokines in, 356 in children, epidemiology of, 787 and chronic cough, 410 chronic stable environmental control for, 820–821 immunotherapy for, 822 management of, 820–830 nonpharmacologic therapy for, 820–822 patient education about, 820 pharmacologic management of, 822–830, 823t–829t vaccinations in, 821–822

I-13 Index clinical presentation of, 816–819 common cold and, 774–775, 2086 conditions associated with, treatment of, 832–833 in crab processors, 988 definition of, 787–788 diagnosis of, 788, 816–819 allergy tests in, 819 blood tests in, 818–819 bronchial challenge testing in, 818 laboratory studies in, 817–819 physical examination in, 817 radiographic findings in, 819 sputum examination in, 819 differential diagnosis of, 816, 819, 819t drug therapy for, 822–830, 823t–829t, 2634, 2635–2636, 2638 combination inhalers, 822, 823t, 826t, 2638 dyspnea in, 398 in elderly, 816 emergency department visits for, 789, 790f, 835 racial differences in, 789, 790f epidemiology of, 773, 787–797 ethnicity and, 795 exacerbations chronic sinusitis and, 807 management of, 834–835 nonpharmacologic therapy for, 834 patient monitoring with, 835 pharmacologic therapy for, 834–835 viral infection and, 796 exercise-induced, 313, 807–812, 815 airway rewarming and, 809 bronchial reactivity tests for, 585t clinical presentation of, 807–808, 808f differential diagnosis of, 809–810, 810t in elite athletes, 807 genetics of, 809 heat exchange and, 808–809 historical perspective on, 807 history-taking in, 816 inflammation and, 809 pathophysiology of, 808–809 physiological documentation of, 810–811, 811f treatment of, 811–812, 811t in Olympic athletes, 812 water loss and, 808–809 extrinsic, 815 flow-volume curves in, 421, 422f gene-environment interactions in, 793–794 genetic susceptibility in, 793–794 health care costs of, 787 history-taking in, 816–817 hospitalization rates for, 789, 789f, 790f

current trends in, implications of, 797 racial differences in, 789, 789f, 790f and hypercapnic respiratory failure, 2607, 2607f imaging of, 2022 immune response in, 356 impairment due to evaluation of, 682–683, 683t rating of, 683, 684t indoor air pollutants and, 1031 initial assessment of, 421 intermediate phenotypes of, 789–793 intrinsic, 815 large airway lesions in, differential diagnosis of, 700, 701t laryngeal, 859 lifetime prevalence of, 788, 788f management of, 820–834 action plans for, 833 maternal smoking and, 752 mild intermittent, treatment of, 830 persistent, in adults management of, 821t treatment of, 830 moderate, persistent, in adults management of, 821t treatment of, 830–831 mold-sensitive, and allergic bronchopulmonary aspergillosis, 839 molecular mediators in, 777–782, 779t–781t morbidity in beta-adrenergic agonists and, 2635 current trends in, implications of, 797 mortality rate for beta-adrenergic agonists and, 2635 current trends in, implications of, 797 racial differences in, 789, 791f trends in, 789, 791f new-onset, in elderly, 421 nocturnal symptoms in, 816 obesity and, 795–796 occupational, 815, 934t, 935, 981, 983–990 agents causing, 984, 985t mechanism of action of, 986 bronchial provocation testing in, 987, 987f case definition of, 984, 984t clinical presentation of, 817, 984–986 definition of, 983–984 diagnosis of, 986–987 and disability determination, 988 high-molecular-weight compounds and, 985t, 986

history-taking in, 986 immunologic tests in, 986 with latency, 984 low-molecular-weight compounds and, 985t, 986 management of, 987–988 pathology of, 986 physical examination in, 986 pulmonary function testing in, 986–987 risk factors for, 984 skin testing in, 986 without latency (irritant-induced), 984–986 occupational exposures and, 933–934 pathogenesis of, 774–775 late-phase asthmatic response and, 774, 774f respiratory viruses and, 774–775 pathophysiology of, 773–774 patient monitoring in, 833–834 persistent, in adults, management of, 820–834, 821t in pregnancy, 259, 259t prevalence of, 788, 788f current trends in, implications of, 797 prognosis for, 796–797 pulmonary function testing in, 603, 604t, 605, 606t, 817–818 racial distribution of, 788, 794, 795 respiratory chemosensitivity in, 2595 respiratory muscle action in, 2597–2598, 2598f risk factors for, 794–796 perinatal, 794 schistosomiasis and, 395 severe, persistent, in adults management of, 821t treatment of, 831 severity classification of, 815–816 treatment regimens tailored to, 830–832 impairment classification for, 682–683, 683t Social Security listings for, 686 sex distribution of, 788 and sleep, 1725 small airway lesions in, differential diagnosis of, 702–703 socioeconomic status and, 795 steroid-resistant, 2639 as syndrome, 773 treatment of, 773–774, 820–834 by severity classification, 830–832 Asthmatic response(s) acute-phase, 774, 774f late-phase, 774, 774f Ataxia-telangiectasia (AT), pulmonary infection in, 2237

I-14 Index Atelectasis, 477 basilar, 508, 508f causes of, 477–480 computed tomography of, 480, 482, 488f discoid, 508, 508f lobar patterns of, 478, 484f–488f neoplasia and, 2014 nonobstructive, 2020 platelike, 508, 508f with pleural effusions, 480 with pneumonia, 2027–2028 postobstructive, radiation-related, 1184 postoperative, 478–480, 488f, 508 prevention of, 2580 and respiratory failure, 2579–2580 rounded, 488f asbestos-related, 947, 947f computed tomography of, 1115t Atelecta-trauma, 2546 Athletes, exercise-induced asthma in, treatment of, 812 Atomic theory, 9 Atopic dermatitis, 427–428, 428f Atopy, 427–428 Atovaquone, 2407 for Pneumocystis pneumonia, 2368t, 2369–2370 prophylactic, for Pneumocystis pneumonia, 2367 ATPS. See Ambient temperature and pressure, saturated with water Atrial fibrillation, after lung resection, 1746 Atrial natriuretic peptide (ANP), ectopic production of, 1930t, 1932–1933 Atrial septal defect, closure, response to, assessment of, using cardiopulmonary exercise testing, 623 Atrial septostomy, for pulmonary arterial hypertension, 1392 Atropine, 2635–2636 ATS. See American Thoracic Society AUC, 2054 Auenbrugger, Leopold, 5t, 14 Auerbach, Leopold, 15 Augmentin. See Amoxicillin/clavulanate AUIC, 2054 Aureobasidium hypersensitivity pneumonitis caused by, 1164t in indoor air, 1031 infection (incl. pneumonia), in cancer patients, 2217 Auricular cellulitis, 2091 Auscultation, of lungs, 392 Autoimmune disease, imaging of, 2022 Autoimmune hemolytic anemia (AIHA), sarcoidosis and, 1135, 1136t

Autonomic nervous system, pulmonary innervation by, 32 Autonomy, patient, 2723, 2729 Auto-PEEP, in acute respiratory failure, 2670, 2671, 2672f AVCO2 R. See Arterial venous CO2 removal Avesicular zone, of alveolar capillary endothelium, 40 Avian influenza, 1994, 2384, 2428 Azalides characteristics of, 2055 penetration into lung, 2053 pharmacokinetics and pharmacodynamics of, 2054 Azathioprine, 2639 for idiopathic pulmonary fibrosis, 1157 for sarcoidosis, 1140t, 1141 Azithromycin for acanthamoebiasis, 2401 adverse effects and side effects of, 2494, 2503 for cryptosporidiosis, 2404 for cystic fibrosis patient, 876, 2178–2179 dosage and administration of, 2055 indications for, 2060, 2157 interactions with immunosuppressive agents, 2503t for melioidosis, 2440 for Moraxella catarrhalis infection, 2445 for Mycobacterium avium complex infection, 2505 in HIV-infected (AIDS) patients, 2493–2494, 2494t prophylactic regimen, 2495, 2495t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t organisms susceptible to, 2055 penetration into lung, 2053, 2053t for protozoan infection, 2407 for Rhodococcus pneumonia, 2429t for streptococcal pharyngitis, 2086 Aztreonam pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2056 Azygos vein, imaging of, 461f, 469 B Babesia divergens, 2407 Babesia microti, 2407 Babesiosis, 2407 diagnosis of, 2407 epidemiology of, 2407 pathogenesis of, 2407 in splenectomized patient, 2219 treatment of, 2407 Bacille Calmette-Gu´erin (BCG) vaccine, 2066t, 2069–2070, 2454–2455, 2463

Bacillus contamination of bronchoscope, 2279 infection (incl. pneumonia), 2271 in neutropenic host and cancer patient, 2217 Bacillus anthracis, 2005t, 2006, 2428t. See also Anthrax bacteriology of, 2428t, 2436 culture of, 2429t ecology of, 2436 exotoxin, 2436 edema factor, 2436 lethal factor, 2436 protective antigen, 2436 staining characteristics of, 2429t vaccine against, 2437 Bacillus cereus, infection (incl. pneumonia), 2271 Bacillus fragilis, infection (incl. pneumonia), nosocomial, 2281t Bacillus subtilis, hypersensitivity pneumonitis caused by, 1163t, 1165t Bacillus subtilis inhalational challenge test, 585t Bacteremia, 2001 in cancer patients, 2216 in neutropenic host and cancer patient, 2217 and unresolving pneumonia, 2009–2010 Bacteria adherence mechanisms, 281–282 colonization by, 282 in cystic fibrosis, 866, 880–881 exoproducts of, and acute lung injury, 2527 in indoor air, 1030t, 1031 sources of, 1022t in oral cavity, 281 Bacterial infection(s), 2005t, 2006. See also Pneumonia, bacterial; specific bacteria and acute bronchitis, 2097 and acute exacerbations of chronic obstructive pulmonary disease, 741, 742t, 2116–2117 and acute mediastinitis, 2166t and acute otitis media, 2092–2093, 2093f animal product, 2435–2441 and aspiration pneumonia, 2150t in bone marrow and stem cell transplant recipients, 2224 and bronchiectasis, 2186 bronchoalveolar lavage cellular profile in, 1121t bronchopneumonia caused by, 2042 in cancer patients, 2215, 2221, 2221t croup caused by, 2087 cytopathology of, 518, 518f and diffuse alveolar damage, 2042

I-15 Index environmental, 2435–2441 epidemiology of, 2004 gram-negative. See Gram-negative bacteria gram-positive. See Gram-positive bacteria histopathology of, 2034 in HIV-infected (AIDS) patients, 2212t, 2213, 2242t, 2245, 2246, 2250–2253, 2251f, 2252f radiographic findings in, 2214–2215, 2214t, 2249t in IgA deficiency, 332 immune defect associated with, 1983t, 2210t immune defense against, 1971 laryngitis caused by, 2087 leukocyte migration in, 354–355 and lung abscess, 2154t in lung transplant recipient, 1790 lymphadenopathy in, 2028 neonatal incidence of, 2125 microbiology of, 2125–2126 pathogenesis of, 2126 pneumonia caused by, 2125–2127 nosocomial, 2008–2009 occupational, 934t of oral cavity, 2086–2087 pathogenesis of, 2079–2081 and pharyngitis, 2086 pneumonia caused by in children, 2130–2134 in early infancy, 2127–2128, 2127f neonatal, 2125–2127 pyogenic, 2043t sinusitis caused by, 2089–2090 staining characteristics of, 2035t, 2036 supraglottitis caused by, 2088 systemic effects of, 451–453, 451t tracheitis caused by, 2088 vaccines against, 2066–2070, 2066t Bacterial superinfection in cancer patients, 2217, 2217f in varicella pneumonia, in children, 2135 in viral pneumonia, 2393 Bacterial synergy, 2142 in acute mediastinitis, 2166 Bacteroides, 2007, 2086 in acute mediastinitis, 2166, 2166t in empyema, 2144t infection (incl. pneumonia), 2156t Bacteroides fragilis, 2007 in acute mediastinitis, 2166t in empyema, 2144, 2144t infection (incl. pneumonia), 2156t conditions underlying, 2145t morphology of, 2147f staining characteristics of, 2147f Bacteroides gracilis, in empyema, 2144t

Bacteroides melaninogenicus, infection (incl. pneumonia), nosocomial, 2281t Bacteroides urealyticus, infection (incl. pneumonia), 2156t Bagassosis, 2012 etiology of, 1163t Baillie, Matthew, 13, 694 Bainbridge reflex, 1340 Bakers’ asthma, 988–989 BAL. See Bronchoalveolar lavage (BAL) Balantidium coli, 2409–2410 BALT. See Bronchial-associated lymphoid tissue (BALT) Band 3 protein, 204 BAPE. See Benign asbestos pleural effusions Barbiturates, for agitated ICU patient, 2705 Barcroft, Joseph, 5t, 9, 10, 10f, 224, 224f Barium swallow, 466, 466f, 498–499 Barotrauma in airplane flight, 918 pulmonary, 1045–1047, 1046f Bartonella infection (incl. pneumonia) histopathology of, 2034 in HIV-infected (AIDS) patients, 2212t, 2215 in immunocompromised host, 2207, 2208 pathology of, 2050 staining characteristics of, 2037 Basal energy expenditure, 2696–2697 Basaloid carcinoma of lung, 1840, 1840f Base deficit, 214 Base excess, 214 Basement lung, etiology of, 1164t Basement membrane, 174f injury, in idiopathic pulmonary fibrosis, 1154 Basophil(s), 307–308 in asthma, 775 Bat wing pattern of consolidation, 478f, 1282, 2542 Bayle, 13, 15 Bazex syndrome, 432, 432f BCA-1. See B-cell-attracting chemokine-1 B-cell-attracting chemokine-1, 340t B cells (B lymphocytes), 1974 activation, 323 affinity maturation, 324 anergy, 323 apoptosis, 323 B1, 324–325 biology of, 321–324 chemotherapy and, 2216 in chronic obstructive pulmonary disease, 715 clonal deletion, 323 clonal inactivation, 323 defects of, 330–331

associated infections, 1983t, 2210t causes of, 1983t, 2210t infections associated with, 1983t pulmonary infection in, 2233–2236 development of, 322–323, 322t differentiation of, 322–323, 322t and antibody responses in secondary lymphoid tissues, 323–324 marginal zone, 324 memory, 324 BCG. See Bacille Calmette-Gu´erin (BCG) BCNU. See Carmustine Beckwith-Wiedemann syndrome, 2647 Beclomethasone dipropionate adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t Bed rest cardiac effects of, 1741 respiratory effects of, 1741 Behc¸et’s syndrome, 1462 alveolar hemorrhage in, 1293 erythema nodosum in, 434 Bellows apparatus, age-related changes in, 264t BeLPT, 940 Benedict, F. G., 8 Beneficence, principle of, 2722–2723 Benign asbestos pleural effusions, 1507, 1509 Benign lymphocytic angiitis and granulomatosis, 1959 Benzene airborne, 1020 exposure to, 1027t in indoor air, 1026 sources of, 1021t sources of, 1027t bis-Benzimidazole, for Pneumocystis pneumonia, 2370 Benzo[a]pyrene in indoor air, sources of, 1021t toxicology of, 1026 Benzodiazepines, for agitated ICU patient, 2703 properties of, 2703, 2704t Benzoic acid derivatives, sensitivity to, in aspirin-sensitive asthmatics, 802 Beraprost, for pulmonary arterial hypertension, 1388, 1390 Bernard, Claude, 5t, 16, 227, 227f Bernoulli equation, 1374 Bert, Paul, 5t, 9 Berylliosis, 2025 bronchoalveolar lavage in, 940 cellular profile in, 1121t bronchoscopy in, 1120t computed tomography of, 1115t cytopathology of, 517, 517f exposures associated with, 1109t impairment due to, evaluation of, 684 radiographic features of, 492f

I-16 Index Beryllium, lung disease caused by, 934, 934t. See also Berylliosis occupational, 935t Beryllium lymphocyte proliferation test, 940 Beta-adrenergic agonists, 2631–2635 adverse effects and side effects of, 824t–825t, 2634–2635 in ALI/ARDS, 2556–2557 and anticholinergics, combination therapy with, in chronic obstructive pulmonary disease, 740 for asthma, 822, 823t, 824t–825t for asthma exacerbations, 834–835 for chronic obstructive pulmonary disease, 737–738, 738t, 739 clinical use of, 2634 delivery, 2633–2634 dosage forms, 2633–2634 for exercise-induced asthma, 811–812, 811t inhaled, for asthma, 822, 823t long-acting adverse effects and side effects of, 827t for asthma, 822, 823t, 827t mechanism of action of, 827t mechanism of action of, 824t nonselective, for asthma, 825t pharmacology of, 2631–2632 safety of, 2634–2635 short-acting, for asthma, 822, 823t, 824t–825t structure-activity relationships, 2632–2633, 2633f tolerance to, 2634 Beta-adrenergic blockers bronchoconstriction caused by, 389, 1096 and interstitial lung disease, 1110t pulmonary toxicity of, 1089, 1090t, 1091t, 1093, 1096–1097 β-lactams. See Beta-lactams Beta-galactosidase, 1272 Beta-galactosidosis, 1272, 1273f Beta-lactamase, extended spectrum, 2110, 2280–2282 organisms producing, neonatal nosocomial pneumonia caused by, 2126 Beta-lactam/beta-lactamase inhibitors, 2056 indications for, 2131, 2157 Beta-lactams characteristics of, 2056 indications for, 2060–2062, 2061t mechanism of action of, 2056 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2056 resistance to, 2099

Bevacizumab for advanced stage NSCLC, 1876 pulmonary effects of, 1081t, 1082–1083 Bezold’s abscess, 2094, 2094f Bicarbonate, 193–194, 203, 204–205, 208, 211 in mixed acid-base disturbances, 219 reclamation, renal, 209, 209f Bichat, 13, 15 Bilobalide, for Pneumocystis pneumonia, 2370 Bioethics definition of, 2721 principles of, 2722–2724, 2722f Biologic agents, in indoor air, 1030–1032, 1030t Biologic enzymes, and occupational asthma, 985t, 986, 989 Biologic response modifiers, pulmonary effects of, 1081–1083, 1081t Biopsy bronchial, bronchoscopic, 635, 635f kidney, in immune-mediated diffuse alveolar hemorrhage, 1284–1285, 1285f, 1286f lung, 2031–2033, 2042. See also Fine-needle aspiration biopsy bronchoscopic, 2003 CT-guided, in HIV-infected (AIDS) patients, 2250 in diffuse alveolar hemorrhage, 1282–1284, 1283f–1284f in environmental lung disease, 940 indications for, 423 in interstitial lung disease, 1120–1122 needle (percutaneous transthoracic), 513, 1987, 2003–2004. See also Transthoracic needle aspiration and biopsy in occupational lung disease, 940 open, 1987, 2004, 2106 in HIV-infected (AIDS) patients, 2250 in interstitial lung disease, 1120–1122 optical, 634 percutaneous transthoracic fine-needle aspiration. See Transthoracic needle aspiration and biopsy in Pneumocystis pneumonia, 2361t, 2365 in sarcoidosis, 1135–1136 thoracoscopic, 652–653 in interstitial lung disease, 1120–1122 tissue samples from, handling of, 2032–2039 transbronchial, 652, 1987, 2032, 2033 in HIV-infected (AIDS) patients, 2247t, 2250

transbronchial aspiration, 513 transbronchial needle aspiration, 2032 transthoracic needle. See Transthoracic needle aspiration and biopsy transthoracic needle aspiration. See Transthoracic needle aspiration and biopsy video-assisted thoracoscopic, 2032, 2033 in children, 2132 in HIV-infected (AIDS) patients, 2247t, 2250 of mediastinal mass, 1590–1591 parenchymal, bronchoscopic, 635, 635f pleural, 651 of solitary pulmonary nodule, 1823–1824 transbronchial, in interstitial lung disease, 1120, 1120t Biopsy forceps, for bronchoscopy, 631 Biotrauma, 2530, 2546 BIP. See Bronchiolitis obliterans interstitial pneumonia BIPAP. See Biphasic airway pressure ventilation Biphasic airway pressure ventilation, in ALI/ARDS, 2551 Bipolaris in allergic fungal sinusitis, 2091 in invasive fungal sinusitis, 2091 Birbeck granules, 42 Bird allergen(s), exposure to, 1031 Bird fancier’s disease, 1161 etiology of, 1164t prognosis for, 1171–1172 radiographic features of, 1167f treatment of, 1171 Bird proteins, hypersensitivity pneumonitis caused by, 1164t Birt-Hogg-Dub´e syndrome, 437, 437f Bitolterol adverse effects and side effects of, 825t for asthma, 823t, 825t dosage and administration of, 825t Bivalirudin, for pulmonary embolism, 1439 Black, John, 5t, 7 Black, Joseph, 5t, 8–9 Black Lung program (federal), 688–689 Bladder cancer, smoking and, 751 Blastomas pleuropulmonary, 1841 pulmonary, 1840–1841, 1842f, 1920, 1921f Blastomyces, 2005t. See also Blastomycosis pneumonia, 2024 staining characteristics of, 2035t, 2332f Blastomyces dermatitidis antigen, detection of, 2346, 2348t culture of, 2346–2347, 2348t

I-17 Index identification of, in tissue, 2038t, 2332f infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t, 2255–2256 mycology of, 2345–2346 sputum culture for, 2000 staining characteristics of, 2037f, 2332f, 2346 Blastomyces hominis, in lung abscess, 2154t Blastomycosis, 1990, 1997, 2006, 2345–2348. See also Blastomyces and acute respiratory distress syndrome, 2346, 2347f clinical manifestations of, 2346 cutaneous manifestations of, 430, 431f cytology of, 2346, 2348t cytopathology of, 520 diagnosis of, 2346–2347, 2348t disseminated, 2346 epidemiology of, 2327, 2346 geographic distribution of, 2327, 2328f histopathology of, 2346, 2348t in HIV-infected (AIDS) patients, 2247, 2254–2256 treatment of, 2348 in immunocompromised host, 2204, 2346 mycology of, 2345–2348 pathogenesis of, 2346 pathology of, 2346 pneumonia in, 2346, 2347f serology of, 2347, 2348t South American, 2007 treatment of, 2348, 2348t Blatella germanica, 1031 Bleb(s), 914f characteristics of, 913, 915t Bleomycin and interstitial lung disease, 1110t lung damage caused by, 389 and pleural effusion, 1506t pneumonitis caused by, 2011, 2012, 2012t pulmonary effects of, 1069–1071, 1070f, 1070t, 1072f, 1088, 1089, 1181, 1295 radiation therapy and, 1181 Blocks, definition of, 1895 Blood coughed up. See Hemoptysis culture, 2001, 2104 in HIV-infected (AIDS) patients, 2247t, 2248, 2250 in pneumonia, 1986 gas transport in, 201–206 pH, and pulmonary vasomotor control, 1346 vomited. See Hematemesis Blood dendritic cell antigen (BDCA) 2, 1974 Blood dyscrasia, hemoptysis associated with, 414

Blood gas(es) in chronic obstructive pulmonary disease, 2104 knowledge of, historical perspective on, 5t, 8–9 and pulmonary arterial pressure, early observations on, 16–17, 17f symbols for, 1328, 2740 Blood-gas barrier, 174f, 176 Blood pressure arterial, measurement of, 2660–2661 in exercise, 616 mean arterial, in pregnancy, 257t monitoring, in cardiopulmonary exercise testing, 611 in pregnancy, 258 Blood tests, in dyspnea, 405, 405t Blood transfusion(s), pulmonary leukoagglutinin reaction after, 2014 Blood urea nitrogen, in mixed acid-base disturbances, 219 Blood vessel(s) bronchopulmonary anastomoses, 32 nutritive, 32 wall structure of, 31–32 Blood volume in pregnancy, 256–257, 257f pulmonary. See Pulmonary blood volume pulmonary capillary. See Pulmonary capillary blood volume BLT1, 350–351, 350f Blue bloater, 476, 713, 1403–1405, 1406f Bmp3, and lung development, 86 Bmp4, and lung development, 82, 84, 85, 87, 88f, 89 Bmp5, and lung development, 86 Bmp7, and lung development, 86 Bocavirus and bronchiolitis, 2376t, 2382 characteristics of, 2375t BODE index, 732, 733t Body plethysmograph, historical perspective on, 11 Body position, and diffusing capacity, 197 Body temperature and pressure, saturated with water, 574, 574t Body wasting in chronic obstructive pulmonary disease, 2605 in pulmonary disease, 452–453 Boeck, Caesar, 1125 Boerhaave’s syndrome, 1560–1561, 1562f Bohr, Christian, 5t, 9, 9f Bohr effect, 9, 9f, 202, 205t Bohr equation, 58, 592 Bone marrow transplantation (BMT) alveolar hemorrhage complicating, 1294 bronchoalveolar lavage cellular profile in, 1121t

pulmonary complications of, 2222–2229, 2222t clinical presentation of, 2224–2225 temporal sequence of, 2222–2224 pulmonary function testing in, 2229 respiratory complications of, 906–907, 907f and risk of infection, 2205, 2206f, 2218 Bone morphogenetic protein, BMP4, and lung development, 85–86 Bone morphogenetic protein(s) (BMP), BMP-4, in lung development, 92–94 BOOP. See Bronchiolitis obliterans-organizing pneumonia Bordetella pertussis and acute bronchitis, 2097 direct fluorescent antibody staining of, 1999 infection (incl. pneumonia) clinical features of, 2381 nosocomial, 2289 pathogenesis of, 2079, 2080 reactive nitrogen species in, 365 toxin, IgA against, 1979 vaccine against, 2066t, 2069 Borelli, Giovanni Alfonso, 5t, 11 Borg Category Scale, 397, 397t Borrelia burgdorferi, and sarcoidosis, 1126–1127 Bosentan drug interactions with, 1392 for idiopathic pulmonary fibrosis, 1158 for pulmonary arterial hypertension, 1387–1388 for scleroderma, 430 Botrytis cinerea, hypersensitivity pneumonitis caused by, 1163t Botulinum toxin, 1656 Botulism, ventilatory impairment in, 1656, 1668t Boyle, Robert, 5t, 7, 7f, 8, 11 Boyle’s law, 12, 917, 1046f BPF. See Bronchopleural fistula BPT. See Bronchoprovocation testing Brachiocephalic vein, obstruction of, percutaneous transluminal angioplasty and stenting for, 540 Brachytherapy definition of, 1895 endobronchial, 638–639 in upper airway obstruction, 862 Bradykinin, and pulmonary circulation, 1347 Brain natriuretic peptide, 405 in acute respiratory failure, 2661 plasma level, evaluation of, 2543 BRAK/bolekine, 340t Brambell receptor, 326

I-18 Index Branhamella, in acute mediastinitis, 2166t Branhamella catarrhalis. See Moraxella catarrhalis Breast cancer metastases, survival rates for, 1941, 1942t and pleural effusion, 1505, 1506t pulmonary metastases, 1943 radiation therapy for, and risk of radiation pneumonitis/fibrosis, 1188 Breathing abnormal patterns of, 403–404 control of, 596–599 age-related changes in, 268–270 knowledge of, historical perspective on, 5t, 12–13 in kyphoscoliosis, 1620–1621 in neuromuscular disorders, 1636–1640 in obesity, 1628–1629 postoperative changes in, 665 diaphragmatic, 766 efficiency of, and dyspnea, 396 feedback control of, instability in, and recurrent apnea, 170 level of, factors affecting, 161, 162f mechanics of in chronic obstructive pulmonary disease, 398 and dyspnea, 396 knowledge of, historical perspective on, 5t, 11–12 normal, 1323, 2735 terminology for, 1327, 2739 noisy, in upper airway obstruction, 846 oxygen cost of, 159–160 in chronic obstructive pulmonary disease, 398 and dyspnea, 396, 397f mechanical ventilation and, 2676, 2677f pattern of, factors affecting, 161, 162f periodic, altitude and, 1040 pursed-lips, 389–390, 403, 766–767 rapid, shallow, in respiratory failure, 2602–2605 pathogenesis of, 2604–2605, 2605f reflex regulation of, 13 respiratory pressures during, 147–148, 148f in trauma patient, initial management of, 1757–1758 work of, 158f, 159 in chronic obstructive pulmonary disease, 398 and dyspnea, 396, 396f mechanical ventilation and, 2676, 2677f Breathing reserve, 396, 583

in chronic obstructive pulmonary disease, 398 Breathing retraining, in pulmonary rehabilitation, 766–767 Breathlessness. See also Dyspnea evaluation of, scales for, 679, 679t positional forms of, 400–401 Breath sounds. See Lung sound(s) Breaths per minute. See also Respiratory rate normal, 1323, 2735 Bremsstrahlung, 1175 Breuer, Joseph, 5t, 13 Bromocriptine, and interstitial lung disease, 1110t Bronchial artery(ies), 32 embolization, 529f, 538 complications of, 538 efficacy of, 538 indications for, 538 for management of hemoptysis with aspergilloma, 2303 Bronchial-associated lymphoid tissue (BALT), 31, 282, 326–327, 329, 1923, 1924f, 1948, 1948f, 1977 in chronic obstructive pulmonary disease, 715 hyperplasia, diseases associated with, 1948, 1948f, 1952 inducible, 329 Bronchial brushes, for bronchoscopy, 631 Bronchial brushings, 513 Bronchial circulation, 32, 1332, 1352–1353 in disease, 1353–1354, 1354f Bronchial C receptors, 164 Bronchial fistula, closure of, therapeutic bronchoscopy for, 643 Bronchial gland(s), 281 Bronchial hyperresponsiveness, measurement of, in asthma, 833–834 Bronchial provocation testing, 818 Bronchial reactivity, tests of, 585, 585t Bronchial stenosis, radiation-induced, 1184 Bronchial stump aspergillosis, 2304 Bronchial washings, 512 Bronchiectasis allergic bronchopulmonary aspergillosis and, 840f–841f, 841–842, 2185t, 2187, 2190 and anaerobic pleuropulmonary infections, 2145t anatomical causes, 2185t anti-inflammatory therapy for, 2191 aspiration and, 2185t, 2186 bronchial circulation in, 1353, 1354f bronchial hygiene in, 2190 bronchodilator therapy for, 2191 bronchography of, 468f

in chronic obstructive pulmonary disease, 2183 clinical manifestations of, 2183, 2184 computed tomography of, 463, 463f cylindrical, 2184–2185, 2185f in cystic fibrosis, 2176 cystic fibrosis and, 2185t, 2186–2187 definition of, 2183 diagnosis of, 2188–2189 differential diagnosis of, 819t dry, in tuberculosis, 2469–2470 hemoptysis in, 413 in hyperimmunoglobulin E syndrome, 2239 idiopathic, 2185t immunodeficiency and, 2185t infection and, 2185–2186, 2185t microbiology of, 2189, 2189t treatment of, 2189–2190 large airway lesions in, differential diagnosis of, 700–702, 701t lung transplantation in, 1774t, 1775–1777 mucus clearance in, 2190–2191 pathology of, 1990 pathophysiology of, 2184 with pneumonia, 2028 predisposing/associated factors, 2185–2188, 2185t prevalence of, 2183–2184 primary ciliary dyskinesia and, 2185t, 2187 Pseudomonas aeruginosa in, 2184 radiologic classification of, 2184–2185, 2185f rheumatoid arthritis and, 2185t, 2187 saccular, 2185, 2185f surgery for, 2191 treatment of, 2189–2191 tuberculous, 2469–2470 ulcerative colitis and, 2185t, 2188 varicose, 2185, 2185f wet, in tuberculosis, 2470 in X-linked hypogammaglobulinemia, 331, 2188 Young syndrome and, 2185t, 2187 Bronchiole(s) branching of, 26, 26f peripheral, 47f respiratory, 26, 26f, 47, 47f, 53, 174f, 695 age-related changes in, 264 in host (immune) defense, 282 terminal, 26, 26f, 174f, 695 transitional, 26, 26f, 47, 47f, 53 Bronchiolectasis, with pneumonia, 2028 Bronchiolitis. See also Respiratory bronchiolitis interstitial lung disease acute, imaging of, 2021 BOOP pattern, 888 in children, 896–897 classification of, 888–889

I-19 Index clinical, 888, 889t histopathological, 888–889, 890t–891t radiologic, 888 clinical features of, 2381–2382 in collagen vascular disease, 1194t histopathology of, 1197, 1197f in connective tissue disease, 903–905 constrictive, 888–889, 890t–891t, 892f, 1106t. See also Bronchiolitis, obliterative differential diagnosis of, 703 pathogenesis of, 889–891, 893f in rheumatoid arthritis, 903–904 cryptogenic adult, 898–899, 899f definition of, 887–888 diagnosis of, 2383 differential diagnosis of, 2382 disorders associated with, 888, 889t drug-induced, 889t, 905–906 epidemiology of, 2382 follicular, 1949, 1952, 1952f differential diagnosis of, 703 in rheumatoid arthritis, 904–905, 904f, 905f, 1203–1204, 1204f in scleroderma, 905 idiopathic, 889t, 898–903 imaging of, 2022 infectious causes, 889t, 896–898 in adults, 897–898, 898f in children, 896–897 inhalational injury causing, 889t, 892–896, 893t obliterative, 1106t. See also Bronchiolitis, constrictive in allergic bronchopulmonary aspergillosis, 842 in collagen vascular disease, 1194t histopathology of, 1197, 1197f in organ transplant recipients, 906–909 pathogenesis of, 889–892, 893f, 2382–2383 prevention of, 2383–2384 proliferative, 888, 890t–891t, 891f in allergic bronchopulmonary aspergillosis, 842 differential diagnosis of, 703 pathogenesis of, 891–892, 893f in systemic lupus erythematosus, 1201 treatment of, 2383–2384 viral causes of, 896, 2376t, 2382 Bronchiolitis obliterans, 887–888, 2013 in bone marrow and stem cell transplant recipients, 2227–2228 bone marrow transplantation and, 906–907, 907f computed tomography of, 1115t drug-induced, 1089–1091, 1090t heart-lung transplantation and, 907–908, 907f

imaging of, 2022 in lung transplant recipient, 908 occupational exposures and, 935t radiographic features of, 491f toxin exposure and, 998, 999f, 1000t Bronchiolitis obliterans interstitial pneumonia, 1144 Bronchiolitis obliterans-organizing pneumonia, 429, 888, 2013, 2020, 2043, 2045f, 2541t in bone marrow and stem cell transplant recipients, 2225 in collagen vascular disease, 1194t histopathology of, 1196, 1196f drug-induced, 1089–1091, 1090t and hypersensitivity pneumonitis, 1168 idiopathic, 888, 891f, 900–903 imaging of, 2022 localized, 903 in polymyositis-dermatomyositis, 1208–1209, 1209f rheumatoid arthritis and, 904 in Sj¨ogren’s syndrome, 1211 toxin exposure and, 998, 1000t Bronchiolitis obliterans syndrome, 888 in chronic rejection of lung transplant, 1787–1788, 1788f, 1788t clinical findings in, 908 histopathology of, 909 lung transplantation for, 1158–1159 management of, 909 radiographic findings in, 909 Bronchioloalveolar cell carcinoma, 1832t, 1835–1838, 1838f, 2020 imaging of, 2022 intermediate type, 1837 mixed nonmucinous and mucinous, 1837 mucinous, 1837 nonmucinous, 1837 presenting as solitary pulmonary nodule, 1816 Bronchitis acute, 2097 differential diagnosis of, 2381 viral, 2376t, 2380, 2381 bronchoalveolar lavage cellular profile in, 1121t chemical, aspiration-related, 858 chronic, 742t, 2183. See also Chronic obstructive pulmonary disease (COPD) acute exacerbations of, treatment of, 742t, 2055, 2056, 2057 asthmatic, 730 in bird breeders, 1167 clinical characteristics of, 730 complicated, 742t cyanosis in, 415 differential diagnosis of, 1167 in farm workers, 1167

heart failure in, radiographic features of, 476 large airway lesions in differential diagnosis of, 700–702, 701t gross findings in, 699 microscopic findings in, 699–700, 700f obstructive, 730 occupational, 934t pulmonary function testing in, 603, 604t, 605, 606t radiographic findings in, 476, 476f suppurative, 742t follicular, 1949, 1952, 1952f hemoptysis in, 413 in HIV-infected (AIDS) patients, 2213 in hyperimmunoglobulin E syndrome, 2239 industrial, 981 grain dust–induced, 983 pathology of, 1989–1990 Bronchoalveolar cell carcinoma, cytopathology of, 529–530, 530f Bronchoalveolar lavage (BAL), 512–513, 635–636, 1987, 2003, 2031 in asbestosis, 949, 952 cellular profile in, 1121t in bone marrow and stem cell transplant recipients, 2225–2227, 2226t catheters and balloons for, 631 cellular profiles, in interstitial lung disease, 1120, 1121t in coal worker’s pneumoconiosis, 973 in cryptogenic-organizing pneumonia, 902 in diagnosis of ALI/ARDS, 2544 in environmental lung disease, 940 fluid, immunoglobulins in, 329 in HIV-infected (AIDS) patients, 2247t, 2250 in idiopathic pulmonary fibrosis, 1149–1150 indications for, 2105 in interstitial lung disease, 1114–1120 in nosocomial pneumonia, 2283 in occupational lung disease, 940 in Pneumocystis pneumonia, 2361–2364, 2361t quantitative, 636 Bronchocentric granulomatosis, 2013 Bronchoconstriction hypocapnic, 180 ventilatory adaptations to, 167–168 Bronchodilator(s), 2631–2637. See also specific drug for acute exacerbations of chronic obstructive pulmonary disease, 2118t, 2119, 2119t for allergic bronchopulmonary aspergillosis, 842, 2299

I-20 Index Bronchodilator(s) (Cont.) anticholinergic, for chronic obstructive pulmonary disease, 737–738, 738t for asthma, 822, 823t for asthma exacerbations, 834–835 for bronchiectasis, 2191 and corticosteroids, combination therapy with in asthma, 2638 in chronic obstructive pulmonary disease, 740, 2638 for cystic fibrosis patient, 876–877 therapy with, for ventilated patient, 2684–2685 Bronchogenic carcinoma, 2014 and anaerobic pleuropulmonary infections, 2145t hemoptysis in, 413 lymphadenopathy in, 2028 presenting as solitary pulmonary nodule, 1816 Bronchography, 466, 467f–468f Broncholithiasis, 1563–1564 Bronchophony, 392 Bronchopleural fistula, 1532, 2028 early, after lung resection, 1748–1749 in hyperimmunoglobulin E syndrome, 2239, 2239f in tuberculosis, 2469 Bronchopneumonia, 2018, 2020–2022 bacterial, 2020 pathology of, 2042–2043 in Chediak-Higashi syndrome, 2238 differential diagnosis of, 2020 etiology of, 2020 fungal, pathology of, 2045 imaging of, 2020–2022, 2021f, 2022f noninfectious processes mimicking, 2022 parasitic, pathology of, 2045–2047 pathogenesis of, 2020 pathology of, 2042–2047 viral, 2020, 2021f pathology of, 2043–2045 Bronchoprovocation testing, 585 contraindications to, 587–588, 587t in evaluation of impairment/disability, 681 indications for, 586 methods for, 586–587 precautions with, 587–588, 587t Bronchopulmonary anastomoses, 32 Bronchopulmonary sequestration, 1355–1356 extralobar, 1355 intralobar, 1355 Bronchoscopy anesthesia for, complications of, 643–644 blood gas abnormalities in, 644 for bronchial biopsy, 635, 635f

complications of, 643–645 diagnostic accessories for, 630–632 applications of, 632–636 in diffuse parenchymal disease, 1120, 1120t in hemoptysis, 634 of peribronchial structures, 634–635 in environmental lung disease, 940 fiberoptic in HIV-infected (AIDS) patients, 2247t, 2364–2365 in Pneumocystis pneumonia, 2364–2365 flexible fiberoptic, 630 in hemoptysis, 413 hemorrhage in, 645 historical perspective on, 629 indications for, 2105 instrumentation for, 630 in interstitial lung disease, 1120, 1120t monitoring during, 630, 644 and nosocomial pneumonia, 2279 in occupational lung disease, 940 for parenchymal biopsy, 635, 635f patient preparation for, 630 in pulmonary alveolar proteinosis, 1318 and quantitative microbiologic techniques, 636 rigid, 630 for balloon dilatation, 636–637 for debulking procedures, 636–637 safety considerations in, 643 for sampling airway and alveolar constituents, 635–636 in sarcoidosis, 1135–1136 of solitary pulmonary nodule, 1824, 1824f spectrophotometric techniques, 634 therapeutic applications of, 640–643 for laryngotracheal stenosis, 855 techniques for, 636–640 types of, 630 in upper airway obstruction, 861–862 virtual, of upper airway obstruction, 851 Bronchospasm causes of, 395 drug-induced, 1093 exercise-induced, 587 Bronchospirometry, preoperative, for lung resection, 672 Bronchus (pl., bronchi), 173 anatomy of, on bronchogram, 467f–468f branching of, 25, 25f, 26, 26f, 173 embryology of, 81, 82f lobar, 25 mainstem, 24–25, 25f

obstruction, and bronchiectasis, 2186 perforation of, in bronchoscopy, 644 topographic anatomy of, 477, 479f–481f Brooks syndrome. See Reactive airway dysfunction syndrome Brucella, 2428t, 2437–2439. See also Brucellosis bacteriology of, 2428t, 2437 culture of, 2429t ecology of, 2437–2438 staining characteristics of, 2429t Brucella abortus, 2438, 2439 bacteriology of, 2437 Brucella canis, 2438 bacteriology of, 2437 Brucella melitensis, 2438 bacteriology of, 2437 Brucella suis, 2438, 2439 bacteriology of, 2437 Brucellosis, 2428t, 2437–2439 and acute mediastinitis, 2166t clinical features of, 2438 diagnosis of, 2429t, 2438 epidemiology of, 1984t, 2428t, 2438 in neutropenic host and cancer patient, 2217 pathogenesis of, 2438 pathophysiology of, 2438 prevention of, 2439 radiologic features of, 2438 treatment of, 2429t, 2438–2439 Brugia malayi, 2414t, 2418–2419, 2418t and eosinophilic pneumonia, 1214t, 1219 Brush cell, 30–31, 30f, 33, 280f Bruton’s agammaglobulinemia, 331, 2139 pulmonary infection in, 331, 2233–2234 treatment of, 331 BTPS. See Body temperature and pressure, saturated with water Budesonide adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t Budesonide/formoterol adverse effects and side effects of, 826t for asthma, 822, 823t, 826t dosage and administration of, 826t Buffer(s), 208 Building-related illnesses, 1032, 1034, 1035f Bulla (pl., bullae) atmospheric pressure effects on, 917–918 characteristics of, 913, 915t classification of, 913, 914, 914f, 915t clinical features of, 918, 919f–920f

I-21 Index definition of, 913 distribution of, 917 etiology of, 914 external drainage of, 928 fluid in, 918–920, 922f infection in, 918, 921f, 922f, 923–925 treatment of, 926 laser surgery for, 928 localized, with abnormal intervening lung, treatment of, 928 medical management of, 926 pathogenesis of, 914–917, 916f radiologic features of, 918–921, 919f–922f reduction pneumoplasty for, 928 surgical management of, 926–928 treatment of, 926–928 type I, 914, 914f type II, 914, 914f type III, 914, 914f types of, 914, 914f VATS for, 928 Bullous lung disease clinical features of, 918, 919f–920f complications of, 923–926 definition of, 913 exercise testing in, 923 pathophysiology of, 921–923 pulmonary circulation in, 923 pulmonary function testing in, 921–922, 925t, 926t, 927t surgical management of, 926–928 treatment of, 926–928 VATS management of, 654–655 , 654f Bullous myringitis, 2101t Bupropion, in smoking cessation, 755–756 Burkholderia cenocepacia, infection (incl. pneumonia), in cystic fibrosis, 2176 Burkholderia cepacia genomovars, 2176 infection (incl. pneumonia), in cystic fibrosis, 875, 880, 2176 treatment of, 875, 2179 pneumonia, 2009 staining characteristics of, 2036f Burkholderia mallei, infection (incl. pneumonia), 2146 Burkholderia multivorans, infection (incl. pneumonia), in cystic fibrosis, 2176 Burkholderia pseudomallei, 2428t, 2439–2440. See also Melioidosis bacteriology of, 2428t, 2439 culture of, 2429t ecology of, 2439 infection (incl. pneumonia), 2146 history and physical findings in, 2100t in lung abscess, 2154t

staining characteristics of, 2429t transmission of, 2439 Burn(s). See also Inhalation injury; Smoke inhalation airway management with, 1060 and risk of infection, 2306, 2317 upper airway obstruction caused by, 858 ventilation therapy in, 1060–1061 Burn injury, 1053 Busulfan and interstitial lung disease, 1110t pneumonitis caused by, 2011, 2012t pulmonary effects of, 1073, 1074t, 1075, 1181, 1295 Butyrophenones, for agitated ICU patient, 2704–2705 Byssinosis, 934t clinical presentation of, 982 endotoxin and, 983, 983t epidemiology of, 982 grading of, 982, 982t historical perspective on, 981–982 pathogenesis of, 982–983 pathology of, 982–983 prevention of, 983 pulmonary function testing in, 982 risk factors for, 982 stages of, 982 treatment of, 983 C C. See Compliance Cachexia, 2692 in pulmonary disease, 452–453 Cadmium compounds airborne, 1020 inhalation injury caused by, 1000t, 1002–1003 Cadmium oxide, bronchiolitis caused by, 893t Caesalpinus, Andreas, 5t, 6 Caf´e coronary syndrome, 2151 ´ y, 13 Cajal, Ramon CALBG. See Cancer and Leukemia Group B trial Calcification(s) diffuse pulmonary, 1236–1237, 1236f dystrophic, 1236 metastatic, 1234t, 1236, 1236f Calcineurin inhibitors, interactions with drugs for nontuberculous mycobacteria, 2503t Calcipotriene, for scleroderma, 430 Calcium intracellular, 361–362 in regulation of airway smooth muscle contraction, 116, 117f Calcium-channel blockers for pulmonary arterial hypertension, 1386–1387 pulmonary effects of, 1093

Campylobacter in empyema, 2144t infection (incl. pneumonia) in HIV-infected (AIDS) patients, 2212t immune defect associated with, 1983t, 2210t Canals of Lambert, 151 Cancer and Leukemia Group B trial, 1869t, 1870 Cancer patient(s) empiric antibiotic therapy in, 2220, 2221–2222 fever in empiric antibiotic therapy in, 2220 initial management of, 2219–2220 with pulmonary infiltrates, 2220 infection in, 2215–2219 clinical manifestations of, 2219 initial management of, 2219–2220 microbiology of, 2216–2219 pneumonia in causes of, 2220, 2221t differential diagnosis of, radiologic findings in, 2220–2221, 2221t and risk of infection, 2317 risk of venous thromboembolism in, 1426 Cancrum oris, 2087 Candida, 1994 in bronchial wash specimen, 515, 515f colonization by, 2313 in empyema, 2144 hypersensitivity pneumonitis caused by, 1164t identification of, in tissue, 2038t, 2315 infection (incl. pneumonia), 2313. See also Candidiasis in bone marrow and stem cell transplant recipients, 2222–2223 in cell-mediated immunodeficiency, 2236 in Chediak-Higashi syndrome, 2238 in HIV-infected (AIDS) patients, 2212t, 2215 immune defect associated with, 1983t, 2210t in leukocyte adhesion deficiency, 2239, 2239f in neutropenic host and cancer patient, 2217 nosocomial, 2280t, 2281t, 2282 in surgery and trauma patients, 2197 laryngitis caused by, 2087 molecular detection of, 2002 oral infection, 2087 staining characteristics of, 2035t Candida albicans, 2313–2314 in acute mediastinitis, 2166t in allergic bronchopulmonary mycosis, 837

I-22 Index Candida albicans (Cont.) hypersensitivity pneumonitis caused by, 1165t infection (incl. pneumonia). See also Candidiasis in neutropenic host and cancer patient, 2217 nosocomial, 2279 staining characteristics of, 2037f Candida glabrata, 2313–2314 identification of, in tissue, 2038t infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 staining characteristics of, 2034, 2036f Candida krusei, 2313–2314 infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 Candida parapsilosis, 2313–2314 staining characteristics of, 2036f Candidate gene analysis, 710–711, 793 Candida tropicalis, 2313–2314 in acute mediastinitis, 2166t in myositis, 2315 Candidiasis cytopathology of, 519 disseminated, diagnosis of, 2315 epidemiology of, 2313 extrapulmonary involvement in, 2314–2315 mycology of, 2313–2314 pathogenesis of, 2314 pulmonary, 2313–2316 clinical manifestations of, 2314–2315 diagnosis of, 2315 in lung transplant recipient, 2315 radiographic findings in, 2314, 2315f treatment of, 2315–2316 Cannon, Walter B., 226–227, 226f Canon of Avicenna, 4 CAP. See Pneumonia, community-acquired Capillaritis after lung transplantation, 1464 biopsy in, 1282, 1284f idiopathic pauci-immune pulmonary, 1462 pulmonary, 1092–1093 with diffuse alveolar hemorrhage, 1237, 1239f, 1241, 1281–1282, 1282t causes of, 1237, 1239t in collagen vascular disease, 1194t, 1197, 1197f histopathology of, 1197, 1197f Capillary(ies), pulmonary. See Pulmonary capillary(ies) Caplan’s syndrome, 973, 1202, 1203f Capnocytophaga, infection (incl. pneumonia), immune defect associated with, 1983t, 2210t

Capreomycin adverse effects and side effects of, 2483t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for tuberculosis, 2479 dosage and administration of, 2482t Carbamate ion, 193–194, 205 Carbamazepine and interstitial lung disease, 1110t pneumonitis caused by, 2012t pulmonary effects of, 1089, 1090t, 1092, 1097 Carbapenems penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 Carbocholine inhalational challenge test, 585t, 586 Carbon, cell loading with, in lung, 42, 44 Carbon dioxide (CO2 ). See also Hypercapnia; Hypocapnia alveolar, 592 alveolar and blood capacitances, and diffusive equilibrium, 192 arterial, set-point for regulation of, and ventilatory demands of exercise, 236–238, 239f central chemoreceptors for, 163–164 chemical reactions of, 193–194, 193f, 194f clearance, in exercise, 235, 235f, 236–237, 236t, 238f discovery of, 7, 8–9 dissolved form of, 204 elimination, 591–592 assessment of, in acute respiratory failure, 2669 exchange, 193–194, 193f, 194f kinetics of, 205–206, 205t in indoor air, sources of, 1021t metabolic source of, 613 nonmetabolic source of, 613 output in exercise, 613, 613f at rest, 613 normal, 1323, 2735 production of, 203, 208, 211, 611 removal arterial venous, for burn patient, 2556 extracorporeal, in ALI/ARDS, 2556 transport, 193–194, 193f, 194f, 203–206, 211, 611 ventilatory response to, 161, 162f, 597, 597f determination of rebreathing method, 597 steady-state method, 597 factors affecting, 597, 598t normal, 597

Carbon dioxide (CO2 ) equilibrium curve, 204, 204f Carbonic acid, 193–194, 204, 208, 209, 209f Carbonic anhydrase, 193–194, 204, 206, 209, 209f, 211 discovery of, 11 Carbon monoxide in blood, 1023–1024 blood levels of, in smokers, 752 diffusing capacity for, 195, 195f, 592–593, 603, 607, 607t age-related changes in, 273 determination of factors affecting, 197–199, 594 rebreathing method, 195–196 single-breath method, 195–196, 593–594 steady-state method, 195–196, 593–594 in emphysema, 732 factors affecting, 197–199 interpretation of, 199 reduced, 607, 607t, 608t exposure to, and myocardial ischemia, 1033 in indoor air, 1020–1024 acute and chronic effects of, 1023 sources of, 1021t National Ambient Air Quality Standards for, 1011t in outdoor air exposures to, 1019 health effects of, 1019 poisoning with, 203, 1054, 1055–1056 diagnosis of, 1055 oxygen therapy in, 2619 signs and symptoms of, 1055, 1055t treatment of, 1055–1056, 2617 in smoke and inhalation injury, 1054, 1055–1056 source of, 1054t sources of, 1011t uptake by red cells, 193 Carbon tetrachloride exposure to, 1027t sources of, 1027t Carboxyhemoglobin, 1019, 1023–1024, 1055, 1055t and myocardial ischemia, 1033 Carboxypeptidase A, mast cell, 310t, 311 Carcinoid syndrome, 433, 444–445 Carcinoid tumor(s), 444 anatomical distribution of, 433 bronchial hemoptysis caused by, 413 presenting as solitary pulmonary nodule, 1816 cytopathology of, 531 endocrine and hematologic syndromes associated with, 1930t

I-23 Index pulmonary, 1841–1845, 1920–1921, 1922f atypical, 1843–1845, 1845f, 1920–1921 cytopathology of, 531 typical, 1842–1843, 1843f–1844f, 1920–1921, 1922f thymic, 1601 Carcinosarcoma, 1840–1841, 1841f, 1921, 1922f Cardiac asthma, 402 Cardiac catheterization historical perspective on, 16 in pulmonary hypertension, 1374, 1375, 1375f Cardiac failure chronic, 616–621 cardiopulmonary exercise testing in, 616–620 chronotropic dysfunction in, 620 diastolic dysfunction in, 619–620 exercise training in, 620–621 prognosis for, 620 response to medications in, evaluation of, 620 survival, 620 systolic dysfunction in, 616–619, 617f–619f classification of, 614–615, 615t definition of, 616 Cardiac index, predicted, in classification of cardiac and circulatory failure, 614–615, 615t Cardiac output, 612, 1337–1338, 1338f in acute respiratory failure, 2663 changes, in response to ventilation-perfusion inequality, 186–187, 186f determination of, historical perspective on, 16 in exercise, 224–225, 225f, 612–613 inadequate (low-flow state), oxygen therapy for, 2619 intrapulmonary distribution of, 1338 maldistribution, and tissue hypoxia, 2616t, 2617 measurement of, 2663 normal, 1334t in pregnancy, 256, 257t fetal effects of, 258 in respiratory failure, 2518t, 2519 Cardiomyopathy, peripartum, 259t Cardiopulmonary bypass, and respiratory failure, 2584 Cardiopulmonary exercise testing, 225–226, 611–628 in chronic cardiac failure, 616–620 in chronic circulatory failure, 621–624 in chronic lung diseases, 624–625 in chronic obstructive pulmonary disease, 624–625 clinical application of, 613–614

in congenital heart disease, 622–623 in dyspnea, 405 in emphysema, 624–625 in environmental lung disease, 940 in evaluation of impairment/disability, 681 in exertional dyspnea, 625–626, 626t in heart transplant candidates, 626 in heart transplant recipients, 626, 627f in ischemic heart disease, 621 in obstructive sleep apnea, 622 in occupational lung disease, 940 in pulmonary hypertension, 623–624, 623t, 624f in restrictive lung disease, 625 in surgical risk assessment, 626–628 in valvular heart disease, 621–622, 621f, 622f Cardiopulmonary resuscitation Hollywood code and, 2729 for ICU patient, outcomes with, 2716 slow code and, 2729 Cardiovascular disease hemoptysis in, 414, 414f smoking and, 751–752 Cardiovascular surgery, and mediastinitis, 2162–2164, 2163t, 2164t Cardiovascular system age-related changes in, 264t circadian clock in, 1694 Carmustine immunologic effects of, 2216 and interstitial lung disease, 1110t pneumonitis caused by, 2011, 2012t pulmonary effects of, 1078–1080, 1079t, 1080f, 1181, 1295 therapeutic uses of, 1078 Carotid body(ies) afferent activity, 161–163, 162f type I cells, 163 type II cells, 163 Caseous necrosis, 2048 Caspase(s), 1977 Caspofungin for candidiasis, 2316 for coccidioidomycosis, 2345 for invasive fungal infections, 2310t, 2311, 2311t, 2312 Castleman’s disease, 1604, 1605f, 1954–1955 multicentric, 1954–1955, 1955f solitary, 1954, 1954f Cat(s), allergens, exposure to, 1031 Catalase(s), Aspergillus, 2294 Cat allergen(s), and risk of asthma, 794 Catecholamines. See also specific drug dosage forms, 2632t and pulmonary circulation, 1347 receptor activity, 2632t structure-activity relationships, 2632 structure of, 2633f

Catechol-O-methyltransferase, 2633 β-Catenin, 86 Cathelicidin, in airway surface liquid, 281 Cathepsin C, 720 Cathepsin G, 718t, 1973 mast cell, 310t, 311 Cathepsin L, 718t, 720 Cathepsin S, 718t, 720 Caveolae, 31, 34, 34f, 40 Caveolin, 31 Cavernous hemangioma, 1918 Cavitation, 1988t, 2022, 2023f, 2043, 2148f chronic pathogenesis of, 1990–1991 pathology of, 1990–1991, 1991f–1993f computed tomography of, 478, 482f, 483f etiology of, 1990–1991 in HIV-infected (AIDS) patients, 2214t, 2215, 2248, 2249t microbiology of, 2146 with pneumonia, 2027–2028, 2146 CC. See Closing capacity CC10. See Clara cell protein 10 CCNU. See Lomustine CCP. See Ciliocytophthoria CCPA. See Aspergillosis, pulmonary, chronic, cavitary CCR5 gene, mutations of, in HIV-infected (AIDS) patients, 2243 CCSP. See Clara cell secretory protein CD5, 324 CD28, 1976 CD40, 1974 CD80, 1971, 1974, 1976 CD86, 1971, 1974, 1976 CD11b, 1974 CD11c, 1974 CD40 ligand (CD40L), 323, 1976 Cdyn. See Dynamic compliance C/EBP, and eosinophil development, 313 Cefazolin, for staphylococcal pneumonia, in children, 2132 Cefdinit, for streptococcal pharyngitis, 2086 Cefepime, 2056 for hospital-acquired pneumonia, 2061, 2061t, 2062 Cefotaxime, 2056 for pasteurellosis, 2429t, 2430 Cefotetan, indications for, 2157 Cefoxitin indications for, 2157 interactions with immunosuppressive agents, 2503t for nontuberculous mycobacteria, 2505 Cefpodoxime indications for, 2060 for streptococcal pharyngitis, 2086

I-24 Index Ceftazidime, 2056 for cystic fibrosis patient, 875 for hospital-acquired pneumonia, 2061t, 2062 for melioidosis, 2429t, 2440 resistance to, 2099 Ceftriaxone, 2056 for children, 2131 for hospital-acquired pneumonia, 2061t, 2062 for pasteurellosis, 2430 resistance to, 2099 Cefuroxime, 2056 indications for, 2060 for Moraxella catarrhalis infection, 2445 for staphylococcal pneumonia, in children, 2132 Celecoxib, lack of airway response to, in aspirin-sensitive asthmatics, 801, 802f Celiac disease, sarcoidosis and, 1136t Cell adhesion molecules, 347 and airway smooth muscle proliferation, 119 counter receptors, 347–348 expression of, by airway smooth muscle cells, 121–122, 122t in inflammation, 782–783 in inflammatory/fibrotic lung disease, 374 and leukocyte adherence and migration, 347–349 oxidative lung injury and, 363 Cell cycle, molecular genetic changes and, 1809–1811, 1810f Cell-mediated immunity, 280 Cell-mediated immunodeficiency in cancer patients, 2215–2216 in children, 2139 in HIV-infected (AIDS) patients, 2243–2244 immunologic work-up of, 2234t pulmonary infection in, 2236 Cellulitis auricular, 2091 orbital, 2090, 2090f preseptal, 2090, 2090f Centigray (cGy), 1177 definition of, 1895 Central nervous system (CNS) abnormalities, and respiratory failure, 2513–2514 pneumonia and, 2101t Central venous catheter/catheterization in acute respiratory failure, 2661–2663 in ALI/ARDS, 2554, 2554t Central venous pressure in acute respiratory failure, 2662, 2665 in pregnancy, 257t CEP. See Eosinophilic pneumonia(s), chronic Cephalexin, for cystic fibrosis patient, 875

Cephalization, 474f, 494 Cephalosporins for children, 2131 for cystic fibrosis patient, 875 fourth-generation, 2056 indications for, 2157 for Moraxella catarrhalis infection, 2445 newer, 2056 for pasteurellosis, 2430 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2056 pneumonitis caused by, 2012t pulmonary effects of, 1089, 1090t resistance to, 2108, 2280–2282 second-generation, 2056 for staphylococcal pneumonia, in children, 2132 for streptococcal pharyngitis, 2086 third-generation, 2056 for yersiniosis, 2429t, 2441 Cephalosporium, hypersensitivity pneumonitis caused by, 1164t c-erbB-1, in lung cancer, 1806 c-erbB-2, in lung cancer, 1806–1807 Cerebellar ataxia, 2101t, 2113 Cerebellar degeneration, paraneoplastic, 1937 in small cell lung cancer, 1905t, 1906 Cerebral edema, high-altitude, 1042 Cerebrospinal fluid (CSF), and acid-base balance, 211 Cervical spine and airway management, 2647–2648 arthritis, pain caused by, 420 C1 esterase inhibitor deficiency, 2236 Cestodes, 2413, 2421–2423 CFA. See Cryptogenic fibrosing alveolitis C-Fos, 87 c-fos, in lung cancer, 1807 CFPA. See Aspergillosis, pulmonary, chronic, fibrotic CFTR. See Cystic fibrosis transmembrane conductance regulator Chagas’ disease, 2407–2409, 2408f in cancer patients, 2219 in immunocompromised host, 2209 Chance, 2614 Charcoal, activated, bronchiolitis caused by, 894t Charcot, 409 Charcot-Leyden crystals, 313, 515, 515f in allergic bronchopulmonary aspergillosis, 842 Charles’s law, 917 Chauveau, 5t, 16 Chediak-Higashi syndrome, pulmonary infection in, 2238 Cheese worker’s disease, etiology of, 1163t Chemical(s) inhalation of, 2013

occupational lung disease caused by, 934t, 935t upper airway obstruction caused by, 858 Chemical weapons, bronchiolitis caused by, 894t Chemokine(s), 351, 352t, 1973 in asthma, 778 and B-cell migration to secondary lymphoid tissues, 323 C, 339, 340t, 351, 1973 CC, 339, 340t, 342–344, 351, 1973 in pulmonary fibrosis, 343–344 in pulmonary inflammation, 343 receptors, 342–343, 343t CXC, 339, 340t, 351, 1973 with angiogenic activity, 339, 341t in pulmonary fibrosis, 341–342, 342f in pulmonary inflammation, 339–341 receptors, 339, 341t CXXXC, 339, 340t, 351, 1973 eosinophils and, 310t, 314–315 and fibrocyte trafficking in lung, 342 and immune cell migration, 351–353 and mast cells, 311 in pulmonary fibrosis, 341–344, 342f, 372–374, 373f in pulmonary inflammation, 339–343, 372–374, 373f release of, by airway smooth muscle cells, 121 Chemokine receptors, 324, 351, 352t, 1975, 1977 CCR5, and HIV infectivity, 351 in pulmonary inflammation/fibrosis, 372–374, 373f Chemoreceptor(s), 2592–2593 arterial, 245–246, 247f and control of respiration, 1037–1039 central, 163–164, 211, 244–245 knowledge of, historical perspective on, 13 and dyspnea, 397 knowledge of, historical perspective on, 5t, 13 peripheral, 161–163, 211 knowledge of, historical perspective on, 13, 14f reduced function of, pathophysiology of, 168 Chemosensitivity, respiratory, 2592–2595 abnormalities of, treatment of, 2610 blunted, and development of respiratory failure, 2594–2595, 2594f–2595f central, 244–245 Chemotaxins, 1973 Chemotherapy drug toxicity in, 2221 immune defects caused by, 2215–2216

I-25 Index for mesothelioma, 1546–1547 for non-small cell lung cancer, 1867–1878 and pleural effusion, 1506t pulmonary effects of, 1181, 1295 pulmonary toxicity of, 1067–1084, 1093 approach to patient with, 1067–1068 cytopathology of, 526–527, 527f diagnosis of, 1069 difficulties of, 1067–1068 differential diagnosis of, 1067–1068, 1068t epidemiology of, 1067 monitoring, 1068–1069 and pulmonary function testing, 1068–1069 and radiation therapy, combined, and risk of pneumonitis, 1181 for small cell lung cancer, 1908–1909 second-line, 1909–1910 Chest elastic properties of, knowledge of, historical perspective on, 11–12 injury, hemoptysis caused by, 413t, 414 inspection of, 390 palpation of, 390–392 percussion of, 392 Chest pain, 418 anxiety and, 420 with bulla, 925 in interstitial lung disease, 1108 with mediastinal lesions, 1587, 1587t in pulmonary hypertension, 1371, 1371t Chest radiograph(s), 388, 420, 421f, 423, 423f, 2017, 2018f. See also Portable chest examination in ALI/ARDS, 2536, 2536t, 2540–2542, 2543f in allergic bronchopulmonary aspergillosis, 840f, 841–842, 2296, 2298f in anaerobic infections, 2153 of asbestos-related pleural plaques, 945, 945f of aspergilloma, 2301–2303, 2302f in asthma diagnosis, 819 in bronchiectasis, 2188 of bullae, 919f–922f, 920 contrast examination, 465 in cystic fibrosis, 870–871, 871f in dyspnea, 404 in emphysema, 473f in environmental lung disease, 937–939 in evaluation of impairment/disability, 680 expiratory film, 458 historical perspective on, 18 in HIV-infected (AIDS) patients, 2248, 2249t

in hypersensitivity pneumonitis, 1165, 1166f, 1167f in idiopathic pulmonary fibrosis, 1147f, 1148 International Labour Office classification of, 939 of interstitial lung disease, 483, 490f–491f in Langerhans’ cell histiocytosis, 1246–1247, 1246f lateral, 456, 456f, 457f lateral decubitus projection, 457–458, 458f lordotic view, 458, 459f in lymphangioleiomyomatosis, 1258, 1259f, 1260f multiple thin-walled airspaces on, differential diagnosis of, 921t oblique view, 457 in occupational lung disease, 937–939, 938f over-penetrated grid, 458, 459f in oxygen toxicity, 2628 in Pneumocystis pneumonia, 2357f, 2358–2359, 2359f, 2360f in pneumonia, 2099–2101, 2101f–2103f posteroanterior, 456, 456f, 457f preoperative, 670 with pulmonary embolism, 1430–1431 in routine examination, 456, 456f, 457f of sarcoidosis, 1132–1133, 1132f of solitary pulmonary nodule, 1818 supplementary projections, 456–458, 458f, 459f Chest trauma. See Trauma, thoracic Chest wall abnormalities, and respiratory failure, 2514 age-related changes in, 267, 267f anatomical changes in, and ventilation, 2598 elastic properties of, 151–152 muscles, in dyspnea, 2596–2597 nonmuscular diseases of, 1617–1632 pain in, 418–419 pressure difference across, 575f, 576 pressure-volume relationships of, 151–152, 152f, 2598 radiographic evaluation of, 500–503 resection, in non-small cell lung cancer, 1859–1860, 1860f static compliance of, 575–576, 575f, 576f tumors of, computed tomography of, 461, 462f Chest wall compliance, definition of, 1328, 2740 Chest wall resistance, 583 Cheyne-Stokes respiration, 169–170, 169f, 403–404, 404f, 1712, 1712f Chicken breeder’s disease, etiology of, 1164t

Chicken feather proteins, hypersensitivity pneumonitis caused by, 1164t Chickenpox, vaccine against, 2070t, 2072–2073 Child(ren) aspiration pneumonia in, 2136, 2136f cell-mediated immunodeficiency in, 2139 granulocyte disorders in, 2138–2139 HIV-infected (AIDS) patients, 2139 humoral immunodeficiency in, 2138 influenza in, morbidity and mortality with, 2125 lower respiratory tract infections in diagnosis of, 2125 morbidity and mortality with, 2125 Pneumocystis jiroveci pneumonia in, 2136–2137, 2137f pneumonia in. See also specific pathogen morbidity and mortality with, 2125 recurrent, 2137–2139, 2137f tuberculosis in, 2134–2135, 2134f Chills, in pulmonary disease, 452 Chlamydia, infection (incl. pneumonia) and asthma, 816 pathogenesis of, 2080 pathology of, 2043–2045 treatment of, 831 Chlamydia pneumoniae. See also Chlamydophila pneumoniae and acute bronchitis, 2097 infection (incl. pneumonia) in children, 2133–2134 clinical features of, 2381 diagnosis of, 2106 differential diagnosis of, 2266 history and physical findings in, 2101t pharyngitis caused by, 2086 pneumonia, 2020 and sarcoidosis, 1126–1127 Chlamydia psittaci, infection (incl. pneumonia) chest radiograph in, 2102f history and physical findings in, 2100t Chlamydia trachomatis infection (incl. pneumonia), in early infancy, 2130 pneumonia in early infancy, 2127–2128, 2127f in newborn, 2006 Chlamydophila pneumoniae, 1992, 1996.

See also Chlamydia pneumoniae infection (incl. pneumonia) diagnosis of, 2113 hospitalization rate for, 2105t reactivation-type, 2113 treatment of, 2053, 2055, 2057, 2113 molecular detection of, 2002 pneumonia, 2005, 2005t

I-26 Index Chlamydophila psittaci, 2005t, 2006.

See also Psittacosis epidemiology of, 1984t, 2004 infection (incl. pneumonia), ICU admission rate for, 2106t Chlorambucil, pulmonary effects of, 1073, 1074t, 1075 Chloramines, inhalation injury caused by, 1000 Chloramphenicol for anthrax, 2429t for cystic fibrosis patient, 875 indications for, 2157 for melioidosis, 2429t, 2440 for meningococcal pneumonia, 2444 for pasteurellosis, 2429t, 2430 penetration into lung, 2053 for plague, 2429t, 2432 for tularemia, 2429t, 2434 for yersiniosis, 2429t, 2441 Chlordane exposure to, 1027t sources of, 1027t Chloride, secretion of, in submucosal glands, 142, 142t Chloride channels. See also Cystic fibrosis transmembrane conductance regulator epithelial, 139, 139f Chloride transport, epithelial, 138, 138f cellular and molecular mechanisms of, 139, 139f Chlorine gas as air toxic, 1020 bronchiolitis caused by, 893t, 894 inhalation injury caused by, 1000–1001, 1000t in smoke and inhalation injury, 1054, 1057 water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995t Chloroacetophenone, inhalation injury caused by, 1003–1004 ortho-Chlorobenzylidene malonitrile, inhalation injury caused by, 1003–1004 Chlorofluorocarbon propellants (CFCs), 2634 Chloroform exposure to, 1027t sources of, 1027t Chloropicrin, bronchiolitis caused by, 893t, 895 Chloroquine, 2407 for sarcoidosis, 1140, 1140t Chlorozotocin pulmonary effects of, 1079t, 1080–1081 therapeutic uses of, 1078 Chlorpromazine, lupus-like syndrome caused by, 2012t

Chlorpyrifos exposure to, 1027t sources of, 1027t Cholesteatoma, chronic suppurative otitis media and, 2093–2094, 2093f Cholesterol pneumonia, 2014 Chondritis, of pinna, 2091 Chondroitin sulfate(s) mast cell, 310–311, 310t in mast cells, 308 Chondroma, 1918 Chordoma, 1596 Choriocarcinoma of anterior mediastinum, 1607 primary pulmonary, 1925 Chromium, and occupational asthma, 990 Chromobacterium violaceum, infection (incl. pneumonia), in chronic granulomatous disease, 2237 Chronic critical illness, 2565 Chronic granulomatous disease (CGD), 2138–2139 pulmonary infection in, 2237–2238, 2238f and risk of infection, 2307 subacute invasive pulmonary aspergillosis in, 2292 Chronic lymphocytic leukemia (CLL), 1949 Chronic obstructive pulmonary disease (COPD), 693–694. See also Bronchitis, chronic; Emphysema and abnormal breathing pattern, 403 acute exacerbations, 2115–2123 bacterial causes of, 741, 742t, 2116–2117 clinical findings in, 740–741, 742t, 2118 definition of, 2115 environmental exposures and, 741, 2118 etiology of, 741, 2116–2118 evaluation of, 741, 741t, 2118–2119 and health care utilization, 2116 and health status, 2116 hospitalization for, 741, 741t, 2123, 2123t ICU admission for, 741–742, 741t laboratory findings in, 2118 physiologic changes in, 2119 pulmonary effects of, 2116 treatment of, 740–742, 742t, 2118f, 2118t, 2119–2123, 2119t viral causes of, 742t, 2116, 2116t airflow obstruction in, 729–730 air pollution and, 1032–1033, 1032t air travel in, 735–736 anemia in, treatment of, 737 apoptosis in, 716, 717 BODE index for, 1775, 1776t

bronchiectasis in, 2183 cardiopulmonary exercise testing in, 624–625 chronic ventilator support in, 745 complement in, 349 complications of prevention of, 734 treatment of, 740–743 CO2 retainers in, 398 cor pulmonale in, 743, 1403–1405 acute, treatment of, 1407–1408 definition of, 707 diagnosis of, 731–732 differential diagnosis of, 729–730, 819t drug therapy for, 737–740, 737f, 738t, 2634, 2635–2636, 2638 adherence to, 739 dyspnea in, 393–398 epidemiology of, 707–708 exercise and rehabilitation in, 734–735.

See also Rehabilitation FDG-PET in, 565f, 566 flow-volume loop in, 849, 850f genetics and, 710–711 heart failure in, radiographic features of, 476 in HIV-infected (AIDS) patients, 2260 hypercapnia in, 743 and hypercapnic respiratory failure, 2605–2607, 2606f inflammation and, 715 initial assessment of, 421 large airway lesions in differential diagnosis of, 700–702, 701t gross findings in, 699 microscopic findings in, 699–700, 700f lung transplantation in, 744–745, 1774t, 1775–1777 lung volume reduction surgery in, 743–744, 744f mechanical ventilation in, inspiratory flow rate with, 2681–2682, 2682f medium airway pathology in, 730 mortality rate for, 708 mucus hypersecretion in, 717 natural history of, 730–731, 730f nutritional status in, 2605, 2692 nutritional support in, 735 and obstructive sleep apnea, concurrent, 1725 occupational, 934t, 935 occupational exposures and, 933–934 outcomes of, 2714 oxidant-antioxidant imbalance and, 716–717, 716f oxygen therapy in, 2620, 2620t and air travel, 735–736, 736f long-term, 736–737 pathogenesis of, 715–717

I-27 Index pathologic descriptions of, historical perspective on, 694 pathology of, 398, 399f pathophysiology of, 711–715 patient education about, 732–734, 733t physical findings in, 389–390 physiological-pathological correlations in, 714–715, 714f and pneumonia, 2100t, 2110 pneumothorax in, 742–743 treatment guidelines for, 1530–1531 and postoperative pulmonary complications, 667 posture in, 2597 prognosis for, 732, 733t, 2714 progression, prevention of, 734 proteinase-antiproteinase imbalance and, 715–716 pulmonary function testing in, 604t, 605, 606t, 729, 731–732 pulmonary hypertension in, 1393–1395, 1394f pulmonary vasculature in, 703–704, 704f respiratory muscle action in, 76, 78, 2597–2598, 2598f risk factors for, 708–711, 708t and risk of postoperative respiratory failure, 2574–2575 scintigraphy in, 551 severity of classification of, 731, 732t Social Security Listings for, 686, 686t and sleep, 1725 sleep disorders in, 735 small airway pathology in, 702–703, 715, 715f, 730 differential diagnosis of, 702–703 histopathology of, 702 microscopic findings in, 702, 702f smoking and, 749–751 stable, treatment of, 732–740 supraventricular arrhythmias in, 743 technetium-99m-labeled aerosols in, 551 treatment of, 398 advanced, 743–745 type A (emphysematous), 713, 713f type B (chronic bronchitis), 713, 713f Chronic thromboembolic pulmonary hypertension, 1362t, 1400–1402, 1400f, 1401f, 1429, 1442 Churg-Strauss syndrome, 1091, 1093, 1289–1290 and asthma, 1226 bronchoalveolar lavage cellular profile in, 1121t cardiac involvement in, 1225 clinical course of, 1223–1224

clinical features of, 435, 1118t, 1231t, 1457–1458 computed tomography of, 1115t, 1118t cutaneous manifestations of, 1225 diagnosis of, 1457–1458, 1458f diagnostic criteria for, 1226 differential diagnosis of, 1226, 1231t and diffuse alveolar hemorrhage, 1241 eosinophilic phase of, 1224 epidemiology of, 1223 gastrointestinal manifestations of, 1225 histology of, 1118t histopathology of, 1225, 1226f historical perspective on, 1223 immunologic test for, 1112t laboratory findings in, 1225 neurological manifestations of, 1225 organ systems affected by, 1452t pathogenesis of, 1225–1226 pleural effusion in, 1497 prodromal phase of, 1224 prognosis for, 1226–1227 pulmonary involvement in, 1224–1225, 2013 renal manifestations of, 1225 skin lesions in, 435 survival with, 1227 treatment of, 1118t, 1226–1227, 1461 vasculitic phase of, 1224 Chylothorax, 1499–1500 after lung resection, 1745–1746 Chymase, mast cell, 308, 310t, 311 α 2 -Chymotrypsin, 1970 Ciclesonide, for asthma, 823t Cidofovir, indications for, 2375t, 2394, 2395 Cigarette smoking. See Smoking Cilia, 27, 28f. See also Primary ciliary dyskinesia diseases of, 2138 immotile, 2138 Ciliary dyskinesia syndromes, 144 Ciliated bronchial columnar cells, 515 Ciliocytophthoria, 513, 522, 522f Ciprofloxacin, 2056 adverse effects and side effects of, 2483t for anthrax, 2437 for cystic fibrosis patient, 875 dosage and administration of, 2057 for hospital-acquired pneumonia, 2061, 2061t, 2062 for melioidosis, 2440 for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for plague, 2432 for Rhodococcus pneumonia, 2429t for tularemia, 2434 Circadian rhythms of cardiopulmonary function, 1694 and sleepiness, 1731–1732, 1732f Circulation Galen’s scheme of, 4, 6f

Harvey’s description of, 6–7 pulmonary. See Pulmonary circulation Circulatory failure chronic, 621–624 classification of, 614–615, 615t definition of, 621 Cirrhosis hepatic and bronchial circulation, 1353–1354 circulatory effects of, 448–449 ventilatory effects of, 447–448 and pulmonary arteriovenous communications, 1468 Cis-platinum, pulmonary effects of, radiation therapy and, 1181 Citrobacter infection (incl. pneumonia) nosocomial, 2280, 2281t in surgery and trauma patients, 2197 pneumonia, 2019, 2022 c-jun, in lung cancer, 1807 6Ckine, 340t c-kit ligand. See Stem cell factor CL. See Lung compliance Cladosporium hypersensitivity pneumonitis caused by, 1165t in indoor air, 1031 infection (incl. pneumonia), in cancer patients, 2217 Clara cell(s), 29–30, 30f, 87, 138, 281, 282 surfactant synthesis and secretion by, 39 Clara cell protein 10, 85, 87 Clara cell secretory protein, 30 Clarithromycin adverse effects and side effects of, 2494, 2503 dosage and administration of, 2055 indications for, 2060, 2157 interactions with immunosuppressive agents, 2503t with rifabutin, 2503 with rifamycins, 2503 for Moraxella catarrhalis infection, 2445 for Mycobacterium avium complex infection, 2505 in HIV-infected (AIDS) patients, 2493–2494, 2494t prophylactic regimen, 2495, 2495t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t organisms susceptible to, 2055 penetration into lung, 2053, 2053t resistance to, mycobacterial, 2505 for Rhodococcus pneumonia, 2429t Clavulanic acid, 2056 CLC protein, 310t, 314 Clean Air Act, 1010, 1016, 1032 Clear cell carcinoma, 1840 Cleft palate, 2647

I-28 Index Clindamycin for anaerobic infections, 2157, 2157t for anthrax, 2437 mechanism of action of, 2055 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 plus aztreonam, for hospital-acquired pneumonia, 2061t, 2062 for protozoan infection, 2407 resistance to, 2099 for staphylococcal pneumonia, in children, 2132 for toxoplasmosis, 2402 Clindamycin and primaquine, for Pneumocystis pneumonia, 2368t, 2370 Clofazimine adverse effects and side effects of, 2483t interactions with immunosuppressive agents, 2503t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t Clonidine, in smoking cessation, 756 Clonorchis sinensis, and eosinophilic pneumonia, 1214t Closed-circuit helium dilution, 571–572, 572f, 574 Closing capacity age-related changes in, 271, 271f definition of, 1326, 2738 normal, 1323, 2735 postoperative, 664, 665f, 665t Closing volume, 589–590, 589f normal, 1323, 2735 Clostridium in empyema, 2144t infection (incl. pneumonia), 2156t conditions underlying, 2145t Clostridium botulinum, 1656 Clostridium difficile, colitis, 2207 Clostridium perfringens, in empyema, 2144t Clostridium septicum, infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 Clubbing of digits, 416, 417f, 453, 453f characteristics of, 416, 417f in chronic obstructive pulmonary disease, 731 disorders associated with, 390, 390t, 416 paraneoplastic, 445 pathogenesis of, 416 Cmax, 2054 Cmax/MIC, 2054 CMV. See Cytomegalovirus (CMV) CNPA. See Aspergillosis, pulmonary, chronic, necrotizing Coagulopathy, and diffuse alveolar hemorrhage, 1295

Coal, 968 bronchiolitis caused by, 894t, 895–896 lung disease caused by, 934, 934t Coal miner(s) gas exchange in, 972 lung function in, 972 respiratory impairment in, 972 and smoking cessation, 973 ventilatory function in, 972 Coal mining, 968, 968f Coal workers’ lung disease(s). See also Coal worker’s pneumoconiosis; Progressive massive fibrosis clinical features of, 971 epidemiology of, 968–970 historical perspective on, 967–968 management of, 973–974 mortality rate for, 970 pathology of, 970–971, 971f prevention of, 979 radiographic findings in, 969, 971–972 ventilatory lung function in, 969–970 Coal worker’s pneumoconiosis, 2025. See also Progressive massive fibrosis bronchoalveolar lavage in, 973 clinical features of, 971 complicated, 970–971 computed tomography of, 1115t epidemiology of, trends in, 969, 969f, 970f exposures associated with, 1109t hemoptysis in, 412f historical perspective on, 967–968 immunology of, 972–973 management of, 973–974 mortality rate for, 970 pathology of, 970–971, 971f radiographic findings in, 971–972 simple, 970 Cobalt lung disease caused by, 934, 934t and occupational asthma, 990 occupational lung disease caused by, 935t Cobb angle, 1618, 1619f Cocaine free-base, bronchiolitis caused by, 894t pneumonitis caused by, 2012t pulmonary effects of, 1090t, 1091t, 1093, 1101, 1294 and vasculitis, 1464 Coccidioides, infection (incl. pneumonia), in organ transplant recipient, 2230 Coccidioides immitis, 1092, 1994, 2005t, 2006. See also Coccidioidomycosis antigen, detection of, 2343, 2343t culture of, 2343t, 2344 diagnosis of, 2002 host defense against, 1970 identification of, in tissue, 2038t, 2332f

infection (incl. pneumonia) history and physical findings in, 2100t–2101t in HIV-infected (AIDS) patients, 2212t, 2254–2255 radiographic findings in, 2214, 2249t lymphadenopathy in, 2028 pleural effusion in, 1494 in lung abscess, 2154t mycology of, 2341 pneumonia, 2024 sputum culture for, 2000 staining characteristics of, 2037f, 2040f, 2332f Coccidioides posadasii, mycology of, 2341 Coccidioidin skin test, 2002, 2344 Coccidioidomycosis, 1092, 1990, 2006–2007, 2341–2345. See also Coccidioides immitis clinical findings in, 2341–2343 cutaneous lesions in, 390 cutaneous manifestations of, 430 cytology of, 2343 cytopathology of, 520, 520f diagnosis of, 2343–2344, 2343t disseminated, 2342–2343, 2342f diagnosis of, 2343t treatment of, 2344t, 2345 epidemiology of, 1984t, 2327, 2341 extrapulmonary involvement in, 2343 treatment of, 2344t, 2345 geographic distribution of, 2327, 2328f histopathology of, 2331f, 2343, 2343t in HIV-infected (AIDS) patients, 2254–2256, 2341 and pneumothorax, 1523 in immunocompromised host, 2204, 2341 meningitis in, 2343 treatment of, 2345 mycology of, 2341 pathogenesis of, 2341 pathology of, 2341 pneumonia in acute focal, diagnosis of, 2343t acute uncomplicated, treatment of, 2344–2345, 2344t chronic progressive fibrocavitary, 2342 diagnosis of, 2343t treatment of, 2344t, 2345 diffuse, 2342 diagnosis of, 2343t localized, 2342 prevention of, 2345 primary pulmonary, 2341–2343 pulmonary cavity in, 2342, 2342f diagnosis of, 2343t treatment of, 2344t, 2345

I-29 Index pulmonary nodules in, 2342, 2342f diagnosis of, 2343t treatment of, 2344t, 2345 serology in, 2343–2344, 2343t solitary pulmonary nodule in, 1817 staining characteristics of, 2035t treatment of, 2344–2345, 2344t adjunctive surgical therapy in, 2345 duration of, 2345 Coccidiosis intestinal, 2402–2404 systemic, 2401–2402 Cockroach allergen(s), and risk of asthma, 794 Cockroaches, allergens, exposure to, 1031 Coefficient of retraction, 575 Coffee worker’s lung, etiology of, 1163t Cohn, Ferdinand, 15–16 Cohnheim, Julius, 15–16 Coin lesions, 1815, 1917 Colchicine, 2639 for asthma treatment, 832 pulmonary effects of, 1088 Cold-air challenge test, 585t Colistin aerosolized, 2059 for cystic fibrosis patient, 2179 Collagen, 53 age-related changes in, 267 in lung, 151 in lung development, 94 turnover, and emphysema, 719, 719f Collagen vascular disease, 428–430, 1193–1211, 1281–1282. See also Ankylosing spondylitis; Mixed connective tissue disease (MCTD); Polymyositis-dermatomyositis; Rheumatoid arthritis; Scleroderma; Sj¨ogren’s syndrome; Systemic lupus erythematosus (SLE) alveolar hemorrhage in, 1241, 1293 bronchoalveolar lavage cellular profile in, 1121t interstitial lung disease associated with, computed tomography of, 1115t parenchymal reactions in, histopathology of, 1195–1198, 1195f–1198f pathophysiology of, 1193 pleural effusion in, 1496–1497 pulmonary complications of, incidence of, 1193, 1194t radiographic features of, 483, 484 and risk of infection, 1193 scintigraphy in, 559 and vasculitis, 1462–1463 Collapse receptors, 164, 164f Collateral blood flow, 179 Collateral ventilation, 151, 179

Collectin proteins, 39, 41, 127, 127f, 130–131, 1973 Colloid oncotic pressure, in pregnancy, 257t Colonizing organisms in cystic fibrosis, 866, 880–881 infection (incl. pneumonia), immune defect associated with, 1983t, 2210t Colorectal cancer carcinogenesis of, 1807–1809, 1808f metastases, survival rates for, 1941, 1942t pulmonary metastases, 1942 Columbus, Realdus, 5t, 6 Coma, nontraumatic outcomes of, 2715 prognosis for, 2715 Combustion byproducts, in indoor air, sources of, 1021t Common cold, 2085–2086 clinical features of, 2376 complications of, 2086 differential diagnosis of, 2376 epidemiology of, 2085 pathogenesis of, 2085–2086, 2376–2377 prevention of, 2086, 2377 transmission of, 2085 treatment of, 2086, 2377 viral causes of, 2085, 2376, 2376t viral diagnosis in, 2377 Common variable hypogammaglobulinemia, 2139 Common variable immunodeficiency (CVID), 331–332 and bronchiectasis, 2188 pathophysiology of, 331–332 pulmonary infection in, 2234–2235, 2235f sarcoidosis and, 1135, 1136t treatment of, 332 Compensatory overinflation, differential diagnosis of, 699 Competency, 2731 Complement, 1983 in alveolar fluid, 282–283 C3a, 315, 349–350, 349f receptors, 349–350 C5a, 315, 349–350, 349f receptors, 349–350 C3a receptors, expression of, by airway smooth muscle cells, 122, 122t C5a receptors, expression of, by airway smooth muscle cells, 122, 122t cascade, activation pathways for, 349, 349f C3b, 349, 349f in alveolar fluid, 282–283 C5b, 349, 349f C3 convertase, 349, 349f C5 convertase, 349, 349f deficiency of, 2139

associated infections, 1983t, 2210t causes of, 1983t, 2210t immunologic work-up of, 2234t pulmonary infection in, 2236 in immune defense, 349–350, 1973 Complement receptor(s) 1, 1972 3, 1972 Complete blood count, in HIV-infected (AIDS) patients, 2247–2248, 2247t Complete reverse precautions, 2207–2208 Compliance. See also Chest wall compliance; Lung compliance; Static compliance definition of, 149 dynamic. See Dynamic compliance Composite body(ies), 38 Compost lung, etiology of, 1163t Computed tomographic angiography, 462–463, 462f, 470f, 503f in diagnosis of pulmonary embolism, 554–556, 556f Computed tomography (CT), 420–421, 460–463, 2017–2018, 2018f in acute respiratory distress syndrome, 2673 advantages of, 460 in allergic bronchopulmonary aspergillosis, 840f–841f, 841–842, 2296, 2299f in asbestosis, 950–951, 951f of asbestos-related pleural plaques, 945–946 of aspergilloma, 2302–2303 of bullae, 914, 916f, 920–921, 922f, 928f in cancer patients, 2221 of chest wall, 462f, 502 contrast examination, 465–466 of critically ill patient, 509 in dyspnea, 405, 405t in emphysema, 473f, 475–476 in environmental lung disease, 939 in evaluation of impairment/disability, 680 helical, of upper airway obstruction, 850–851, 852f high-resolution, 463, 463f, 492f in asbestosis, 950–951, 951f in bronchiectasis, 2185f, 2188, 2188f in bronchiolitis, 888, 897 in chronic obstructive pulmonary disease, 731 in cystic fibrosis, 871, 872f in environmental lung disease, 939 in evaluation of impairment/disability, 680 in hemoptysis, 413 in hypersensitivity pneumonitis, 1165, 1167f in idiopathic pulmonary fibrosis, 1146–1147, 1148–1149, 1149f

I-30 Index Computed tomography, high-resolution (Cont.) in interstitial lung disease, 484 of interstitial lung disease, 1112–1113, 1113f–1114f, 1116t–1119t in occupational lung disease, 939 in HIV-infected (AIDS) patients, 2247t, 2248 of interstitial lung disease, 1112–1113, 1113f–1114f, 1115t, 1116t–1119t in Langerhans’ cell histiocytosis, 1247, 1247f of localized alveolar disease, 478, 478f, 482f–483f of lung volume, 574–575 in lymphangioleiomyomatosis, 1258–1259, 1260f of mediastinal masses, 1588, 1588f, 1589f of mesothelioma, 563–564 in occupational lung disease, 939 of pleural effusion, 505, 506f in Pneumocystis pneumonia, 2356f, 2360–2361 and positron emission tomography, integrated. See PET/CT of pulmonary arteriovenous malformation, 1470, 1471f of pulmonary embolism, 1432, 1433f, 1434t in pulmonary infection, 1997 in pulmonary tuberculosis, 2469 of sarcoidosis, 1133 screening, 388 of solitary pulmonary nodule, 1818–1819, 1819f, 1820, 1821f of upper airway obstruction, 850–852, 851f–852f Concentric laminar intimal fibrosis, 1364 Conedown, definition of, 1895 Conformal radiotherapy, definition of, 1895 Congenital heart disease cardiopulmonary exercise testing in, 622–623 pregnancy and, 258 Congenital lobar hyperinflation, 699 Congestive heart failure differential diagnosis of, 819t lymphadenopathy in, 2028 Connectionist hypothesis, for SIRS/MODS, 2567–2568 Connective tissue, perivascular, 41–42, 41f, 42f Connective tissue disease (CTD). See also Mixed connective tissue disease (MCTD) bronchiolitis in, 903–905 interstitial lung disease associated with, 2013 pulmonary hypertension in, 1365

Connective tissue growth factor, in lung inflammation and injury, 339 Consciousness, level of, altered, 2101t Consolidation, 1988t, 2019–2020 in cancer patient, 2220–2221, 2221t detection of, 392 in HIV-infected (AIDS) patients, 2248, 2249t localized, postoperative, 508 neoplasia and, 2014 in organ transplant recipient, 2231, 2233t in pneumonia, 2099 radiographic features of, 477–478, 477f–479f Consolidative radiotherapy, definition of, 1895 Continuous positive airway pressure in ALI/ARDS, 2545 complications of, 1717, 1718t mask, 2649 for obstructive sleep apnea, 1715–1718, 1715f, 1716f, 1717f postoperative, 674 for sleep apnea, 1713 Continuous venovenous hemodialysis (CVVHD), for SIRS/MODS, 2570 Contractile cells, of alveolar septum, 40f, 41 Contraction alkalosis, 218 Contrast media and interstitial lung disease, 1110t pulmonary effects of, 1091t, 1093, 1295 Contusion, pulmonary, in trauma patient, 1761–1762, 1761f COP. See Cryptogenic organizing pneumonia Corner vessels, 1349, 1349f Coronary artery bypass grafting phrenic nerve injury in, 2586–2587 pulmonary complications of, 666, 666t Coronavirus and acute bronchitis, 2097 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t characteristics of, 2375t and common cold, 2085, 2376, 2376t and diffuse alveolar damage, 2042 infection (incl. pneumonia) in bone marrow and stem cell transplant recipients, 2229 diagnosis of, 2106 in early infancy, 2129–2130 treatment of, 2394 NL-63, and bronchiolitis, 2376t, 2382 and pharyngitis, 2086 SARS, 2427, 2428. See also Severe acute respiratory syndrome (SARS) serotypes of, 2374 transmission of, 2374

Cor pulmonale acute, 1402 in chronic obstructive pulmonary disease, treatment of, 1407–1408 in pulmonary arterial hypertension, 1408–1409 arrhythmias with, 1377 chronic, 1402 in chronic obstructive pulmonary disease, 731, 743, 1403–1405 clinical evaluation of, 1405–1406 definition of, 1360, 1402 epidemiology of, 1360 hemodynamic features of, 1403 history-taking in, 1371–1372 incidence of, 1402–1403 pathogenesis of, 1379–1380, 1380f, 1395, 1397f, 1402 pathology of, 1360, 1361f, 1362 prevalence of, 1402–1403 severity of, Social Security Listings for, 687, 687t Corticosteroid(s) for acute exacerbations of chronic obstructive pulmonary disease, 741, 2118t, 2119–2120, 2119t adjunctive therapy with, in tuberculosis, 2484 adverse effects and side effects of, 2638–2639 in ALI/ARDS, 2555t, 2556, 2557t for asthma, 2638 for chronic obstructive pulmonary disease, 2638 clinical use of, 2638 for community-acquired pneumonia, 2110 for eosinophilic disorders, 318 for hypersensitivity pneumonitis, 1171 for idiopathic pulmonary fibrosis, 1157 immunologic effects of, 2216 inhaled adverse effects and side effects of, 826t–827t for asthma, 822, 823t, 826t–827t for chronic obstructive pulmonary disease, 740 mechanism of action of, 826t–827t oral, for chronic obstructive pulmonary disease, 740 pharmacology of, 2637 for Pneumocystis pneumonia, 2370 pulmonary effects of, 1091t safety of, 2638–2639 for sarcoidosis, 1139–1140, 1140t systemic adverse effects and side effects of, 827t for asthma, 823t, 827t mechanism of action of, 827t

I-31 Index therapy with and allergic bronchopulmonary aspergillosis, 842, 2296, 2298, 2299 and risk of infection, 2306, 2307 topical for atopic dermatitis, 428 for scleroderma, 430 Corticosteroid-sparing agents, 2639 Cortisol, pharmacology of, 2637 Corvisart, Jean Nicolas, 5t, 13–14 Corynebacterium diphtheriae in acute mediastinitis, 2166t pharyngitis caused by, 2086 Corynebacterium equi. See Rhodococcus equi Corynebacterium jeikeium, in neutropenic host and cancer patient, 2217 Corynebacterium pseudodiphtheriticum, infection (incl. pneumonia) in HIV-infected (AIDS) patients, 2271 in immunocompromised host, 2271 Corynebacterium ulcerans, laryngopharyngitis caused by, 2087 Costodiaphragmatic recess, 24, 24f Costophrenic sulcus, radiographic evaluation of, 457, 457f, 458f Cotton dust, lung disease caused by, 981.

See also Byssinosis Cough. See also Manually assisted coughing; Mechanically assisted coughing acute, 2380–2381 in acute bronchitis, 2097 chronic etiology of, 410 evaluation of, algorithm for, 410, 411f drug-induced, 1093 evaluation of, in evaluation of impairment/disability, 679 in immune defense, 281 in interstitial lung disease, 1108 with mediastinal lesions, 1587, 1587t in pneumonia, 2099 seal’s bark, 2087 Cough reflex, postoperative changes in, 665 Cournand, Andr´e Frederic, 5t, 13, 16, 17f Course, of radiotherapy, definition of, 1895 Coxiella burnetii, 2005–2006, 2005t. See also Q fever epidemiology of, 1984t, 2004 infection (incl. pneumonia) chest radiograph in, 2101f diagnosis of, 2002, 2106 history and physical findings in, 2100t, 2101t hospitalization rate for, 2105t

Coxsackievirus, and pharyngitis, 2086, 2378 CPA. See Aspergillosis, pulmonary, chronic Crab processors, asthma in, 988 Crack cocaine inhalation cytopathology of, 517, 518f pulmonary effects of, 1093, 1101, 1295 Crackles, 393, 393t causes of, 393 coarse, 393, 393t early vs. late, 393 fine, 393, 393t in pneumonia, 2099 wet vs. dry, 393 CRAG. See Cryptococcal antigen Cranial nerve(s), in invasive (malignant) otitis externa, 2092 C-reactive protein (CRP), 1970 assay for, 2107 Creola bodies, 513, 515, 516f Crescent sign, 482f, 2024, 2025f CREST syndrome, 429–430 pulmonary hypertension in, 1365 pulmonary vascular disease in, 1207–1208 Cricopharyngeal dysfunction, 1307f Cricothyroidotomy, 861 Cricothyrotomy, percutaneous emergency technique for, 2655 kit for, 2654 Criteria pollutants, 1011, 1011t Critical illness polyneuropathy, ventilatory impairment in, 1654–1655 Crohn’s disease (CD) erythema nodosum in, 434 and risk of infection, 2306 sarcoidosis and, 1135, 1136t Cromolyn sodium adverse effects and side effects of, 827t, 2640 for asthma, 822, 823t, 827t, 2640 clinical use of, 2640 dosage and administration of, 827t for exercise-induced asthma, 811t, 812, 2640 pharmacology of, 2639–2640 Cromones adverse effects and side effects of, 827t for asthma, 824t, 827t mechanism of action of, 827t Croup, 2087–2088 adult, upper airway obstruction in, 853 clinical features of, 2379 membranous, 2088 pathogenesis of, 2379–2380 prevention of, 2380 treatment of, 2380 upper airway obstruction in, 853 viral causes of, 2376t, 2379

Crouzon’s syndrome, 2647 CRP. See C-reactive protein (CRP) Cruzan, Nancy, 2724–2725 Cryotherapy endobronchial, 638 in upper airway obstruction, 862 Cryptococcal antigen BAL, 2330t, 2332 cerebrospinal fluid, 2330, 2330t in HIV-infected (AIDS) patients, 2247t, 2254, 2332 serum, 2330, 2330t, 2332 Cryptococcosis, 1991, 2327–2334 in cancer patients, 2215 in children, immune defects and, 2139 clinical findings in, 2328–2330 cytology of, 2330t, 2331–2332 cytopathology of, 519, 519f, 520f diagnosis of, 2330–2333, 2330t disseminated, 2328, 2330 treatment of, 2333–2334, 2333t epidemiology of, 2328 histopathology of, 2330t, 2331–2332, 2331f history-taking in, 388 in HIV-infected (AIDS) patients, 2246–2247 and pneumothorax, 1523 treatment of, 2333–2334, 2333t immune response to, 2328 in immunocompromised host, treatment of, 2333–2334, 2333t meningoencephalitis in, 2330 diagnosis of, 2330t, 2333 treatment of, 2333–2334, 2333t mycology of, 2328 pathogenesis of, 2328 pleural effusion in, 1494 prevention of, 2334 pulmonary, 2328–2330, 2329f diagnosis of, 2330–2333, 2330t treatment of, 2333–2334, 2333t pulmonary alveolar proteinosis complicated by, 2014 risk factors for, 2328 treatment of, 2333–2334, 2333t Cryptococcus infection (incl. pneumonia), 2024. See also Cryptococcosis in cancer patients, 2221 in HIV-infected (AIDS) patients, 2209f, 2245 imaging of, 2026f immune defect associated with, 1983t, 2210t in immunocompromised host, 2209, 2209f laryngitis caused by, 2087 staining characteristics of, 2035t, 2037–2038, 2331f

I-32 Index Cryptococcus neoformans, 1994, 2327–2328 culture of, 2000, 2330t, 2332–2333 fluconazole resistance, 2334 identification of, in tissue, 2038t, 2331f immune response to, 343, 1970, 2328 infection (incl. pneumonia), 2018f.

See also Cryptococcosis history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2212t, 2254 radiographic findings in, 2214t, 2215, 2249t in neutropenic host and cancer patient, 2217 in organ transplant recipient, 2230, 2232f serotypes of, 2328 sputum culture for, 2000 staining characteristics of, 2041f, 2331f var. gatti, 2328 epidemiology of, 2327 geographic distribution of, 2327, 2328f var. neoformans, 2327 Cryptogenic fibrosing alveolitis, 1106t, 1144 Cryptogenic organizing pneumonia, 888, 891f, 900–903, 1106t, 1145, 2541t BAL cellular findings in, 902 chest imaging in, 901, 902f clinical course of, 903 clinical features of, 901, 1116t computed tomography of, 1115t, 1116t diagnosis of, 902–903 drug-induced, 1089–1091, 1090t histology of, 1116t histopathology of, 902 laboratory findings in, 901 physiological findings in, 901–902 treatment of, 903, 1116t Cryptosporidiosis, 2402–2404. See also Cryptosporidium, infection (incl. pneumonia) clinical features of, 2402–2403 diagnosis of, 2404 in HIV-infected (AIDS) patients, 2402–2404 pulmonary, 2404, 2404f treatment of, 2404 Cryptosporidium, infection (incl. pneumonia). See also Cryptosporidiosis in bone marrow and stem cell transplant recipients, 2224 in cancer patients, 2219 in HIV-infected (AIDS) patients, 2212t, 2248, 2258 in immunocompromised host, 2208

Cryptosporidium parvum, 2402, 2404f life cycle of, 2402 Cryptostroma corticale, hypersensitivity pneumonitis caused by, 1163t CSOM. See Otitis media, chronic suppurative c-src, in lung cancer, 1807 Cst. See Static compliance, of lung CTACK, 340t CTEPH. See Chronic thromboembolic pulmonary hypertension CTGF. See Connective tissue growth factor CTL. See Cytotoxic (cytolytic) T lymphocytes (CTL) Cuboidal metaplasia, 35 Cullen, William, 15 Cunninghamella bertholletiae, 2316t, 2317 infection (incl. pneumonia) in cancer patients, 2217 epidemiology of, 2317 CURB-65 rule, 2102, 2103, 2108t Curie, Pierre and Marie, 1173 Curschmann spirals, 512, 513 in allergic bronchopulmonary aspergillosis, 842 Curvularia in allergic fungal sinusitis, 2091 infection (incl. pneumonia), in cancer patients, 2217 in invasive fungal sinusitis, 2091 Curvularia lunata, in allergic bronchopulmonary mycosis, 837 Cushing’s syndrome, 432–433, 444–445, 1933–1934 in small cell lung cancer, 1904–1905, 1905t Cutaneous nodule(s), 2101t Cuthbertson, 2693 Cutis laxa, 437 and bullous emphysema, 917 CV. See Closing volume C/VL. See Specific compliance Cw. See Chest wall compliance CWP. See Coal worker’s pneumoconiosis CXCR5, in HIV-infected (AIDS) patients, 2243 Cyanide poisoning with diagnosis of, 1056 signs and symptoms of, 1056, 1056t treatment of, 1056–1057 in smoke and inhalation injury, 1054, 1056–1057 source of, 1054t Cyanosis abnormal pigments in blood and, 415–416 causes of, 415–416

definition of, 415 peripheral, 415 in pulmonary disease, 415 venous admixture and, 415 Cyclic adenosine monophosphate (cAMP), and surfactant production, 132 Cyclooxygenase (COX) COX-1 in arachidonic acid metabolism, 803–804, 803f and aspirin-induced asthma, 801 COX-2, in arachidonic acid metabolism, 803–804, 803f Cyclophosphamide for idiopathic pulmonary fibrosis, 1157 immunologic effects of, 2216 and interstitial lung disease, 1110t and pleural effusion, 1506t pneumonitis caused by, 2011, 2012t pulmonary effects of, 1073, 1074–1075, 1074t, 1181, 1295 radiation therapy and, 1181 for sarcoidosis, 1141 Cycloserine adverse effects and side effects of, 2483t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for tuberculosis, 2479 dosage and administration of, 2482t Cyclospora, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t Cyclospora cayetanensis, 2404–2405 Cyclosporiasis, 2404–2405 Cyclosporine, 2639 adverse effects and side effects of, 2207 for asthma treatment, 832 interactions with drugs for nontuberculous mycobacteria, 2503t for sarcoidosis, 1141 Cyst(s) bronchogenic, 856, 1608, 1608f clinical presentation of, 1573–1575, 1575t diagnosis of, 1573–1575 embryology of, 1572–1573 intrapulmonary, 1573, 1574f mediastinal, 1573, 1573f, 1574f presenting as solitary pulmonary nodule, 1817 radiographic features of, 498 terminology for, 1572–1573 treatment of, 1575–1576 characteristics of, 913, 915t congenital, mediastinal, anatomic distribution of, 1571–1572 echinococcal, as solitary pulmonary nodule, 1817

I-33 Index enterogenous (duplication), 856, 1576 clinical presentation of, 1576, 1577f diagnosis of, 1576 embryology of, 1576 treatment of, 1576 esophageal, 1608 in interstitial lung disease, 1113f, 1115t mediastinal congenital, anatomic distribution of, 1571–1572 primary epidemiology of, 1572, 1572t origin of, 1572, 1572t mesothelial, 1609 neurenteric, 1576–1578, 1608 clinical presentation of, 1576–1578 diagnosis of, 1576–1578 embryology of, 1576 treatment of, 1578 parathyroid, upper airway obstruction caused by, 857 pericardial, 856, 1578–1579, 1580f, 1609, 1609f pleural, 856 pleuropericardial, 1609 saccular, upper airway obstruction caused by, 857 thoracic duct, 1579–1580, 1580f, 1609 thymic, 856, 1578, 1578f, 1579f thyroid, upper-airway obstruction caused by, 849f Cystatin C, in lung parenchyma, 721t, 722 Cystatins, in lung parenchyma, 721t, 722 Cystic fibrosis, 398, 2138 adult patient with, psychosocial issues of, 882 airway surface liquid regulation in, 2174–2175, 2174f and allergic bronchopulmonary aspergillosis, 839, 2176–2177, 2294–2296 anti-inflammatory therapy for, 876–877 atelectasis in, 878, 879f and bronchiectasis, 866–867, 2185t, 2186–2187 bronchodilator therapy for, 876–877 chest physiotherapy in, 874–875 chest radiographs in, 870–871, 871f cholestasis in, 878 clinical evaluation of, 870–874 clinical presentation of, atypical, 874 complications of, 878–882 computed tomography of, 1115t diabetes in, 867, 2177 diagnosis of, 868–870, 870f, 2173 eosinophils in, 318 epithelial chloride transport in, 138, 138f, 865, 865f and fertility, 868, 873, 882–883 gas exchange abnormalities in, 872 gastrointestinal involvement in, 2177 pathophysiology of, 867–868, 869f

gene therapy in, 884 genetics of, 863–865 genetic testing for, 870 genotype-phenotype correlation in, 873–874 hemoptysis in, 880 hepatobiliary involvement in, 867, 873, 878, 2177 historical perspective on, 2173 hypoelectrolytemia in, 878, 878t incidence of, 863 infection in, 866–867, 880–881 antibiotic therapy for, 875–876 clinical aspects of, 2175–2177 and inflammation, 2175 pathogenesis of, 866–867, 2173–2178 intestinal obstruction in, 878 liver function tests in, 873 liver transplantation in, 878 lung disease in antibiotic therapy for, 2178–2179 anti-inflammatory agents for, 2179 complications of, 878, 879f exacerbations of, 2176 antibiotic therapy in, 2179 manifestations of, 2176 microbiology of, 2175–2176 pathogenesis of, 868f pathophysiology of, 866–867, 868f treatment of, 874–876, 2178 lung transplantation in, 1774t, 1775–1777 complications of, 881–882, 882f lung volume changes in, 872 metabolic alkalosis in, 878, 878t mist therapy for, 876 mucociliary clearance in, 2174–2175, 2174f mucolytic therapy for, 876 mucus in, 866, 2175 multisystem manifestations of, 2175, 2175f mutation analysis in, 873–874 nasal disease in, 2177 natural history of, 877–878 non-respiratory manifestations of, 2177–2178 nontuberculous mycobacterial infection in, 2502 nutrition in, 877, 2177 pancreatic function tests in, 873, 877 pancreatic involvement in, 2177 management of, 877 pathogenesis of, 865–866 pathophysiology of, 144, 866–868 pneumonia in, nosocomial, 2282, 2283 pneumothorax in, 880, 1521–1522 treatment guidelines for, 1531 and pregnancy, 260, 882–883 prenatal screening for, 870, 883 prognosis for, 877–878

Pseudomonas aeruginosa infection in, 2081–2082 pathogenesis of, 2175 treatment of, 875–876, 883–884, 2178–2179 psychosocial issues in, 882 pulmonary complications of, 878, 879f pathology of, 1394f pulmonary function testing in, 604t, 871–872 reproductive issues in, 882–883 reproductive tract involvement in, 882–883, 2177–2178 pathophysiology of, 868 respiratory failure in, 881 semen analysis in, 873 severity of familial pattern of, 871f, 877 Social Security Listings for, 686–687, 687t sinus disease in, 2177 skin in, 437 small airway obstruction in, 872 sputum culture in, 872–873 survival with, 874, 874f, 877–878, 2173 sweat gland involvement in, pathophysiology of, 868 treatment of, 874–877 advances in (future directions for), 883–884 pharmacologic approaches, 883–884 Cystic fibrosis transmembrane conductance regulator chloride channel, 139–140, 140f domains, 864f domain structure of, 139–140, 140f and epithelial transport, 2173–2174 membrane-spanning domains, 139–140, 140f mutations of, 144, 864–865, 864t, 2173, 2174f and allergic bronchopulmonary aspergillosis, 837–838, 2295–2296 analysis of, 873–874 carriers, 863, 865 classification of, by molecular and biochemical abnormalities, 865–866, 866f genotype-phenotype correlation with, 873–874 pharmacologic therapy for, 883–884 racial/ethnic distribution of, 863, 864t and susceptibility to Pseudomonas aeruginosa, 2081–2082 testing for, 865 nucleotide-binding domains, 140, 140f structure of, 864, 864f Cystic hygroma, 1596 Cystine storage disease, 1276

I-34 Index Cytarabine, immunologic effects of, 2216 Cytochrome P450, 1088, 1094 Cytokines activities of, 336 adjunctive therapy with in invasive pulmonary aspergillosis, 2312 for zygomycosis, 2321 and airway smooth muscle proliferation, in vitro, 119 in allergy, 792, 792f in aspergillosis, 2293, 2312 in asthma, 118, 777–778, 779t–781t and B-cell production, 323 chemotactic, 339, 340t and inflammatory response, 339 definition of, 335 early-response, 336–337, 347 eosinophils and, 310t, 313, 314–315 fibrotic, in lung inflammation and injury, 338–339 in hypersensitivity pneumonitis, 1171 in idiopathic pulmonary fibrosis, 1154 in inflammation, 336–337 inflammatory, 280f, 1970, 1978 in initiation of pulmonary inflammation, 336–337 mast cell, 310t, 311 mast cells and, 310t, 312 produced by macrophages, 1972t profibrotic, epithelial cell expression of, 377–378 release of by airway smooth muscle cells, 121 antibiotics affecting, 2054–2055 and SIRS/MODS, 2566–2567 sources of, 335 targets of, 335 T-cell-derived, and isotype switching, 324 therapy with, for Pneumocystis pneumonia, 2370 and tuberculosis, 2461 type I, 337 type II, 337 Cytology, bronchopulmonary, normal, 514–516 Cytomegalovirus (CMV) assays for, 1989t characteristics of, 2375t diagnosis of, 2000–2001 and diffuse alveolar damage, 2042 infection (incl. pneumonia), 2027f in bone marrow and stem cell transplant recipients, 2222–2223, 2224, 2228 in cancer patients, 2218 in children, 2391 cytopathology of, 523, 523f in early infancy, 2130 history and physical findings in, 2100t

in HIV-infected (AIDS) patients, 1294, 2212t, 2245, 2257 radiographic findings in, 2214, 2215, 2249t immune defect associated with, 1983t, 2210t in immunocompromised host, 2204, 2207, 2209, 2391–2392 in lung transplant recipient, 1790–1791, 1791f lymphadenopathy in, 2028 and net state of immunosuppression, 2205 in organ transplant recipient, 2230, 2232 pathogenesis of, 2393 pathology of, 2044f pleural effusion in, 1494 and Pneumocystis pneumonia, 2355, 2357f, 2358, 2359, 2360f, 2364 and pneumothorax, 1523 prevention of, 2394–2395 radiographic findings in, 483 in severe combined immunodeficiency, 2236 treatment of, 2394–2395 molecular detection of, 2002 and pharyngitis, 2376t, 2378 pneumonia, 1994, 2024 diagnosis of, 2001, 2003 in immunocompromised host, 1997 and sarcoidosis, 1127 staining characteristics of, 2035t, 2037 Cytopathology of asbestosis, 516, 517f of aspiration pneumonia, 524, 524f of bacterial infections, 518, 518f of berylliosis, 517, 517f of chemotherapy effects, 526–527, 527f of crack cocaine inhalation, 517, 518f of fungal infections, 519–522, 519f–522f of intra-alveolar hemorrhage, 524–525, 525f, 526f of lipid pneumonia, 524, 525f of parasitic infestations, 523–524, 524f of pulmonary infarct, 524–525, 525f of pulmonary neoplasms, 527–531 of radiation injury, 526–527 of sarcoidosis, 525–526, 526f of smoking, 516, 517f specimens for ancillary diagnostic techniques and, 514 cell block technique for, 514 cellulosic (Millipore) filter for, 514 collection of, 512–513 cytospin preparations, 514 direct smears, 514 processing of, 513–514 Saccamanno’s fixative and, 514 of viral infections, 522–523, 522f–523f Cytopathology report, 511–512

Cytosine arabinoside, pulmonary effects of, 1076t, 1077–1078 Cytotoxic (cytolytic) T lymphocytes (CTL), 1977 in HIV-infected (AIDS) patients, 2243 D Dactinomycin immunologic effects of, 2216 pulmonary effects of, radiation therapy and, 1181 DAD. See Diffuse alveolar damage DAH. See Diffuse alveolar hemorrhage Dalbavancin, 2058 Dalfopristin, 2058 pharmacokinetics and pharmacodynamics of, 2054 Dalton, John, 5t, 9 Dapsone, 2639 methemoglobinemia caused by, 416 for Pneumocystis pneumonia, 2368t, 2369 prophylactic, for Pneumocystis pneumonia, 2367 Daptomycin, 2058 da Vinci, Leonardo, 5t, 11 Davy, Humphrey, 11, 568 DC-CK-1. See Thymus and activation-regulated chemokine D-dimer testing, with pulmonary embolism, 1431–1432 Dead space, 592 anatomic, 173–175, 592 conducting airway, 173–175 percentage total ventilation wasted in, calculation of, 187 physiological. See Physiological dead space De Castro, F., 13 Decision-making capacity, of ICU patients, 2724, 2729 assessment of, 2731–2732, 2731t Decompression sickness, 1047–1048 clinical manifestations of, 1048 hyperbaric oxygen therapy for, 1050–1051 pulmonary, 1048 Deep breathing exercises, postoperative, 673t, 674 Deep venous thrombosis, 1423 in cancer patient, 433 prevention of, 835 scintigraphy in, 551 Defensins, 1973 in airway surface liquid, 281 Deferoxamine, therapy with, and risk of infection, 2317, 2318, 2321 Definitive radiotherapy, definition of, 1895 Deflation receptors, 164, 164f Delavirdine, and antituberculosis therapy, 2491

I-35 Index Delayed hypersensitivity skin tests of, 2002 testing, in nutritional assessment, 2694 Delta1, 87 Dendritic cell(s), 280, 282, 1974–1975, 1975f, 1976 airway, 42 in airways, 280f in aspergillosis, 2293 in asthma, 777 and isotype switching, 324 myeloid, 1974 plasmacytoid, 1974 and tuberculosis, 2080 Dense-cored vesicles, 30, 30f Dental extraction, and anaerobic pleuropulmonary infections, 2145t Dentition, assessment of, 2647 DeO2 . See Erythrocyte conductance Deontological theory, 2724 Depositional disease(s), of lung, 1233, 1234t Depression, smoking cessation (nicotine withdrawal) and, 757, 759 Depressor reflex, 1340 Dermatomyositis. See Polymyositis-dermatomyositis Dermatophagoides farinae, 1031 Dermatophagoides pteronyssinus, 1031 Dermatoses neutrophilic, 434 reactive, 433–436 Desert rheumatism, 2342 Desquamative interstitial pneumonia, 491f, 1106t, 1144, 1145, 2013 clinical features of, 1116t computed tomography of, 1115t, 1116t drug-induced, 1110t–1111t histology of, 1116t treatment of, 1116t Detergent worker’s disease, etiology of, 1165t Dexfenfluramine and interstitial lung disease, 1110t pharmacology of, 1370 pulmonary effects of, 1093 and pulmonary hypertension, 447, 1383 Dexmedetomidine, for agitated ICU patient, 2705, 2706t DFMO. See Difluoromethylornithine Diabetes insipidus, pulmonary Langerhans’ cell histiocytosis and, 1246 Diabetes mellitus in cystic fibrosis, 2177 and risk of infection, 2317 sleep apnea and, 1713 Diabetic ketoacidosis dyspnea in, 403 and pneumonia, 2100t

Diacetyl-popcorn lung, 896, 935t Diaphragm, 72f actions of, 74–75, 74f, 77 pathological conditions affecting, 77–78 contraction of, 74–75 appositional component of, 74, 74f insertional component of, 74–75, 74f dome ultrasound of, 1642, 1642t dysfunction postoperative, 664 and respiratory failure, 2586–2587 in systemic lupus erythematosus, 1201, 1201f fatigue, 166 and abnormal breathing pattern, 403 activity and, 2601, 2602f, 2603f blood flow and, 2601–2602 in chronic obstructive pulmonary disease, 2606–2607, 2607f pathogenesis of, 2601–2602, 2602f, 2603f fiber types in, 72 flattening of, 2597–2598 fluoroscopy of, 459–460, 460f force-frequency relationships of, 73, 74f, 2599–2601, 2600f force-length relationships of, 72–73, 73f force-velocity relationships of, 73–74, 74f function, 165–166 hyperinflation and, 713–714, 714f injury to, in trauma patient, 1763–1764, 1764f innervation of, 166 length–tension relationship, in emphysema, 2598, 2598f mitochondria in, 72 motor unit organization, 72 oxygen uptake capacity of, 72 paralysis in neuromuscular disease, 1653 ventilatory impairment in, 1653 power-frequency relationships of, 73–74 radiographic evaluation of, 459–460, 460f, 500–503 testing of, 1642, 1642t tumors of, 503 ultrasound of, in acute lung injury, 2673 zone of apposition ultrasound of, 1642, 1642t Diaphragmatic eventration, 460, 460f, 502 Diaphragmatic pacing, in neuromuscular disorders, 1663–1664, 1663f Diaphragm tension–time index, 2601–2602, 2602f, 2603f Diarrhea, in respiratory failure, 2518t, 2519 Diazepam, for agitated ICU patient, 2703, 2704t

Diazinon exposure to, 1027t sources of, 1027t p-Dichlorobenzene exposure to, 1027t sources of, 1027t Dickkopf (Dkk), 86, 89f Diclofenac, and aspirin-induced asthma, 802t Dicloxacillin, for cystic fibrosis patient, 875 Didanosine, adverse effects and side effects of, with isoniazid, 2490 Dietary pulmonary hypertension, 446–447 Dieterle stain, 2037 Difenfluramine, pulmonary effects of, 1347 Diffuse alveolar damage, 1106t, 2042, 2539 in collagen vascular disease, 1194t histopathology of, 1195 drug-induced, 1092, 1093, 1110t–1111t occupational exposures and, 935t in polymyositis-dermatomyositis, 1208–1209 Diffuse alveolar hemorrhage, 1237, 1281–1297, 2541t, 2544 with ANCA-associated drug-induced vasculitis, 1241–1242 in ANCA-associated syndromes, treatment of, 1292 autoimmune, 1281–1282, 1282t bronchoalveolar lavage in, 1282, 1284 clinical features of, 1282 diagnosis of, 1282–1285 kidney biopsy in, 1284–1285, 1285f, 1286f pathology of, 1285t radiographic features of, 1282 and renal function, 1281–1282 serology of, 1285t bland, 1295 in collagen vascular disease, 1194t histopathology of, 1197, 1197f in bone marrow and stem cell transplant recipients, 1294, 2227 bronchoscopy in, 1120t with capillaritis, 1237, 1239f, 1281–1282, 1282t causes of, 1237, 1239t in collagen vascular disease, 1194t histopathology of, 1197, 1197f causes of, 1237, 1239t nonimmunologic, 1242 in collagen vascular disease, 1193, 1194t histopathology of, 1197, 1197f computed tomography of, 1115t drug-induced, 1091t, 1092, 1241–1242, 1281, 1294–1295 and glomerulonephritis, 1281–1282 in HIV-infected (AIDS) patients, 1294 immune-mediated

I-36 Index Diffuse alveolar hemorrhage (Cont.) kidney biopsy in, 1284–1285, 1285f, 1286f lung pathology of, 1285t renal pathology of, 1285t serology of, 1285t treatment of, 1285–1287 in immunocompromised patients, 1293–1294 in mixed connective tissue disease, 1210 occupational exposures and, 935t with or without capillaritis, causes of, 1237, 1239t in polymyositis-dermatomyositis, 1208–1209 in systemic lupus erythematosus, 1199–1200, 1200f without capillaritis, causes of, 1237, 1239t Diffuse infiltrative lymphocytosis syndrome, 1953–1954 in HIV-infected (AIDS) patients, 2260 Diffuse lymphoid hyperplasia, 1949, 1952 Diffuse panbronchiolitis, 909–910, 910f Diffuse parenchymal lung disease, 1145 Diffusing capacity, 58–61, 58f, 65, 194–199, 592–594 age-related changes in, 273 in AMA Guides classification of impairment, 682t for carbon monoxide. See Carbon monoxide, diffusing capacity for in dyspnea, 405t factors affecting, 197–199 measurement of, 195–196 nonuniform physiological parameters and, 199 technical considerations in, 198–199 membrane age-related changes in, 273 measurement of, 196–197 morphometry of lung and, 60–61, 60t for nitric oxide. See Nitric oxide, diffusing capacity for normal values, 1324, 2736 for oxygen. See Oxygen, diffusing capacity for in pregnancy, 255 preoperative, analysis, for lung resection, 671–672 reduced, 607, 607t terminology for, 1328, 2740 Diffusing capacity per unit alveolar volume definition of, 1328, 2740 normal, 1324, 2736 Diffusion, 191–192 partial pressure gradient and, 191–192 physical factors affecting, 191–192 rate of, physical factors affecting, 192 Diffusional screening, 63–65 Diffusion cell, 64

Diffusion defect, and arterial hypoxemia, 2616–2617, 2616t Diffusion equilibrium, 192 Diffusion limitation, 177 Difluoromethylornithine, for Pneumocystis pneumonia, 2370 DiGeorge’s syndrome, 2139 pulmonary infection in, 2236 Digestive tract, selective decontamination of, in prevention of nosocomial pneumonia, 2289 Digitalis, for pulmonary hypertension, 1377 Diisocyanates and occupational asthma, 985t, 986 occupational lung disease caused by, 934t DILS. See Diffuse infiltrative lymphocytosis syndrome DIP. See Desquamative interstitial pneumonia Dipalmitoylphosphatidylcholine, in surfactant, 126–127 Diphenylhydantoin, pulmonary effects of, 1097, 1242, 1294 Diphenylmethane di-isocyanate hypersensitivity pneumonitis, etiology of, 1164t Diphosphoglycerate, 9 2,3-Diphosphoglycerate, and oxygen exchange, 202–203 Diphtheria differential diagnosis of, 2087 pharyngitis in, 2086 Direct fluorescent antibody (DFA), sputum staining with, 1999 Directly observed therapy, in tuberculosis, 2476, 2484 Dirofilaria immitis, 2419, 2420f and eosinophilic pneumonia, 1219 infection, pathology of, 2050 Dirofilariasis, 2419, 2420f solitary pulmonary nodule in, 1817 Disability, 941. See also Impairment definition of, 677 Social Security Administration, 685 determination of, in occupational asthma, 988 evaluation of, 677–678 American Thoracic Society criteria for, 684–685 Social Security and, 685–687 occupation-related, workers’ compensation programs for federal, 688–690 state, 687–688 Distributive justice, principle of, 2722, 2723 Diuretics inhaled, 2637 pneumonitis caused by, 2010, 2012t pulmonary effects of, 1093

for pulmonary hypertension, 1376–1377 Diving, decompression during, 1045–1046 alveolar rupture in, 1045–1046 sequelae, 1046–1047 Diving injury(ies), annual numbers of, 1045 Dl. See Diffusing capacity DlCO . See Carbon monoxide, diffusing capacity for DLH. See Diffuse lymphoid hyperplasia DlNO . See Nitric oxide, diffusing capacity for DlO2 . See Oxygen, diffusing capacity for DL /VA . See Diffusing capacity per unit alveolar volume Dm. See Diffusing capacity, membrane DMO2 . See Membrane conductance DNA gyrase, 2056–2057 DNAR orders, 2722, 2730–2733 carrying out, 2733 classification of, by goals, 2732, 2732t deciding on, 2732–2733 levels of intervention and associated therapeutic goals in, 2732, 2732t Docetaxel, pulmonary effects of, 1083–1084, 1083t Dock, William, 13 Dog(s), allergens, exposure to, 1031 Domestic allergic alveolitis, etiology of, 1164t Donders, Franciscus Cornelius, 5t, 11 Do not attempt resuscitation (DNAR) orders. See DNAR orders Dornase alpha, 2641 Dosimetry, radiation, 1173, 1175–1177 definition of, 1895 DOT. See Directly observed therapy Double wall sign, 918 Doubling time, 487, 493f of solitary pulmonary nodule, 1822 Doxapram, as respiratory stimulant, 2643 Doxorubicin, pulmonary effects of, 1083t, 1181 radiation therapy and, 1181 Doxycycline for anthrax, 2429t, 2437 for brucellosis, 2429t, 2438–2439 interactions with immunosuppressive agents, 2503t for melioidosis, 2440 for plague, 2429t, 2432 for protozoan infection, 2407 for sarcoidosis, 1140, 1140t for tularemia, 2434 DPI. See Dry powder inhaler DPLD. See Diffuse parenchymal lung disease DPPC. See Dipalmitoylphosphatidylcholine

I-37 Index Drechslera in indoor air, 1031 infection (incl. pneumonia), in cancer patients, 2217 Drechslera hawaiiensis, in allergic bronchopulmonary mycosis, 837 DRESS. See Drug rash with eosinophilia and systemic symptoms Dressler’s syndrome, 1502 Drotrecogin alfa, for community-acquired pneumonia, 2110 Drowned lung, neoplasia and, 2014 DRSP. See Streptococcus pneumoniae, drug-resistant Drug(s) cutaneous toxicity of, 439–440 cytotoxic extrinsic allergic alveolitis caused by, 2012, 2012t hypersensitivity lung disease caused by, 2012, 2012t hypersensitivity pneumonitis caused by, 2012, 2012t for idiopathic pulmonary fibrosis, 1157 pneumonitis caused by, 2011, 2012t acute or chronic, with fibrosis, 2011–2012, 2012t pulmonary effects of, 1069–1073, 1070t, 1181 dyspnea caused by, 403 eosinophilic pneumonia caused by, 1215t, 1216–1217 illicit, pulmonary effects of, 1093, 1100–1101 and interstitial lung disease, 1110t lung disease due to. See also Chemotherapy approach to patient with, 1087–1088 diagnosis of, 1087–1088 histopathology of, 1089–1094, 1090t–1091t mechanism of injury in, 1089 nonchemotherapeutic drugs and, 1087–1101 resolution of, 1101 risk factors for, 1088–1089 treatment of, 1101 metabolism of, 1088 methemoglobinemia caused by, 416 nonchemotherapeutic, lung disease due to, 1087–1101 noncytotoxic, pneumonitis caused by, 2010, 2012t pleural effusion caused by, 1498 pulmonary toxicity of, web site about, 1216 and sleepiness, 1732–1733 vasculitis caused by, 1241–1242 Drug abuse deep cervical infection caused by, 852

embolisms caused by, 1446 history-taking in, 389 physical findings in, 390 pulmonary complications of, 1446 pulmonary toxicity due to, 1100–1101 supraglottitis caused by, 853 Drug history, 389 Drug-induced lupus, immunologic tests for, 1112t Drug rash with eosinophilia and systemic symptoms, 1092 Dry-air challenge test, 585t Dry powder inhaler, drug delivery by, in chronic obstructive pulmonary disease, 738, 738t DuBois, Eugene F., 8, 12 Duchenne muscular dystrophy respiratory abnormalities in, 1656–1658, 1657f ventilatory impairment in, 1668t treatment of, 1670, 1670f Ductus arteriosus, 108–109, 1354–1355, 1355f closure of, 1355 patent and clubbing of digits, 416 cyanosis due to, 415 Dumbbell tumors, 1611 Duplication cyst(s) esophageal, radiographic features of, 498, 501f tracheobronchial tree, radiographic features of, 498 Dust(s) inhalation of, 2013 in lung tissue, analysis of, 940 occupational exposure to, and chronic obstructive pulmonary disease, 708t, 709–710 occupational lung disease caused by, 934t Dust mites, 1031 and risk of asthma, 794 Dutch hypothesis, 711 Duvet lung, etiology of, 1164t Dynamic compliance, 158–159, 158f, 588–589, 588f, 589f definition of, 1328, 2740 Dynein gene(s), 2187 Dysphagia, 1305–1308, 1306t cerebrovascular disease and, 1307–1308 mechanical mechanisms of, 1309–1310 with mediastinal lesions, 1587, 1587t stroke and, 1307–1308 Dyspnea, 393–395 acute, causes of, 395, 395t in anemia, 402–403 in asthma, 398 cardiac, 400 chemoreception and, 397 in children, causes of, 395, 395t

chronic (and progressive), causes of, 395, 395t in chronic cardiac disease with stiff lungs, 400 without stiff lungs, 400 in chronic obstructive pulmonary disease, 397–398, 714 clinical presentation of, 395 compensatory response to, age-related changes in, 269–270 definition of, 393 diagnostic studies in, 404–405, 405t evaluation of, 404–405, 405t in evaluation of impairment/disability, 679, 679t Medical Research Council scale for, 679, 679t, 732, 733t exertional in cardiac/circulatory failure, 626, 626t evaluation of, cardiopulmonary exercise testing in, 625–626, 626t in ventilatory failure, 626, 626t in interstitial lung disease, 1108 length-tension inappropriateness and, 397 with mediastinal lesions, 1587, 1587t paroxysmal nocturnal, 401–402 pathophysiology of, 170–171, 397 patients’ terms for, 394–395 physiological correlates of, 395–397 positional forms of, 400–401 of pregnancy, 258 psychogenic, 394 in pulmonary hypertension, 1371, 1371t pulmonary Langerhans’ cell histiocytosis and, 1246 in restrictive lung disease, 400 scaling of, 397, 397t, 398t sensation of, 397 components of, 393–394 pathways to, 393–394, 394f types of, 171 in upper airway obstruction, 846 ventilatory performance and, 395–396 Dystroglycan, in lung development, 94 E E. corodens, in acute mediastinitis, 2166t Ear(s), infections of, 2091–2094 Easpirin, and aspirin-induced asthma, 802t Eaton-Lambert syndrome, ventilatory impairment in, 1656 EBUS. See Endobronchial ultrasound EBV. See Epstein-Barr virus (EBV) ECCO2 R. See Extracorporeal CO2 removal (ECCO2 R) Echinacea, 2086

I-38 Index Echinocandins for candidiasis, 2316 for invasive fungal infections, 2310t, 2311, 2312 for Pneumocystis pneumonia, 2370 for zygomycosis, 2320 Echinococcosis, 1991, 2414t, 2421–2423, 2422f, 2423f Echinococcus and eosinophilic pneumonia, 1214t infection (incl. pneumonia), in immunocompromised host, 2210 infestation, cytopathology of, 524 staining characteristics of, 2035t, 2039, 2041f Echinococcus granulosus, 1995, 2414t, 2418t, 2421, 2422f, 2423f biology of, 2414 disease caused by, epidemiology of, 2415 pleural disease due to, 1495 staining characteristics of, 2041f Echocardiography, 2543 in acute respiratory failure, 2666–2667 in dyspnea, 404–405 with pulmonary arteriovenous malformation, 1470, 1471f–1472f with pulmonary embolism, 1433 in pulmonary hypertension, 1373t, 1374 ECMO. See Extracorporeal membrane oxygenation (ECMO) ECP. See Eosinophil cationic protein Ecthyma gangrenosum, 2101t Edema, alveolar, 35 EDN. See Eosinophil-derived neurotoxin Efavirenz, and antituberculosis therapy, 2490–2491 Egalitarian theory, 2723 Egophony, 392 Ehlers-Danlos syndrome and bullous emphysema, 917 cutaneous manifestations of, 437 Ehrlich, Paul, 307 Ehrlichiosis, in splenectomized patient, 2219 EIA. See Asthma, exercise-induced Eikenella corrodens, 2007 EIT. See Electrical impedance activity Elafin, 1970 in lung parenchyma, 721t Elastance, definition of, 149 Elastase, 1973 mast cell, 310t, 311 Elastic fiber(s), 53 age-related changes in, 266–267, 266f in emphysema, 718–719 Elastic recoil, in chronic obstructive pulmonary disease, 711, 712f Elastin

age-related changes in, 266–267, 266f in lung, 151 in lung development, 94 proteinases affecting, 718, 718t Elderly neck motion in, 2648 new-onset asthma in, 421 pulmonary function testing in, interpretation of, 276 susceptibility to air pollution, 1032t Electrical impedance activity, in acute lung injury, 2673 Electrical stimulation, in detection of respiratory muscle fatigue, 2600 Electrocardiography in cardiopulmonary exercise testing, 611 with pulmonary embolism, 1430, 1433f in pulmonary hypertension, 1374–1375, 1375f Electrocautery, endobronchial, 638, 638f Electromyography (EMG) diaphragmatic, 599 power spectrum, in detection of respiratory muscle fatigue, 2600–2601, 2601f Electron microscopy (EM), 514, 2039 ELR motif, 339, 341, 341t, 351 Elsberg, 2646 EMB. See Ethambutol Emboli (sing., embolus). See also specific embolism septic, 2024, 2024f sources of, 1424–1425 Embryonal carcinoma, of anterior mediastinum, 1607 Emphysema. See also Chronic obstructive pulmonary disease (COPD) anatomic varieties of, 695–696, 695f bullous, 913, 915t, 916f, 920–921 in familial disorders, 917 risk factors for, 917 cardiopulmonary exercise testing in, 624–625 centriacinar (centrilobular), 399f, 695–696, 695f differential diagnosis of, 698–699, 698t morphology of, 696, 696f, 697f radiographic findings in, 473f, 475–476 classification of, 695–696 cyanosis in, 415 definition of, 694–695, 730 anatomic, 694 historical perspective on, 694 differential diagnosis of, 698–699, 698t and elastic properties of respiratory system, 577, 578f heart failure in, radiographic features of, 476 in HIV-infected (AIDS) patients, 731

irregular, 696 differential diagnosis of, 698–699, 698t morphology of, 698 lung collagen turnover in, 719, 719f mediastinal, 1557–1560 diving-related, 1046–1047 morphology of, 696–698 panacinar (panlobular), 399f, 695–696, 695f, 913, 915t differential diagnosis of, 698–699, 698t morphology of, 696f, 697–698, 697f radiographic findings in, 473f, 475–476 paracicatricial, 696 paraseptal (distal acinar), 695–696, 695f, 913, 915t, 920–921, 925 bullae with, 913, 915t, 916f differential diagnosis of, 698–699, 698t morphology of, 698 radiographic findings in, 475–476 pathogenesis of, 717–722 pathologic descriptions of, historical perspective on, 694, 694f pathology of, 399f, 694–699, 1393, 1394f pathophysiology of, 53 proteinases in, 719–721 proximal acinar, 695 pulmonary function testing in, 603, 604t, 605, 606t pulmonary rehabilitation in, 771 radiographic findings in, 473f, 475–476, 476f senile, 264, 699 severity, and airflow obstruction, 714, 714f smoking-related, pathogenesis of, 722–723, 722f subcutaneous after lung resection, 1744–1745, 1745f diving-related, 1046–1047 VATS lung volume reduction in, 655 Empyema, 1489–1493, 1489f, 2028, 2146f after lung resection, 1749–1750 amebic, 2401 clinical features of, 2149t, 2151 definition of, 2141 diagnosis of, 2154 drainage of, 1490–1491, 1491f historical perspective on, 2142–2143 in hyperimmunoglobulin E syndrome, 2239 image-guided drainage of, 535–536 management of, 2157–2158 microbiology of, 2143–2144, 2144t, 2147f mixed, in tuberculosis, 2469 pathogenesis of, 2040

I-39 Index pathophysiology of, 2146–2149 pediatric, treatment of, 2132 pneumococcal, 1490–1493, 1492f radiographic diagnosis of, 2153 in staphylococcal pneumonia, 2143–2144 in children, 2132 in streptococcal pneumonia, 2143–2144 in children, 2133 in surgery and trauma patients, 2199 thoracoscopic management of, 651 thoracostomy for, 1489, 1490t treatment of, 2141–2142 in tuberculosis, 2469, 2473 ENA-78, 340t, 341t, 1973, 2116 Encephalitis, 2101t, 2113 amoebic, 2401 Encephalitozoon, 2410 Encephalomyelitis, paraneoplastic, 1936–1937, 1936t in small cell lung cancer, 1905t, 1906 Endobronchial irradiation, definition of, 1895 Endobronchial ultrasound, 631–632, 632f Endocarditis, 2152–2153, 2154t in HIV-infected (AIDS) patients, 2215 right-sided, 2112 Endocrinopathy(ies), autoimmune, sarcoidosis and, 1135 Endodermal sinus (yolk sac) tumor, of anterior mediastinum, 1607 End-of-life care, 2112 Endothelial cell(s) alveolar vs. extra-alveolar, 40 capillary, 40, 40f Endothelin(s) (ET) ET-1, 445–446 and airway smooth muscle proliferation, in vitro, 118 in pulmonary hypertension, 1369 in Weibel-Palade bodies, 31 and pulmonary vasomotor control, 1343 Endothelin receptor antagonists, for pulmonary arterial hypertension, 1387–1388 Endothelium, 174f capillary, 32–33, 33t, 39, 51–52, 52f avesicular zone of, 40 vascular, 31–32, 31f, 1341, 1342f, 1343f abnormalities of, 446, 447f, 448f injury to, 446 pulmonary, 445–446, 447f–448f Endotoxin and acute lung injury, 2527 in byssinosis, 983, 983t gram-negative, 2081 Endotracheal intubation and aspiration, 1311 complications of, 858 historical perspective on, 2646 indications for, 2649, 2649t

laryngotracheal stenosis after, 854–855 and nosocomial pneumonia, 2196 Endotracheal tube(s), 2651–2653, 2652f, 2653f, 2655–2657, 2656f, 2657f double-lumen, 2657, 2657f placement, monitoring, in acute respiratory failure, 2669–2670 Univent, 2657 Endurance athletes, adaptation in, 230 Energy, conservation of, 8 Energy Employees’ Occupational Illness Compensation Program Act, 689 Enolic acids, and aspirin-induced asthma, 802t Entamoeba infestation, cytopathology of, 524 staining characteristics of, 2037 Entamoeba coli, and eosinophilic pneumonia, 1214t Entamoeba dispar, 2397 Entamoeba histolytica, 1995, 2397–2401 antigen, detection of, 2400 in lung abscess, 2146, 2154t pleural effusion due to, 1494–1495 serology of, 2400 staining characteristics of, 2040f Enteral nutrition, 2694–2695 complications of, 2519, 2695, 2695t nonoral, and aspiration, 1310–1311 Enterobacter in empyema, 2144 infection (incl. pneumonia) in chronic granulomatous disease, 2237 neonatal nosocomial, 2126 nosocomial, 2279, 2280, 2280t, 2281t, 2282, 2289 treatment of, 2285–2288, 2286t in surgery and trauma patients, 2197 pneumonia, 2019, 2022 Enterobacteriaceae in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t in acute mediastinitis, 2166t colonization by, in children, 2136 extended spectrum beta lactamase-producing, 2110 infection (incl. pneumonia) in complement deficiency, 2236 in HIV-infected (AIDS) patients, radiographic findings in, 2249t neonatal nosocomial, 2126 in neutropenic host and cancer patient, 2217 nosocomial, 2581 clinical features of, 2282 diagnosis of, 2282 epidemiology of, 2282 microbiology of, 2282 prevention of, 2282 treatment of, 2282

in lung abscess, 2154t pneumonia, 2008, 2019, 2022 in elderly, 2007 Enterococci, vancomycin-resistant, infection, treatment of, 2058 Enterococcus in acute mediastinitis, 2166t in immunocompromised host, 2204 Enterococcus faecalis infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 vancomycin-resistant, infection, treatment of, 2058 Enterococcus faecium infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 vancomycin-resistant, infection, treatment of, 2058 Enterocytozoon, 2410 Enterocytozoon bieneusi, 2410 Enterovirus, 1992 croup caused by, 2087 infection (incl. pneumonia), seasonal variation in, 2374 and pharyngitis, 2378 Entomophthorales, 2316 Environmental exposure(s), 933–934 and acute exacerbations of chronic obstructive pulmonary disease, 741, 2118 assessment of, 940–941 prevention of, 941–942 Environmental lung disease cause of, establishing, 936–937 classification of, 934, 934t clinical approach to patient with, 937–941 diagnostic criteria for, 936 diagnostic testing in, 937–940 epidemiology of, 936–937 history-taking in, 937, 938t importance of, 936 physical examination in, 937 principles of, 935–936 toxicology of, 936–937 Environmental Protection Agency, U.S. (EPA), 941, 1010–1011 and outdoor air quality, 1034–1035 Environmental tobacco smoke, 1010–1011 Enzyme(s) as antioxidants, 2626 eosinophil, 310t, 314 in inflammatory response, produced by macrophages, 1972t inhibitors, produced by macrophages, 1972t mast cell, 310t, 311 microbicidal, produced by macrophages, 1972t EOA. See Esophageal obturator airway

I-40 Index Eosinophil(s), 313–318 activation, 315–316, 316f anatomic localization of, 313 in asthma, 317, 317t, 775–776 degranulation, 315–316, 316f development of, 313 discovery of, 307 in disease, 317–318, 317t function, 316–317, 1213 pharmacologic modulation of, 318 granule proteins, 310t, 314 in asthma, 782 granules, 313–314, 313f and host defense, 316–317 and mast cells, interactions of, 316 mediators, 310t, 314–316 lipid, 310t, 314 morphology of, 313–314 priming, 315–316 in pulmonary disease, 317–318, 317t in pulmonary fibrosis, 376 recruitment, 315 rolling, 315 sputum levels of, in asthma, 834 structure of, 313–314, 313f surface receptors, 316 Eosinophil cationic protein, 310t, 314, 316, 317 and aspirin-induced asthma, 804 in asthma, 317, 782 Eosinophil-derived neurotoxin, 310t, 314, 317 in asthma, 782 Eosinophilia diseases associated with, 1213, 1214t disorders associated with, 818–819 drug-induced, 1110t–1111t in helminthic disease, 1092, 2414–2415, 2414t infectious causes of, 1092 peripheral blood, 317, 818–819, 1091 in asthma, 776, 818–819 pneumonia with, 2013 pulmonary infiltrate with, 2013 simple pulmonary. See Loeffler syndrome tissue, 2050 tropical pulmonary. See Tropical pulmonary eosinophilia Eosinophilic granuloma of lung, 1106t, 1249, 2014. See also Histiocytosis X computed tomography of, 1112, 1114f Eosinophilic lung disease, drug-induced, 1090t, 1091–1092 Eosinophilic myalgia syndrome, 1093 Eosinophilic pneumonia(s), 1213–1232, 2013 acute, 1091–1092, 1214–1218, 2541t, 2544 clinical features of, 1118t, 1230t computed tomography of, 1118t

differential diagnosis of, 1230t histology of, 1118t idiopathic, 1217–1218, 1217f treatment of, 1118t in allergic bronchopulmonary aspergillosis, 842 bronchoalveolar lavage cellular profile in, 1121t candidiasis and, 2315 chronic, 1091–1092, 1220–1222, 1221f bronchoscopy in, 1120t clinical features of, 1118t, 1231t computed tomography of, 1118t differential diagnosis of, 1231t histology of, 1118t treatment of, 1118t comparative features of, 1229, 1230t–1231t computed tomography of, 1115t differential diagnosis of, 1230t–1231t, 2298 drug-induced, 1091–1092, 1215t, 1216–1217 evaluation of, 1229–1232, 1229f historical perspective on, 1213 idiopathic, 1092 parasitic infestations associated with, 1214, 1214t, 1215–1216 toxin-induced, 1215t, 1216–1217 Eosinophil peroxidase, 310t, 314, 315 in asthma, 782 Eotaxin, 315, 316, 340t in allergic bronchopulmonary aspergillosis, 2296 expression of, by airway smooth muscle cells, 121, 122t, 123 Eotaxin-3, 340t Epicoccum, in indoor air, 1031 Epidermal growth factor (EGF) and airway smooth muscle proliferation, in vitro, 118 in lung development, 92–94 and surfactant production, 132 Epidermal growth factor receptor(s) (EGFR) inhibitors for advanced stage NSCLC, 1877–1878 cutaneous toxicity of, 439 pulmonary effects of, 1081t, 1082 Epiglottis abnormalities, 2647 adult, 2647 anatomy of, 2647 infant, 2647 Epiglottitis acute etiology of, 2088 management of, 2088 clinical features of, 2379 differential diagnosis of, 2087, 2379 epidemiology of, 2379 radiographic assessment of, 850f

treatment of, 853 upper airway obstruction in, 853 Epinephrine adverse effects and side effects of, 825t for asthma, 823t, 825t dosage and administration of, 825t dosage forms, 2632t and pulmonary circulation, 1347 receptor activity, 2632t structure of, 2633f Epithelial cell(s) in airways, 280f alveolar, in immune defense, 1973 apoptosis, 377 and idiopathic pulmonary fibrosis, 1153–1154 in asthma, 777 differentiation of, 96–97, 96f, 97f expression of profibrotic cytokines/growth factors, 377–378 functions of, 137 lineages, in airway, proximal-distal pattern of, 87–88 and loss of antifibrotic function, 378 polarity of, 138 tight junctions of, 137–138 type I, 27f, 31 type II, 27f, 30 Epithelial growth factor, 144 Epithelial-mesenchymal transition, 380 in idiopathic pulmonary fibrosis, 1156 Epithelial neutrophil-activating protein-78. See ENA-78 Epithelioid hemangioendothelioma, 1923 Epithelium, 27–31, 27f, 174f airway biology of, 137–140 cellular composition of, 138 distal, 138 electrolyte transport, 138, 138f cellular and molecular mechanisms of, 139, 139f regulation of, 140 host defense functions of, 143–144 integrated physiology of, 143–144 in vitro studies of, 138 in vivo studies of, 138, 138f ionic permeability of, 138 ion transport across, CFTR and, 2173–2174 morphology of, related to function, 137–138 proximal, 138 repair mechanisms, 144 voltage across, 138, 138f alveolar, 27f, 31, 32–39, 33t, 51–52, 52f.

See also Type I alveolar epithelial cells; Type II alveolar epithelial cells in chronic obstructive pulmonary disease, 700–702, 701t

I-41 Index cuboidal, 27f, 31, 47f differentiation of, 97f, 98–99, 99f interactions with mesenchyme, in embryonic lung development, 92–94 malignant transformation of, 1807 pseudostratified, 27, 28f ciliated, 280f pulmonary, proximal-distal pattern of, 87–88 in pulmonary fibrosis, 376–378, 377f Epoprostenol, for pulmonary arterial hypertension, 1388–1390, 1389f Epstein-Barr virus (EBV) assays for, 1989t characteristics of, 2375t infection (incl. pneumonia), 2025 in bone marrow and stem cell transplant recipients, 2224 in HIV-infected (AIDS) patients, 2212t radiographic findings in, 2214t immune defect associated with, 1983t, 2210t lymphadenopathy in, 2028 and net state of immunosuppression, 2205 in pediatric HIV-infected (AIDS) patients, 2139 pleural effusion in, 1494 and lymphoma, in HIV-infected (AIDS) patients, 2259 molecular detection of, 2002 and pharyngitis, 2086, 2376t, 2378 pneumonia, 1994, 1997 and sarcoidosis, 1127 Epworth Sleepiness Scale, 1706, 1706t, 1728–1729, 1729t Equality, principle of, 2718, 2727 Equal pressure point theory, 156–157, 157f Equity, principle of, 2718 Erasistratus, 4, 5t, 11 Ergots, and interstitial lung disease, 1110t Erionite, and mesothelioma, 1537 ERK, 362 in G protein–coupled chemoattractant receptor signaling, 353, 353f Erlotinib for advanced stage NSCLC, 1877–1878 pulmonary effects of, 1082 ERS. See European Respiratory Society Ertapenem for hospital-acquired pneumonia, 2061t, 2062 pharmacology of, 2056 ERV. See Expiratory reserve volume Erythema multiforme, 390, 2101t Erythema nodosum, 390, 434, 434f, 2006–2007, 2101t chronic/recurrent, 434

clinical presentation of, 434 in coccidioidomycosis, 430 conditions associated with, 434 etiology of, 434 treatment of, 434 Erythrocyte conductance, 58–59 Erythromycin, 2060 indications for, 2157 organisms susceptible to, 2055 pulmonary effects of, 1090t resistance to, 2099 for Rhodococcus pneumonia, 2429t Erythropoiesis, altitude and, 1040 ESBL. See Beta-lactamase, extended spectrum Escherichia, pneumonia, 2019, 2022 Escherichia coli, 1989 and acute lung injury, 2527 in acute mediastinitis, 2166t aspiration pneumonia, 2007 colonization, in cystic fibrosis, 866 in empyema, 2144 immune defense against, 1973 infection (incl. pneumonia) in chronic granulomatous disease, 2237 of deep cervical space, 852 immune defect associated with, 1983t, 2210t in immunocompromised host, 2207 neonatal, 2126 nosocomial, 2279, 2280, 2280t, 2281t, 2282, 2289 treatment of, 2285–2288, 2286t and parapneumonic effusions, 1489 pathogenesis of, 2080 in surgery and trauma patients, 2197 in lung abscess, 2144 pneumonia, 2020 in elderly, 2007 E-selectin, 315, 347 in inflammation, 782 and leukocyte adherence and migration, 347–348 Esophageal balloon technique, for measurement of elastic properties of lungs, 575, 576f Esophageal cancer and aspiration, 1310, 1312f upper airway obstruction caused by, 857 Esophageal diverticulum, 1563, 1563f, 1566, 1596 Esophageal duplication(s), 1576, 1596.

See also Cyst(s), enterogenous Esophageal obturator airway, 2651 Esophageal perforation, 2163t, 2164t and mediastinitis, 1560–1561, 1561f, 1591–1592, 1592f, 2163t, 2164t, 2165, 2166t and pleural effusion, 1495–1496

Esophageal pressure, 2670 in acute respiratory failure, 2672 Esophageal stricture, radiation-related, 1892 Esophagectomy, pulmonary complications of, 666, 666t Esophagitis pain of, 420 peptic, 420 radiation-related, 1892 Esophagomediastinal fistula, 1564 Esophagus contrast examination of, 466, 466f development of, 94, 94f dilated, radiographic features of, 498, 501f duplication cyst, radiographic features of, 498, 501f innervation of, 1302–1304 pain arising from, 420 in swallowing, 1302–1304 tumors, radiographic features of, 498–499 Esparto grass antigens, hypersensitivity pneumonitis caused by, 1164t Esters, in indoor air, sources of, 1023t Etanercept for idiopathic pulmonary fibrosis, 1158 pulmonary toxicity of, 440 Ethambutol adverse effects and side effects of, 2478, 2483t, 2494, 2503 in children, 2135 interactions with immunosuppressive agents, 2503t mechanism of action of, 2478 for Mycobacterium avium complex infection, 2505 in HIV-infected (AIDS) patients, 2494, 2494t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t ocular toxicity of, 2135 pharmacology of, 2478 for tuberculosis, 2464, 2478 in children, 2135 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2490 regimens for, 2481t theoretical basis for, 2476 Ethchlorvynol, pulmonary effects of, 1088 Ethical dilemmas, 2722 Ethics definition of, 2721 and futile medical interventions, 2726 health care law and, 2724 and microallocation of ICU resources, 2726–2728

I-42 Index Ethionamide adverse effects and side effects of, 2483t, 2503 for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for tuberculosis, 2479 dosage and administration of, 2482t Ethylbenzene exposure to, 1027t sources of, 1027t ETS. See Environmental tobacco smoke Eubacterium in acute mediastinitis, 2166t in empyema, 2144t infection (incl. pneumonia), 2156t Euroglyphus maynei, 1031 European Organization for Research and Treatment of Cancer (EORTC), prognostic index for mesothelioma, 1546 European Respiratory Society, definition of chronic obstructive pulmonary disease, 707 Euthanasia, passive, 2725 Evelyn, John, 1010 Exercise adaptation to, 223 arterial blood oxygen pressure in, normal, 1324, 2736 and asthma, 807–812 benefits of, 223 in chronic obstructive pulmonary disease, 734–735 and diffusing capacity, 197–198 hemodynamic response to, in treadmill testing, 615–616 oxygen therapy in, 2620, 2620t in pregnancy, respiratory response during, 256 and pulmonary hemodynamics, 1334t, 1339 in pulmonary hypertension, 1376 in pulmonary rehabilitation, 767–768 and blood-gas changes, 768 upper extremity training in, 768 ventilatory muscle training in, 768 ventilatory control in, 241–247 ventilatory costs of, 247–248 ventilatory requirements in, 233–236, 234f ventilatory response to, 166–167, 233, 234f in treadmill testing, 614–615 Exercise capacity age-related changes in, 273–275, 274f, 275t in ankylosing spondylitis, 1626 in chronic obstructive pulmonary disease, 731 in kyphoscoliosis, 1620 in Langerhans’ cell histiocytosis, 1248, 1248f

in lymphangioleiomyomatosis, 1258, 1259f with pectus excavatum, 1624 preoperative, analysis, for lung resection, 672 Exercise challenge test, for exercise-induced bronchospasm, 587, 810–811, 818 Exercise-induced bronchospasm, 587 Exercise testing in bullous lung disease, 923 for diagnosis of exercise-induced asthma, 810–811, 818 in idiopathic pulmonary fibrosis, 1148 Exercise tolerance mechanical limitations and, 249–250 ventilatory constraints and, 248–249 ventilatory limitations and, 249–250 Exercise training adaptation to, 230 in chronic cardiac failure, 620–621 Expectorant(s), 2642 Expiration, duration of, 2592 Expiratory reserve volume, 149t, 569f definition of, 568t, 1326, 2738 measurement of, 571 normal, 1323, 2735 postoperative changes in, 664 Exserohilum, in invasive fungal sinusitis, 2091 External beam radiotherapy, definition of, 1895 External oblique muscle, 72f, 76–77 Extra-alveolar vessels, 1349–1350, 1349f Extracellular matrix (ECM) airway smooth muscle cells and, 123 in idiopathic pulmonary fibrosis, 1155 proteins and airway smooth muscle proliferation, 119 in pulmonary fibrosis, 371 remodeling, 380–381 Extracellular signal-regulated kinase(s).

See ERK Extracorporeal CO2 removal (ECCO2 R), in ALI/ARDS, 2556 Extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome, in trauma patient, 1765–1766 in ALI/ARDS, 2556 for burn patient, 1061 Extrapleural sign, 502, 505f Extrapulmonary small cell cancer, 1906 Extrapyramidal disorders, upper airway obstruction in, 859 Extrinsic allergic alveolitis, 1106t, 2012.

See also Hypersensitivity pneumonitis aspergillosis and, 2292t, 2294, 2295t, 2301

Extubation, in neuromuscular disorders, 1674–1675 protocol for, 1673–1674, 1673t F Fabry’s disease, 1274–1275 and bullous emphysema, 917 FACTT. See Fluid and Catheter Treatment Trial Face masks, for exercise-induced asthma, 811 Facial swelling, with mediastinal lesions, 1587, 1587t Facial trauma, upper airway obstruction caused by, 858 Facioscapulohumeral dystrophy, respiratory abnormalities in, 1658–1659 Factor V Leiden mutation, and risk of venous thromboembolism, 1426–1427 Fagerstrom test, for nicotine dependence, 756–757, 757t Fairness, principle of, 2718 FAK. See Focal adhesion kinase Famciclovir, 2394 indications for, 2375t Family history, 389 Fansidar, prophylactic, for Pneumocystis pneumonia, 2367 Farmer’s lung, 935t, 1161, 2012 etiology of, 1163t exposures associated with, 1109t prognosis for, 1171 Fas ligand, 1977 FAST Plaque TB, 2462 Fat embolism, 524, 1424–1425, 1443–1444 Fatigue, in pulmonary hypertension, 1371, 1371t Fatty tumors, mediastinal, 1611 Fcγ receptors, 283, 325t, 326, 1972 Fc receptor(s), 283, 325t, 1979 neonatal, 326 FD&C dyes, sensitivity to, in aspirin-sensitive asthmatics, 802 FDG. See Positron emission tomography (PET), F-18 fluorodeoxyglucose Fechner tumors, 1925–1926 FEF. See Forced expiratory flow Fenamates, and aspirin-induced asthma, 802t Fenfluramine and interstitial lung disease, 1110t pulmonary effects of, 1093–1094, 1347 and pulmonary hypertension, 447, 1382–1383 Fenn, Wallace Osgood, 5t, 12, 13 Fentanyl, for agitated ICU patient, 2707–2708, 2709t Ferruginous bodies, 516, 517f Fertility, smoking and, 752 Fertilizer lung, etiology of, 1165t

I-43 Index Fetal liver kinase-1, 87 Fetal liver tyrosinase-1, 87 Fetus maternal cardiovascular function and, 258 pulmonary circulation in, 1354 FEV1 . See Forced expiratory volume at 1 second (FEV1 ) FEV3 . See Forced expiratory volume at 3 seconds (FEV3 ) Fever after bronchoscopy, 644 dyspnea in, 403 in infection, 420 in interstitial lung disease, 1108 in pneumonia, 2099 in pulmonary disease, 452 FEV1 /FVC%, 580–581, 580t, 581f, 602–603 in AMA Guides classification of impairment, 682t in chronic obstructive pulmonary disease, 711–712, 712f, 731 normal, 1323, 2735 postoperative, 664 FEV3 /FVC%, 580, 580t, 581 normal, 1323, 2735 FEVt /FVC%, definition of, 1326, 2738 FEV1 /VC, 602–603 F-18 fluorodeoxyglucose. See Positron emission tomography (PET), F-18 fluorodeoxyglucose Fgf7, and lung development, 84 Fgf9, and lung development, 84 Fgf10, and lung development, 82–83, 83–87, 83f, 88–89, 88f, 89f Fgf18, and lung development, 84 Fgfr1, and lung development, 83 Fgfr2, 87 and lung development, 83 Fgfr3, and lung development, 83, 88 Fgfr4, and lung development, 87, 88 Fgfr2IIIB, 83, 84 Fgfr2IIIb, 83 FGFR2-IIIb, 83, 88 FGFR2-IIIc, 83, 88f FHA. See Filamentous hemagglutinin; Hemagglutinin, filamentous Fiberoptic bronchoscopy, 1987 Fiber system(s) elastic properties of, 53–54 of lung, 52, 52f axial, 52–53, 52f, 54, 56f peripheral, 52–53, 52f, 54, 56f septal, 52–53, 52f, 54, 56f Fibrillin, in lung development, 94 Fibrinolysis, intrapleural, 535–536 Fibroblast(s), 378–381 of alveolar septum, 40f, 41 bone marrow-derived precursors, 379–380 in idiopathic pulmonary fibrosis, 1155

expansion, cytokines/growth factors in, 378, 378t in idiopathic pulmonary fibrosis, 1155–1156 maintenance, in idiopathic pulmonary fibrosis, 1155 phenotypes, in idiopathic pulmonary fibrosis, 1155 in pulmonary fibrosis, 378–379, 379f origin of, 379–380, 379f recruitment, in idiopathic pulmonary fibrosis, 1155 Fibroblast growth factor (FGF) basic and airway smooth muscle proliferation, in vitro, 118 effects/functions of, 779t mast cells and, 310t, 312 sources of, 779t targets of, 779t FGF1, and lung development, 84 FGF7, and lung development, 84 FGF9, and lung development, 88f, 89f FGF10, and lung development, 82–89, 83f, 88–89, 88f, 89f, 92–94 FGF18, and lung development, 84 and lung development, 83–84 Fibrocyte(s), 380 trafficking in lung, chemokines and, 342 Fibroma, intrapulmonary, 1918 Fibrosis mediastinal, in histoplasmosis, 2336–2337, 2336f diagnosis of, 2337t treatment of, 2339, 2339t pulmonary. See also Progressive massive fibrosis bullae in, 913, 915t CC chemokines in, 343–344 chemokines in, 341–344, 342f, 372–374, 373f CXC chemokines in, 341 cyanosis in, 415 cytotoxic drugs and, 2011–2012, 2012t diffuse interstitial, and elastic properties of respiratory system, 577, 578f drug-induced, 1089, 1090t, 1110t–1111t dyspnea in, 400 epithelial pathway to, 371, 372f, 376–378 gene-environment interactions and, 382 gene-gene interactions and, 382 genetic polymorphisms and, 381–382 genetic susceptibility to, 381–382 idiopathic. See Idiopathic pulmonary fibrosis inflammatory cells and, 374–376

inflammatory pathway to, 371–376, 372f interstitial, 2542t in allergic bronchopulmonary aspergillosis, 842 lymphadenopathy in, 2028 radiographic features of, 483 pathophysiology of, 371 pathways to, 371–378, 372f radiation-related, 1890–1892, 1892f.

See also Radiation fibrosis in respiratory failure, 2517, 2518t TNF in, 337 vascular remodeling in, CXC chemokines and, 341–342, 342f Fibrothorax, and abnormal breathing pattern, 403 Fibrous tumor, intrapulmonary, 1918 Fick method indirect, for measurement of cardiac output, 2667–2668 for measurement of cardiac output, 2663 Fick principle, 16 Field, radiation, definition of, 1895 Filamentous hemagglutinin, 2069, 2080 Filariasis, 1995, 2013 lymphatic, 2414t pulmonary, 2418–2419 Fine-needle aspiration biopsy, 534–535, 2032, 2033 endobronchial, 513 endoesophageal, 513 percutaneous transthoracic. See Transthoracic needle aspiration and biopsy Finger in glove opacity, 1222, 1224f in allergic bronchopulmonary aspergillosis, 841 FIO2 . See Fractional inspired oxygen concentration FIVC. See Forced inspiratory vital capacity Fixatives, and occupational asthma, 985t, 986 Flagellin, 1971 Flail chest, 403, 1630–1631, 2514 pathophysiology of, 1630–1631, 1630f, 1631f pulmonary function in, 1630–1631 respiratory mechanics in, 1630–1631, 1630f, 1631f in trauma patient, 1762–1763, 1762f treatment of, 1631–1632, 1632f FLAP. See 5-Lipoxygenase activating protein Flatworms, 2413, 2423–2425 Fleischner’s lines, 508, 508f Flexible fiberoptic bronchoscopy, with lung biopsy, 2003 FLK-1, 87 Flow cytology, 514

I-44 Index Flow-pressure relationships, terminology for, 1327, 2739 Flow-volume curve(s), 581–583, 581f–582f in asthma, 421, 422f helium-oxygen, 590–591, 590f Flow-volume loops, 155, 155f, 156f in chronic obstructive pulmonary disease, 849, 850f in neuromuscular disease, 1646–1647, 1647f in upper airway obstruction, 847, 847f–850f Flow-volume relationships, 581–583, 581f–582f FLT-1, 87 FLT-ligand, and B-cell production, 323 Fluconazole for acanthamoebiasis, 2401 for candidiasis, 2316 for coccidioidomycosis, 2345 for cryptococcosis, 2333–2334, 2333t for histoplasmosis, 2340 for invasive fungal infections, 2310t, 2311t resistance to, 2334 Flucytosine for cryptococcosis, 2333–2334, 2333t for invasive fungal infections, 2310t Fludarabine immunologic effects of, 2216 pulmonary effects of, 1076t, 1078 Fluid and Catheter Treatment Trial, 2544, 2552–2554, 2553t, 2554t Fluid balance, altitude and, 1040 Fluid exchange, in lungs, 2523–2524 Fluid overload, radiographic features of, on portable examination, 508–509 Flukes, 2413 Flunisolide adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t 5-Fluorocytosine, for acanthamoebiasis, 2401 Fluoroquinolones adverse effects and side effects of, 2057, 2480 anti-pneumococcal, indications for, 2060 anti-TB activity, 2464 bioavailability of, 2057 dosage and administration of, 2057 drug interactions with, 2480 indications for, 2061t, 2062 interactions with immunosuppressive agents, 2503t mechanism of action of, 2056–2057 organisms susceptible to, 2057 penetration into lung, 2053, 2057

pharmacokinetics and pharmacodynamics of, 2054 postantibiotic effect of, 2057 resistance to, 2099 for tuberculosis, 2480 dosage and administration of, 2482t for yersiniosis, 2441 Fluoroscopy, 459–460, 460f historical perspective on, 18 5-Fluorouracil, immunologic effects of, 2216 Fluticasone adverse effects and side effects of, 826t for asthma, 823t, 826t for bronchiectasis, 2191 dosage and administration of, 826t pharmacology of, 2637 Fluticasone/salmeterol adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t Fluxes, soldering, and occupational asthma, 985t, 986, 990 FNA. See Fine-needle aspiration biopsy Focal adhesion kinase, 362 in G protein–coupled chemoattractant receptor signaling, 353, 353f Fondaparinux, for pulmonary embolism, 1438–1439 Fontana-Masson stain, 2038, 2041f Foramen of Bochdalek, hernias, 502 Foramen of Morgagni, hernia, 502, 504f, 1566–1567, 1567f Forced expiratory flow between 200 and 1200 ml of forced vital capacity (FEF200−1200 ), definition of, 1326, 2738 between 25% and 75% of forced vital capacity (FEF25−75% ), 580–581, 580f, 580t, 848 definition of, 1326, 2738 in diagnostic spirometry, minimal recommendations for, 570t normal, 1323, 2735 definition of, 1326, 2738 maximal, in chronic obstructive pulmonary disease, 711–712, 712f at 50% of forced vital capacity (FEF50% ), 848 normal, 1323, 2735 Forced expiratory vital capacity, 580–581, 580f, 581f Forced expiratory volume, timed abbreviations for, 1326, 2738 definition of, 1326, 2738 Forced expiratory volume at 1 second (FEV1 ), 580, 580f, 580t, 581f, 582, 582f age-related changes in, 272, 273f in AMA Guides classification of impairment, 682t

in chronic obstructive pulmonary disease, 711–712, 712f, 730–731, 730f, 731, 732t in diagnostic spirometry, minimal recommendations for, 570t and grading severity of abnormal spirometry, 603, 603t measurement of, 571 normal, 1323, 2735 postbronchodilator, in evaluation of permanent impairment in asthma, 683, 683t postoperative with lobectomy, 671 with pneumonectomy, 671 postoperative changes in, 664 in pregnancy, 254–255 preoperative, and risk of complications, 671 ratio of, to vital capacity, 602 in Social Security Listings for severity of COPD, 686, 686t in upper airway obstruction, 846–849 Forced expiratory volume at 3 seconds (FEV3 ), 580, 580f, 580t, 581 Forced expiratory volume at 6 seconds (FEV6 ), in chronic obstructive pulmonary disease, 711 Forced inspiratory flow between 25% and 75% of forced vital capacity (FIF25−75% ), 848 definition of, 1327, 2739 at 50% of forced vital capacity (FIF50% ), 848 Forced inspiratory vital capacity, 581, 581f definition of, 1326, 2738 Forced inspiratory volume at 1 second (FIV1 ), in upper airway obstruction, 848 Forced vital capacity (FVC), 579–581, 580f, 580t, 581f age-related changes in, 271, 272, 273f in AMA Guides classification of impairment, 682t definition of, 1326, 2738 in diagnostic spirometry, minimal recommendations for, 570t measurement of, 571 normal, 1323, 2735 preoperative, and risk of complications, 671 in Social Security Listings for severity of restrictive lung disease, 686, 686t Foreign body(ies) aspiration of, 857–858, 2151 and bronchiectasis, 2186 in children, 2136, 2151 hemoptysis caused by, 414 penetration syndrome caused by, 857–858 in hollow organ, removal of, 542

I-45 Index intravascular, removal of, 540–542, 543f removal of, therapeutic bronchoscopy for, 642–643, 642f Formaldehyde as air toxic, 1020 health effects of, 1026 in indoor air, 1026 sources of, 1022t in smoke and inhalation injury, source of, 1054t Formoterol adverse effects and side effects of, 827t for asthma, 822, 823t, 827t for chronic obstructive pulmonary disease, 738t, 739–740 dosage and administration of, 827t dosage forms, 2632t plus budesonide adverse effects and side effects of, 826t for asthma, 822, 823t, 826t dosage and administration of, 826t receptor activity, 2632t structure-activity relationships, 2633 Forssmann, Werner, 5t, 16 Foscarnet, indications for, 2394 Fothergill, John, 2645 Foxa1, 87 Foxa2, 87 Foxf1, and lung development, 83 Fractalkine, 340t, 1973 Fractal trees, 49 dichotomous branching of, 49 self-similar branching of, 49 Fractional inspired oxygen concentration radiation, definition of, 1895 ventilator setting for, 2682–2683 Francisella tularensis, 2005t, 2006, 2428t, 2432–2434. See also Tularemia bacteriology of, 2428t, 2432 as bioweapon, 2433 culture of, 2429t ecology of, 2432 infection (incl. pneumonia), 2289 hospitalization rate for, 2105t staining characteristics of, 2429t vaccine against, 2434 FRC. See Functional residual capacity Fredericq, Leon, 12 Fremitus, 392 Friction rub, 392 Friedreich’s ataxia, ventilatory impairment in, 1668t Frizzled-related protein, 86 Fume(s), 1053 definition of, 994t occupational lung disease caused by, 934t, 935t Functional residual capacity (FRC), 148, 149t, 568–569, 569f age-related changes in, 271, 271f

and closing capacity, relationship of, 664, 665, 665f, 665t definition of, 568t, 1326, 2738 measurement of by body plethysmography, 571, 572–574, 573f closed-circuit helium method, 571–572, 572f, 574 nitrogen washout method, 571, 572, 574 normal, 1323, 2735 postoperative changes in, 664, 665f, 665t in pregnancy, 254 Fungal infection(s), 1990, 1994–1995, 1996. See also Allergic bronchopulmonary mycosis; Pneumonia, fungal and acute mediastinitis, 2166t in bone marrow and stem cell transplant recipients, 2224–2225, 2229 bronchoalveolar lavage cellular profile in, 1121t bronchopneumonia caused by, 2042 in cancer patients, 2215, 2216, 2221, 2221t risk factors for, 2217, 2219t cavitating, 2146 in cell-mediated immunodeficiency, 2236 in children, immune defects and, 2138, 2139 in chronic granulomatous disease, 2238 in common variable immunodeficiency, 331–332, 2235 computed tomography of, 1115t cytopathology of, 519–522, 519f–522f dematiaceous, staining characteristics of, 2035t, 2038 diagnosis of, 1999, 2002 sputum culture for, 2000 and diffuse alveolar damage, 2042 and diffuse alveolar hemorrhage, 1295 in DiGeorge’s syndrome, 2236 disseminated, in HIV-infected (AIDS) patients, 2246–2247 and empyema, 2144 endemic, 2005–2007, 2005t. See also Blastomycosis; Coccidioidomycosis; Histoplasmosis and extrinsic allergic alveolitis, 2012, 2292t, 2294, 2295t, 2301 in hematopoietic stem cell transplant recipients, 2305–2306, 2307, 2307f hemoptysis in, 412f, 413 histopathology of, 2034 in HIV-infected (AIDS) patients, 2212t, 2213, 2215, 2242t, 2253–2257 radiographic findings in, 2214t

in hyperimmunoglobulin E syndrome, 2239, 2239f identification of, in tissue, 2034–2035, 2038t imaging findings in, 2019 immune defect associated with, 1983t, 2210t immune defense against, 1973 in immunocompromised host, 1997, 2204 invasive, treatment of, 2309–2312, 2310t, 2311t laryngitis caused by, 2087 in leukocyte adhesion deficiency, 2239, 2239f and lung abscess, 2154t lymphadenopathy in, 2028 in neutropenic host and cancer patient, 2217–2218 nosocomial, 2274–2275, 2280t, 2281t occupational, 934t opportunistic, 2321–2324. See also Aspergillosis; Candidiasis differential diagnosis of, 2323t of oral cavity, 2087 pathogenesis of, 2040 pathology of, 2043t, 2045, 2049f, 2050 pleural effusion in, 1494 radiographic features of, 483, 498 severity of, Social Security Listings for, 687 sinusitis caused by, 2090–2091 staining characteristics of, 2034, 2035, 2035t, 2037 supraglottitis caused by, 853 in surgery and trauma patients, 2197 systemic effects of, 451–453, 451t Fungal spores, in indoor air, sources of, 1022t Fungus hypersensitivity pneumonitis caused by, 1164t in indoor air, 1030–1031 Fungus balls, 412f, 413, 1991, 2049–2050, 2049f, 2301 in sarcoidosis, 1141 Furosemide, inhaled, 2637 for exercise-induced asthma, 811t, 812 Fusariosis differential diagnosis of, 2323t pulmonary, 2321–2322 Fusarium, 2293 identification of, in tissue, 2035, 2038t infection (incl. pneumonia) in immunocompromised host, 2207 in neutropenic host and cancer patient, 2217–2218, 2218f pathology of, 2045, 2046f, 2050 pneumonia, 1995 Fusarium dimerum, 2321 Fusarium moniliforme, 2321 Fusarium oxysporum, 2321

I-46 Index Fusarium proliferatum, 2321 Fusarium solani, 2321 Fusarium verticilloides, 2321 Fusobacterium, 1998–1999, 2007 in acute mediastinitis, 2166, 2166t infection (incl. pneumonia), nosocomial, 2281t Fusobacterium mortiferum, morphology of, 2147f Fusobacterium necrophorum infection (incl. pneumonia) conditions underlying, 2145t in Lemierre’s syndrome, 853 morphology of, 2147f Fusobacterium nucleatum, 2087, 2142 in empyema, 2144, 2144t infection (incl. pneumonia), 2156, 2156t conditions underlying, 2145t in lung abscess, 2144 morphology of, 2147f Fusobacterium varium, morphology of, 2147f Futile life support, 2726, 2729 Futility medical, 2726 physiological, 2726 G Gag reflex, absent, 2101t Galactomannan, 2308–2309 α-Galactosidase A deficiency, 1274–1275 Galactosylceramide lipidosis, 1273–1274, 1274f Galen, 4, 5t, 6f, 11 Galilei, Galileo, 5t, 6, 11 Gallium-67 citrate imaging, 557 in asbestosis, 949 in HIV-infected (AIDS) patients, 557, 558f in noninfectious inflammatory lung disease, 558, 559f in Pneumocystis carinii pneumonia, 557, 558f in sarcoidosis, 558, 559f of thorax, in immunocompromised host, 557, 558f Gallium scan, in HIV-infected (AIDS) patients, 2247t Gallium scintigraphy, in HIV-infected (AIDS) patients, 2360, 2361t GALT. See Gut-associated lymphoid tissue Gamma rays, physics of, 1174–1175 Ganciclovir, indications for, 2375t, 2394–2395 Ganglioneuroblastoma, 1611 Gangrene lung, hemoptysis in, 413 pulmonary, 1988, 2141, 2148f, 2153 computed tomography of, 483f

GAS. See Streptococci (Streptococcus spp.), group A Gas(es) definition of, 994t inhalation injury caused by, clinical manifestations of acute, 1000t chronic, 1000t inorganic, lung disease caused by, 934, 934t inspired, distribution of, normal values for, 1323, 2735 irritant bronchiolitis caused by, 893t, 894–895, 894t lung disease caused by, 934, 934t occupational lung disease caused by, 935t in smoke and inhalation injury, 1057 water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995, 995t pleural, reabsorption of, 1518–1519, 1519f respiratory. See also Carbon dioxide (CO2 ); Oxygen chemical reactions of, 192–194 and pulmonary vasomotor control, 1343–1346 toxic bronchiolitis caused by, 889t, 892–894, 893t, 894t, 895f acute phase, 893–894 chronic phase, 894 clinical findings in, 893–894 management of, 894 mechanism of injury in, 892–893 prognosis for, 894 subacute phase, 894 in smoke and inhalation injury, 1054–1057 transport, in blood, 201–206 Gas exchange abnormalities in chronic obstructive pulmonary disease, 398 in cystic fibrosis, 872 detection of, cardiopulmonary exercise testing in, 625 abnormalities of, severity of, Social Security Listings for, 686, 687t in acute lung injury, 2524–2525 age-related changes in, 273, 274f in ankylosing spondylitis, 1626 in kyphoscoliosis, 1621 measurement of, 591–596 normal, 1323–1324, 2735–2736 in obesity, 1629 pathway, 173–177, 174f–176f disruption of, 177–187 postoperative changes in, 664–665

pulmonary, 57–65, 58f acinar design and, 61–65, 62f pulmonary microcirculation and, 1348–1350 quantities of, 191 ventilation-perfusion inequality and, 180–187 Gas-exchange barrier, structure of, 32–33 Gas lesion disease(s), 1045 diving-related, 1045 isobaric counterdiffusion, 1049 Gasping, 404 Gas transfer. See also Diffusing capacity efficiency of, isolated reduction in, 607, 607t, 608t Gas transport, pathway, disruption of, 177–187 Gas trapping, airspace enlargement in, differential diagnosis of, 698–699, 698t Gastrectomy, pulmonary complications of, 666, 666t Gastric cancer metastases, survival rates for, 1941, 1942t and pleural effusion, 1505, 1506t Gastric pH, and nosocomial pneumonia, 2196, 2274 Gastroesophageal reflux disease (GERD), 2087 and aspiration, 1308–1309, 1309f and asthma, 832 and bronchiectasis, 2186 and chronic cough, 410 differential diagnosis of, 819t and idiopathic pulmonary fibrosis, 1156 treatment of, 832 Gastrointestinal source(s), and anaerobic pleuropulmonary infections, 2145t GATA-1, and eosinophil development, 313 GATA3, 1976 Gata-6, 83 and lung development, 83 Gatifloxacin, 2056–2057, 2060 adverse effects and side effects of, 2057 anti-TB activity, 2464 for pasteurellosis, 2430 for tuberculosis, dosage and administration of, 2482t Gaucher’s bodies, 1271, 1271f Gaucher’s cells, 1269–1270, 1269f ultrastructure of, 1270f, 1271, 1271f Gaucher’s disease biochemical features of, 1271 clinical features of, 1268–1269 diagnosis of, 1271–1272 genetics of, 1268, 1269 pathology of, 1269–1270, 1269f treatment of, 1271 types of, 1268–1269

I-47 Index Gaw . See Airway conductance Gaw/VL. See Specific conductance GCP-2. See Granulocyte chemotactic protein-2 Gefitinib for advanced stage NSCLC, 1877–1878 pulmonary effects of, 1081t, 1082 Gelatinase B. See Matrix metalloproteinase (MMP), MMP-9 Gemcitabine, pulmonary effects of, 1076t, 1078 radiation therapy and, 1181 Gemifloxacin, 2056–2057, 2060 dosage and administration of, 2057 General anesthesia and aspiration, 1312 in neuromuscular disorders, 1675 Genetic abnormalities, airspace enlargement in, 698t, 699 Genetic association study(ies), 793 in asthma, 793–794 Genetics, and pulmonary fibrosis, 381–382 Gentamicin for brucellosis, 2438–2439 for hospital-acquired pneumonia, 2061 for plague, 2432 for tularemia, 2429t, 2434 Geotrichum candidum, infection (incl. pneumonia), in cancer patients, 2217 Germ cell tumor(s). See also Seminoma malignant, primary pulmonary, 1925 mediastinal, 1604–1608 benign, 1604–1606, 1606t malignant, 1604 nonseminomatous anterior mediastinal, 1606t, 1607–1608 pulmonary metastases, 1943 Germinal center, 324 Gesell, 12 GH. See Growth hormone Ghon’s complex, 2468 GHRH. See Growth hormone–releasing hormone Giant-cell arteritis, 1461 Giant cell carcinoma, 1840–1841 Giant cell interstitial pneumonia, 1144, 2013 occupational exposures and, 935t Giardia lamblia, 2410 infection (incl. pneumonia), immune defect associated with, 1983t, 2210t in X-linked agammaglobulinemia, 2234 Gibbs formula, 54 Gingivitis, 2087 and anaerobic pleuropulmonary infections, 2145t GIP. See Giant cell interstitial pneumonia Gliotoxin, 2294

Global Initiative on Obstructive Lung Disease, 694, 702 definition of chronic obstructive pulmonary disease, 707 Globoid-cell leukodystrophy, 1273–1274, 1274f Glomerular basement membrane (GBM) antibody, and diffuse alveolar hemorrhage, 1281 autoantibodies against, 1463. See also Goodpasture’s syndrome Glomerulonephritis acute poststreptococcal, 2086 pauci-immune, 1281, 1288 rapidly progressive, 1281, 1283f idiopathic, 1289 Glomus cells, 163 Glossopharyngeal breathing, 1674 in neuromuscular disorders, 1662–1663 1,3-β-D-Glucan assay, in detection of Aspergillus, 2309 Glucocorticoid(s) for asthma, 822, 823t for asthma exacerbations, 834 for hypersensitivity pneumonitis, 1171 pharmacology of, 2637 and surfactant production, 132 Glucose control, in critically ill patients, 2698 Glucose intolerance, in SIRS/MODS, 2565, 2570 Glucose-6-phosphate dehydrogenase (G6PD), deficiency of, 2238 β-Glucuronidase eosinophil, 310t, 314 mast cell, 310t, 311 Glutathione (GSH) redox cycle, 2626 Glycemic control, in critically ill patients, 2698 Glycogen storage disorders, 1275–1276, 1276f G M1 gangliosidosis, 1272, 1273f GMS. See Gomori methamine silver stain Goal-directed therapy, 2569, 2569f, 2663 Goblet cell(s), 27, 28f, 29, 281, 515, 516f in asthma, 777 metaplasia of, 700–702, 701t, 730 Goiter computed tomography of, 495 intrathoracic, 851f substernal, 1595–1596, 1595f upper airway obstruction caused by, 856–857 GOLD. See Global Initiative on Obstructive Lung Disease Goldenhar syndrome, 2647 Gold salts, 831, 2639 bronchiolitis associated with, 905 pneumonitis caused by, 1205–1206, 2010, 2012t

pulmonary effects of, 1089, 1090t, 1093, 1098–1099 Gomori methamine silver (GMS) stain, 2034–2037, 2035t, 2041f Goodpasture’s syndrome, 330, 1463, 1463f alveolar hemorrhage in, 1239–1241, 1240f clinical features of, 1118t, 1239, 1287 computed tomography of, 1118t diagnosis of, 423, 1239 hemoptysis in, 410, 412f, 414, 1239 histopathology of, 1118t, 1239, 1240f, 1287 immunologic tests for, 1112t, 1239 pathogenesis of, 1287–1288 pathology of, 1285t pathophysiology of, 1239 serology of, 1285t treatment of, 1118t, 1239–1241, 1288 Goose proteins, hypersensitivity pneumonitis caused by, 1164t Gottron’s papules, 428, 428f, 1208 Gough, J., 694 Graft-versus-host disease (GVHD) in bone marrow and stem cell transplant recipients, 2222, 2224, 2225, 2226, 2227 in severe combined immunodeficiency, 2236 Grain dust effects, 934t, 981, 983 Gram-negative bacteria in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t in acute mediastinitis, 2166t in acute otitis media, 2092 anaerobic, infection (incl. pneumonia), conditions underlying, 2145t in chronic suppurative otitis media, 2094 in empyema, 2144 endotoxin, 2081 immune defense against, 1973 infection (incl. pneumonia), 330–331, 2156t in bone marrow and stem cell transplant recipients, 2222–2223 in Chediak-Higashi syndrome, 2238 in children, immune defects and, 2138 conditions underlying, 2145t in cystic fibrosis, 875, 880–881, 2176 treatment of, 875, 2179 in HIV-infected (AIDS) patients, 2251 hospitalization rate for, 2105t ICU admission rate for, 2106t immune defect associated with, 1983t, 2210t in leukocyte adhesion deficiency, 2238

I-48 Index Gram-negative bacteria, infection (Cont.) neonatal nosocomial pneumonia caused by, 2126 in neutropenic host and cancer patient, 2217 nosocomial, 2279–2280, 2280t, 2281t, 2282, 2289, 2581 treatment of, 2285–2288, 2286t pathology of, 2042–2043, 2043t, 2049f, 2050 in surgery and trauma patients, 2197 treatment of, 2054, 2056–2057, 2058 in lung abscess, 2144 neonatal infection, 2126 in nosocomial sinusitis, 2089 staining characteristics of, 2034, 2035t, 2036f tracheitis caused by, 2088 Gram-positive bacteria in acute mediastinitis, 2166t immune defense against, 1973 infection (incl. pneumonia), 2156t.

See also Rhodococcus equi; Staphylococcus aureus; Streptococci (Streptococcus spp.), group A; Streptococcus pneumoniae; Streptococcus pyogenes in bone marrow and stem cell transplant recipients, 2222–2223 in HIV-infected (AIDS) patients, 2212t in leukocyte adhesion deficiency, 2238 nosocomial, 2280t, 2281t, 2581–2582 pathology of, 2042–2043 in surgery and trauma patients, 2197 treatment of, 2054, 2056–2057 staining characteristics of, 2034, 2035t, 2036, 2036f Gram stain, tissue, 2034 Granular cell myoblastoma, 1919 Granule proteins, in asthma, 782 Granulocyte(s), 42 transfusion therapy for fusariosis, 2322 in invasive pulmonary aspergillosis, 2312 Granulocyte chemotactic protein-2, 340t, 341t Granulocyte colony-stimulating factor (G-CSF), 1976 adjunctive therapy with, in invasive pulmonary aspergillosis, 2312 effects/functions of, 779t sources of, 779t targets of, 779t Granulocyte disorders, in children, 2138–2139

Granulocyte-macrophage colony-stimulating factor (GM-CSF), 1973, 1976, 1978 adjunctive therapy with in invasive pulmonary aspergillosis, 2312 for zygomycosis, 2321 and alveolar macrophage function, 1315, 1316f antibodies, in primary pulmonary alveolar proteinosis, 1315, 1317f effects/functions of, 779t and eosinophilia, 2414 eosinophils and, 310t, 313, 315 expression of, by airway smooth muscle cells, 121, 122t and innate immunity, 1315 and pulmonary alveolar proteinosis, 1313–1314, 1315, 1317f sources of, 779t and surfactant catabolism, 132 targets of, 779t therapy with, for Pneumocystis pneumonia, 2370 Granulocytopenia, 1983t, 2210t in cancer patients, 2216 causes of, 1983t, 2210t infections associated with, 1983t, 2210t, 2216 Granulocytosis, associated with lung tumors, 1930t, 1935 Granuloma(s), 1978 eosinophilic, radiographic features of, 483–484 infectious, presenting as solitary pulmonary nodule, 1817 mediastinal, 1563 in histoplasmosis, 2335 diagnosis of, 2337t treatment of, 2339, 2339t noninfectious, presenting as solitary pulmonary nodule, 1817 plasma cell, 2014 pulmonary hyalinizing, 1949–1951, 1951f tuberculous, 2048 Granulomatosis allergic angiitis and, 2013 bronchocentric, 2013 in allergic bronchopulmonary aspergillosis, 842 in aspergillosis, 2292t, 2300–2301 lymphoid, 433, 433f lymphomatoid, 1958–1960, 1959f, 1960t Granzymes, 1977 Graphium, hypersensitivity pneumonitis caused by, 1163t Gray (Gy), 1177 definition of, 1895 Greece, Ancient, 3–4, 5t Greenhouse lung, etiology of, 1163t

Gremlin, 85–86 Grepafloxacin, 2057 GRO, 1973 GROα, 2116 GRO-α, 340t, 341t GRO-β, 340t, 341t GRO-γ , 340t, 341t Ground-glass opacity, 482–483, 492f, 2013, 2014, 2019, 2024, 2024f, 2025, 2114 diffuse, 2025, 2027f in interstitial lung disease, 1113f, 1115t in neonatal pneumonia, 2126, 2126f in solitary pulmonary nodule, 1822 Growth factor(s) adjunctive therapy with, in invasive pulmonary aspergillosis, 2312 and airway smooth muscle proliferation, in vitro, 118, 119 in idiopathic pulmonary fibrosis, 1154 and lung development, 83–84 in lung development, 92–94 produced by macrophages, 1972t profibrotic, epithelial cell expression of, 377–378 Growth hormone (GH), ectopic production of, 1930t, 1934–1935 Growth hormone–releasing hormone (GHRH), ectopic production of, 1930t, 1934–1935 Growth-related oncogene. See GRO GTPase, Rab27a, in Weibel-Palade bodies, 31 Guaifenesin, 2642 Guanyl hydrazones, for Pneumocystis pneumonia, 2370 Guedel, Arthur, 2646 Guillain-Barr´e syndrome, 2113 and abnormal breathing pattern, 403 and respiratory failure, 2514 ventilatory impairment in, 1653–1654, 1668t Gum(s), and occupational asthma, 985t, 986 Gut-associated lymphoid tissue (GALT), 326–327 Gut hypothesis, for SIRS/MODS, 2567 Gut-liver-lung axis, 446–449, 448f Gynecomastia, paraneoplastic, 445 H Haemophilus in acute exacerbations of chronic obstructive pulmonary disease, 742t infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2106t Haemophilus influenzae, 1983, 1989, 1990, 1996, 1996f and acute bronchitis, 2097

I-49 Index in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t in acute mastoiditis, 2094 in acute otitis media, 2092 acute sinusitis caused by, 2089 and chronic obstructive pulmonary disease, 2060 colonization in children, 2136 in cystic fibrosis, 866 drug-resistant, 2112–2113 immune response to, 324, 1979 infection (incl. pneumonia), 330–331, 2112–2113 in bone marrow and stem cell transplant recipients, 2224 and bronchiectasis, 2186, 2189, 2189t, 2190 in cancer patients, 2216 in Chediak-Higashi syndrome, 2238 in children, 2132 in common variable immunodeficiency, 331, 2235f in complement deficiency, 2236 complicating influenza, 2388 in cystic fibrosis, 2175 of deep cervical space, 852 differential diagnosis of, 2266 epiglottitis caused by, 853 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2101, 2106t, 2251, 2252 radiographic findings in, 2249t hospitalization rate for, 2105t in hyperimmunoglobulin E syndrome, 2239 ICU admission rate for, 2106t immune defect associated with, 1983t, 2210t in immunocompromised host, 2204 in neutropenic host and cancer patient, 2217 nosocomial, 2277, 2279–2280, 2280t, 2281t, 2289 treatment of, 2285–2288, 2286t pathogenesis of, 2080, 2081 supraglottitis caused by, 853 in surgery and trauma patients, 2197 treatment of, 2055, 2056, 2057, 2062, 2113, 2131 in Wiskott-Aldrich syndrome, 2237 in X-linked agammaglobulinemia, 331, 2233–2234 and orbital complications of sinusitis, 2090 pneumonia, 2005, 2020 diagnosis of, 1998 in elderly, 2007 nosocomial, 2008 protease, 326

and S. pneumoniae, interactions of, 2081 staining characteristics of, 2036 in supraglottitis, 2088 and tracheitis, 2379 tracheitis caused by, 2088 type B infection (incl. pneumonia), 2132 in lung abscess, 2144 vaccine against, 2111, 2132, 2379 type b, vaccine against, 2066t, 2069, 2080, 2088 virulence factors, 2081 Haemophilus parainfluenzae in acute exacerbations of chronic obstructive pulmonary disease, 2121t and epiglottitis, 2379 in supraglottitis, 2088 Hairline shadows, 918, 919f, 920f Haldane, John Scott, 5t, 9, 10, 12 Haldane effect, 9, 204, 204f, 205, 205t, 206 Haloperidol, for agitated ICU patient, 2706t Halo sign, 2024, 2024f Hamartoma presenting as solitary pulmonary nodule, 1817 pulmonary, 1919, 1920f Hamman, Louis, 1144 Hamman-Rich syndrome, 1144 Hamman’s sign, 2166 Hampton’s hump, 1431 Hand-Sch¨uller-Christian disease, 1245 Hantavirus, 1994, 2004, 2427 epidemiology of, 1984t historical perspective on, 2113 infection (incl. pneumonia), 2098 clinical characteristics of, 2113 mortality rate for, 2113 pneumonia caused by, 2019 rodent reservoir for, 2113 Hantavirus pulmonary syndrome, 2113, 2389–2390, 2390f pathogenesis of, 2393 HAP. See Pneumonia, hospital-acquired Hard palate, abnormalities, 2647 Harris-Benedict equation, 2696–2697 Harvey, William, 5t, 6–7, 7f, 16 Hashimoto thyroiditis, sarcoidosis and, 1136t Hay, moldy, 2012 Hay fever, 1031 HCAP. See Pneumonia, health care–associated HCC-1, 340t HCC-2, 340t HCC-4, 340t HCoV. See Coronavirus HCTZ. See Hydrochlorothiazide HDAC. See Histone deacetylase(s)

H & E. See Hematoxylin and eosin stain (H & E) Head and neck cancer clinical presentation of, 854 pulmonary metastases, 1943 treatment of, and aspiration, 1312 upper airway obstruction caused by, 854 Health-related quality of life acute exacerbations of chronic obstructive pulmonary disease and, 2116 in ALI/ARDS survivors, 2559 Heart circadian clock in, 1694 injury to, in trauma patient, emergency department interventions for, 1758–1759, 1759f structure of, in pregnancy, 257 Heart disease dyspnea in, 400 in pregnancy, 258, 259t pulmonary venous hypertension in, radiographic evaluation of, 471, 474f and susceptibility to air pollution, 1032t, 1033 Heart failure in chronic obstructive pulmonary disease, radiographic features of, 476 pulmonary edema in, 2541t, 2542 radiographic features of, 478f, 480f, 494 on portable examination, 508–509 Heart-lung transplantation indications for, 1777 pulmonary complications of, 907–908, 907f in sarcoidosis, 1142 technique of, 1782–1784 Heart rate monitoring, in cardiopulmonary exercise testing, 611 normal, 1334t in pregnancy, 257t Heart transplantation candidate for, cardiopulmonary exercise testing in, 626 chest pain after, 420 recipient, cardiopulmonary exercise testing in, 626, 627f in sarcoidosis, 1142 Heartworm, 2419, 2420f Heberden’s nodes, 416 Hedgehog-interacting protein 1 (Hip1), 85, 88f, 89, 89f Heiner’s syndrome, 1242 Heliox, for upper airway obstruction, 860–861 Helium-oxygen flow-volume curves, 590–591, 590f

I-50 Index Helminthic disease(s), 2413–2425 bronchoalveolar lavage cellular profile in, 1121t causes of, 2413, 2414t epidemiology of, 2415 immune response to, 314, 2414–2415 pulmonary approach to patient with, 2415 host-parasite relationships in, 2415 Helminthosporium, in allergic bronchopulmonary mycosis, 837 Helminths biology of, 2413–2415 hosts for, 2414 life cycle of, 2413–2414 Hemagglutinin, filamentous, 2080 Hemangioendothelioma pleural epithelioid, 1550–1551 presenting as solitary pulmonary nodule, 1816 Hematemesis, 410 Hematologic syndromes, paraneoplastic, 1935–1936 Hematopoiesis, extramedullary, 1596 Hematopoietic stem cell transplantation antifungal prophylaxis in, 2312–2313 and cytomegalovirus infection, prevention of, 2394–2395 pulmonary complications of, 2222–2229, 2222t clinical presentation of, 2224–2225 temporal sequence of, 2222–2224 pulmonary function testing in, 2229 and risk of infection, 2205, 2206f, 2218, 2305–2306, 2307, 2307f Hematoxylin and eosin stain (H & E), 2034, 2035t, 2036f counterstaining, with Gomori methenamine silver, 2036, 2039f Hemodialysis, for SIRS/MODS, 2570 Hemodynamic monitoring in acute respiratory failure indications for, 2659–2660 methods for, 2660–2668 principles of, 2659 invasive, 2543–2544 Hemodynamics. See also Pulmonary hemodynamics changes in pregnancy, 256, 257t in exercise, in treadmill testing, 615–616 management in acute lung injury, 2554, 2554t in acute respiratory distress syndrome, 2554, 2554t Hemoglobin abnormal, oxygen affinity of, 203 carbon monoxide binding to, 203 concentration, and diffusing capacity, 197 knowledge of, historical perspective on, 9

oxygen, 176 oxygen affinity of, 202–203, 202f abnormal, 2617 oxygen binding to, 58–59, 192–193 affinity in, 202, 202f Hemoglobinopathy, and pulmonary hypertension, 1384 Hemolytic anemia, 2113 and pneumococcal infection, 2132 Hemolytic uremic syndrome (HUS), 2207 Hemoptysis, 410–413 after needle biopsy, 534–535 with aspergilloma, 2301 management of, 2303 bronchoscopic evaluation of, 634 with bulla, 925 catamenial, 414 causes of, 410, 412f, 413t control of, bronchoscopy in, 640 definition of, 410 differential diagnosis of, 410 in fibrosing mediastinitis, 856 iatrogenic, 410 in invasive pulmonary aspergillosis, 841f, 2307 massive, management of, 414–415 with mediastinal lesions, 1587, 1587t in pulmonary hypertension, 1371 pulmonary Langerhans’ cell histiocytosis and, 1246 sarcoidosis complicated by, and postoperative pulmonary complications, 667 with transthoracic needle aspiration and biopsy, 647 in tuberculosis, 2470 Hemorrhage. See also Diffuse alveolar hemorrhage alveolar, drug-induced, 1110t–1111t bronchoscopy-related, 645 gastrointestinal, in respiratory failure, 2518t, 2519 intra-alveolar, cytopathology of, 524–525, 525f, 526f mediastinal, spontaneous, 1567 pleural, 2028 postoperative after lung resection, 1750–1751 in lung transplant recipient, 1788 pulmonary, 2020, 2027 in bone marrow and stem cell transplant recipients, 2227 radiographic features of, 482 with transthoracic needle aspiration and biopsy, 647 Hemothorax, 1500–1501, 1500f hemoptysis caused by, 414 in trauma patient, emergency department interventions for, 1758–1759, 1759f

Henderson, Lawrence J., 5t, 10–11, 10f, 227, 227f Henderson-Hasselbalch equation, 207 Henle, Jacob, 15 Henoch-Sch¨onlein purpura, 1463 alveolar hemorrhage in, 1293 Henry’s law, 201 HEPA filters, 942 Heparan sulfate, and lung development, 84 Heparin inhaled, 2639 mast cell, 310–311, 310t in mast cells, 308 pulmonary effects of, 1091t for pulmonary embolism, 1438, 1441 Hepatic veno-occlusive disease, in bone marrow and stem cell transplant recipients, 2225, 2227 Hepatitis, viral, pleural effusion in, 1494 Hepatitis B virus (HBV), infection (incl. pneumonia) in immunocompromised host, 2204 and net state of immunosuppression, 2205 Hepatitis C virus (HCV), infection (incl. pneumonia) in immunocompromised host, 2204 and net state of immunosuppression, 2205 Hepatocellular carcinoma (HCC), pulmonary metastases, 1943 Heptachlor exposure to, 1027t sources of, 1027t Hereditary hemorrhagic telangiectasia (HHT), 437, 437f, 538 complications of, 1477 genetics of, 1468–1469 and pulmonary arteriovenous communications, 1356–1357, 1357f, 1467, 1468 Hering, Ewald, 5t, 13 Hering-Breuer expiratory promoting reflex, 165 Hering-Breuer inspiratory terminating reflex, 168 Hering-Breuer reflex, 165 Hernia(s) diaphragmatic, 502, 504f foramen of Bochdalek, 502 foramen of Morgagni, 502, 504f, 1566–1567, 1567f hiatal, 502, 504f, 1596 traumatic, 502, 504f Heroin pneumonitis caused by, 2012t pulmonary effects of, 1088, 1100–1101 Herpangina, 2378 pharyngitis in, 2086 Herpes simplex virus (HSV), 2001 characteristics of, 2375t

I-51 Index and diffuse alveolar damage, 2042 infection (incl. pneumonia), 2025 in bone marrow and stem cell transplant recipients, 2222, 2228–2229 and bronchiectasis, 2186 in cancer patients, 2218 in common variable immunodeficiency, 2235 cytopathology of, 522, 522f diagnosis of, 2001 in HIV-infected (AIDS) patients, 2212t, 2245, 2258 immune defect associated with, 1983t, 2210t in immunocompromised host, 1997, 2204, 2392 in lung transplant recipient, 1790 neonatal, 2127 in neutropenic host and cancer patient, 2217 pathology of, 2043, 2045f pleural effusion in, 1494 treatment of, 2394 laryngitis caused by, 2087 molecular detection of, 2002 and necrotizing tracheobronchitis, 2381 oral infection, 2087 and pharyngitis, 2086, 2376t, 2378 staining characteristics of, 2035t type 1 assays for, 1989t infection, histopathology of, 2034, 2034f type 2, assays for, 1989t Herpes zoster, pain of, 420 Herpes zoster oticus, 2092 Hess-Murray law, 44, 49 15-HETE, eosinophil, 310t, 314 Hetmans, Cornelius, 5t Hexamethylene di-isocyanate hypersensitivity pneumonitis, etiology of, 1164t β-Hexosaminidase, mast cell, 310t, 311 Heymans, C., 13 Heymans, J. F., 13 HFOV. See High-frequency oscillatory ventilation HHT. See Hereditary hemorrhagic telangiectasia (HHT) Hiatal hernia, 1596 Hif-2α, 87 High altitude simulation test, 735–736 High-frequency jet ventilation, for acute respiratory distress syndrome, in trauma patient, 1765 High-frequency oscillatory ventilation, in ALI/ARDS, 2551–2552 Highly active antiretroviral therapy (HAART), 2210–2211

and immune reconstitution syndrome, 2211, 2261, 2330, 2491, 2494–2495 and Pneumocystis pneumonia, 2355, 2365 Hilum, 24, 26 Hippocrates, 3–4, 4f, 5t, 403 Hippocratic corpus, 4 Hippocratic oath, 4 Hippocratic succession, 4 Histamine, 280f in asthma, 310, 782 mast cell, 310–311, 310t in mast cells, 308 and pulmonary circulation, 1347 Histamine (H2 ) antagonists and airway smooth muscle proliferation, in vitro, 118 and nosocomial pneumonia, 2277–2278 for trauma patient, 2196 Histamine inhalational challenge test, 585t, 586, 789–790, 791f, 818 Histiocyte(s), 41 of alveolar septum, 40f, 41 Histiocytosis, pulmonary Langerhans’ cell. See Langerhans’ cell histiocytosis Histiocytosis X, 1245 pulmonary, 1106t, 2014. See also Eosinophilic granuloma of lung smoking and, 751 Histone deacetylase(s), 363, 365f Histopathology section(s), preparation of, 2033–2034 Histoplasma, 1986, 2005t. See also Histoplasmosis infection (incl. pneumonia), in HIV-infected (AIDS) patients, radiographic findings in, 2214 staining characteristics of, 2035t, 2331f–2332f Histoplasma capsulatum, 1994 antigen, detection of, 2337t, 2338 in chronic mediastinitis, 2161, 2169–2171, 2170t culture of, 2337t, 2338 identification of, in tissue, 2038t, 2331f–2332f, 2337t, 2338 infection (incl. pneumonia), 2024. See also Histoplasmosis diagnosis of, 2002 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2212, 2212t, 2254–2255 radiographic findings in, 2214t, 2249t lymphadenopathy in, 2028 in organ transplant recipient, 2230, 2231f pathology of, 2047f, 2048

in lung abscess, 2154t serological tests for, 2337t, 2338 sputum culture for, 2000 staining characteristics of, 2034, 2037, 2047f, 2331f–2332f, 2337t, 2338 Histoplasmin skin test, 2002, 2338 Histoplasmosis, 1990, 1991, 1997, 2006, 2334–2341. See also Histoplasma asymptomatic, 2335 chronic progressive disseminated, 2087 clinical manifestations of, 2335 cutaneous lesions in, 390 cytopathology of, 519–520, 520f diagnosis of, 2337–2339, 2337t differential diagnosis of, 2338 disseminated, treatment of, 2339t, 2340 epidemiology of, 1984t, 2327, 2334 and fibrosing mediastinitis, 856, 1563, 1565f–1566f geographic distribution of, 2327, 2328f histopathology of, 2331f history-taking in, 388, 388f in HIV-infected (AIDS) patients, 2246, 2254–2255 treatment of, 2340 immune response to, 2334 in immunocompromised host, 2204 inflammatory syndromes of, treatment of, 2339t, 2340 laryngitis caused by, 2087 mediastinal, 2335–2337 mycology of, 2334 pathogenesis of, 2334–2335 pericarditis in, 2337 pleural effusion in, 1494 prevention of, 2340–2341 progressive disseminated, 2337 diagnosis of, 2337t pulmonary, 2335 acute, 2335, 2336f diagnosis of, 2337t treatment of, 2339, 2339t broncholithiasis in, 2335 treatment of, 2340 cavitary, 2336f chronic, 2335 diagnosis of, 2337t treatment of, 2339, 2339t nodules of, 2335 and sarcoidosis, 2335 differentiation of, 2338–2339 subacute, 2335, 2336f diagnosis of, 2337t treatment of, 2339, 2339t pulmonary alveolar proteinosis complicated by, 2014 radiographic findings in, 388f rheumatological syndromes in, 2337 solitary pulmonary nodule in, 1817 treatment of, 2339–2340, 2339t urinary antigen, in HIV-infected (AIDS) patients, 2247t

I-52 Index History-taking, from patient with respiratory symptoms, 388–389 HLMC. See Mast cell(s), human lung HMPV. See Human metapneumovirus Hnf3α, 87 Hnf3β, and lung development, 82, 87 H2 O2 . See Hydrogen peroxide HOA. See Hypertrophic osteoarthropathy Hoarseness acute, 2087 chronic, 2087 with mediastinal lesions, 1587, 1587t in upper airway obstruction, 846 HOBr. See Hypobromous acid HOCl. See Hypochlorous acid Hodgkin’s disease (HD), 1960–1961, 1961f, 2014 bronchoalveolar lavage cellular profile in, 1121t early-stage, radiation therapy for, and risk of radiation pneumonitis/fibrosis, 1188, 1189f in HIV-infected (AIDS) patients, radiographic findings in, 2249t mediastinal, 1602, 1603f primary pulmonary, 1924 radiation therapy for, and risk of radiation pneumonitis/fibrosis, 1186, 1188, 1189f radiographic features of, 497f secondary pulmonary involvement in, 1962 staging system for, 1602, 1602t Hollywood code, 2729 Homeostasis, 226–229 definition of, 226 as feedback process, 228 instabilities of, 229 mechanisms of, 226–228, 228f limitations of, 228 overshooting of, 229 undershooting of, 229 perturbations (malfunctioning) of, 228–229 Homocysteine, effects on vascular endothelium, 451 Honeycombing in interstitial lung disease, 1112, 1115t in Langerhans’ cell histiocytosis, 1247 Honeycomb lung, 698t, 699 in collagen vascular disease, 1194t Hooke, Robert, 5t, 7, 11, 575, 2645 Hookworms, 2414t, 2415–2418 treatment of, 2418, 2418t Hoover’s sign, 392, 2598 Hoppe-Seyler, Felix, 5t, 9 Hormone(s), produced by macrophages, 1972t Hormone replacement therapy (HRT), and venous thromboembolism, 1425–1426

Horner’s syndrome, 390 Hospital, environmental exposures in, 2204–2205 domiciliary, 2204 non-domiciliary, 2204–2205 Host defense(s) and idiopathic pulmonary fibrosis, 1156 pulmonary. See Pulmonary host (immune) defense(s) Hot tub lung, 2502 Hot-tub lung, etiology of, 1165t House dust inhalational challenge test, 585t Hoxa3, and lung development, 83 Hoxa5, and lung development, 83 HP. See Hypersensitivity pneumonitis HRQoL. See Health-related quality of life HSV. See Herpes simplex virus (HSV) Human coronavirus, NL-63, 2129–2130.

See also Coronavirus Human herpesvirus (HHV) HHV-6 infection (incl. pneumonia) in bone marrow and stem cell transplant recipients, 2228–2229 in HIV-infected (AIDS) patients, 2212t and sarcoidosis, 1127 HHV-8, 431, 1954–1955, 1964–1965 infection (incl. pneumonia). See also Kaposi’s sarcoma in HIV-infected (AIDS) patients, 2212t, 2258 in immunocompromised host, 2208 and lymphoma, in HIV-infected (AIDS) patients, 2259 and idiopathic pulmonary fibrosis, 1156 infection (incl. pneumonia) in cell-mediated immunodeficiency, 2236 in DiGeorge’s syndrome, 2236 in severe combined immunodeficiency, 2236 in Wiskott-Aldrich syndrome, 2237 Human immunodeficiency virus (HIV) genome of, 2242 immune defense against, 1971 infection alveolar hemorrhage complicating, 1294 antiretroviral therapy for, 2244–2245 and drug-drug interactions, 2261 associated conditions, progression of, 2205, 2206f blastomycosis in, treatment of, 2348 CCR5 and, 351 CD4 cell count in, 2211–2212, 2248 antiretroviral therapy and, 2244–2245 and empiric therapy, 2262, 2262f, 2263f

in infancy, management of, 2139 and survival, 2244 and susceptibility to infection, 2215, 2245 and tuberculosis, 2489 CD4 cell response in, 2243 in children, 2139 clinical presentation of, 388 cytotoxic T-cell response in, 2243 diagnosis of, 2211, 2211t, 2245 and emphysema, 731 epidemiology of, 2245 histoplasmosis in, treatment of, 2340 HIV-2, 2241–2242 immune reconstitution syndrome in, 2211, 2261, 2330, 2491, 2494–2495 immunization in, 2212 and Kaposi’s sarcoma, 431–432, 432f laboratory findings in, 2211, 2211t late-stage, characteristics of, 2244 lung disease in, 2212, 2241, 2242t clinical presentation of, 2246 epidemiology of, 2245, 2248 evaluation of, 2245–2250 imaging of, 2247t, 2248–2249, 2249t laboratory diagnosis of, 2247–2248, 2247t medication history and, 2246 microbiology of, 2247t, 2250 past medical history and, 2246 pathophysiology of, 2243 physical examination in, 2246–2247 lung-specific immunodeficiency in, 2243–2244 lymphadenopathy in, 2028 management of, 2242–2243 empiric therapy in, 2262, 2262f, 2263f special considerations in, 2260–2261 natural history of, 2244 host factors affecting, 2243 virologic factors affecting, 2243 and net state of immunosuppression, 2205 non-infectious pulmonary involvement in, 2258–2260 causes of, 2242t opportunistic infections in, 2212–2213, 2212t, 2306, 2307 pathophysiology of, 2241–2243 pneumonia in, 1997, 2100t primary, clinical features of, 2244 progression of, 2205, 2206f, 2244 pulmonary infections in, 2241–2263 causes of, 2242t diagnosis of, 2213–2215 radiographic findings in, 2214–2215, 2214t

I-53 Index risk factors for, 2211, 2211t and sarcoidosis, 1135 sarcoidosis and, 1136t signs and symptoms of, 2211, 2211t sputum collection in, 2105 stage of immunosuppression in, clinical or laboratory, 2248 subacute invasive pulmonary aspergillosis in, 2292 systemic immunodeficiency in, 2243 treatment of, 2210–2211 tuberculosis in. See Tuberculosis, in HIV-infected (AIDS) patients life cycle of, 2242 occupational exposure to, 2261–2262 and pharyngitis, 2376t, 2378 postexposure prophylaxis for, 2261 syncytia-inducing, 2243 Human leukocyte antigen(s) (HLA) and allergic bronchopulmonary aspergillosis, 2295–2296 and aspirin-induced asthma, 801 and sarcoidosis, 1127 Human metapneumovirus, 1992 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t assays for, 1989t and bronchiolitis, 2376t, 2382 characteristics of, 2375t infection (incl. pneumonia), 2098, 2114 and asthma, 796 in bone marrow and stem cell transplant recipients, 2228 diagnosis of, 2106 in early infancy, 2128–2130 laryngitis caused by, 2087 pneumonia, 1994 Human papillomavirus (HPV), 1917–1918 infection, 2088–2089 cytopathology of, 523 Human T-cell leukemia virus (HTLV) type 1, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t type 2, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t Human T-lymphotropic virus (HTLV), HTLV1, and sarcoidosis, 1127 Humidifier lung, 2012 Humoral immunity, 280, 321–322, 2293 in chronic obstructive pulmonary disease, 715 in HIV-infected (AIDS) patients, 2244 Humoral immunodeficiency in cancer patients, 2215–2216 in children, 2138 and lung, 330–331 Hunter, William and John, 13, 2645 Hunter’s syndrome, 1275

Hurler’s syndrome, 1275 Hutchinson, John, 5t, 11, 568, 1125 HVOD. See Hepatic veno-occlusive disease Hyaline membrane, 2042, 2525, 2526f Hyalohyphomycetes, pulmonary infection by, 2321–2324 Hydralazine lupus-like syndrome caused by, 2010, 2012t pulmonary effects of, 1090t, 1097 and vasculitis, 1464 Hydrochloric acid, pulmonary injury caused by, 1000 Hydrochlorothiazide and interstitial lung disease, 1110t pneumonitis caused by, 2010, 2012t pulmonary effects of, 1091t, 1093, 1097 Hydrocortisone for asthma, 2638 sensitivity to, in aspirin-sensitive asthmatics, 802–803 Hydrogen chloride inhalation injury caused by, 1000t in smoke and inhalation injury, 1057 source of, 1054t water solubility of, and mechanism of lung injury by, 994–995, 994t Hydrogen cyanide in indoor air, sources of, 1021t in smoke and inhalation injury, 1056–1057 toxicity of, 1056–1057 Hydrogen fluoride, bronchiolitis caused by, 893t Hydrogen ion(s) central chemoreceptors for, 163–164 concentration, regulation of, 207 Hydrogen peroxide, 2624–2625 formation of, 359–360, 360f Hydrogen sulfide bronchiolitis caused by, 893t in smoke and inhalation injury, 1057 source of, 1054t Hydrolase(s), in asthma, 782 Hydromorphone, for agitated ICU patient, 2707–2708 Hydropneumothorax, 507f Hydroxocobalamin, for cyanide poisoning, 1057 Hydroxychloroquine, 2639 for sarcoidosis, 1140, 1140t Hydroxyl radical, 2624–2625 formation of, 359–360, 360f Hydroxyurea, immunologic effects of, 2216 Hyomental distance, 2647 Hyperbaric oxygen therapy, 1049–1051 for arterial gas embolism, 1050–1051, 1050f for carbon monoxide poisoning, 203 in carbon monoxide poisoning, 2617 for decompression sickness, 1050–1051

indications for, 1049–1050, 1050t limitations of, imposed by oxygen toxicity, 1051 for zygomycosis, 2321 Hypercalcemia of malignancy, 1929, 1930–1932, 1930t in small cell lung cancer, 1905–1906, 1905t Hypercapnia, 207, 208t, 217–218, 424 acute and dyspnea, 397 and pulmonary vasomotor control, 1346 adaptive response to, 211–212, 212f ad RNS/ROS, 366, 367f airway occlusion pressure response to, age-related changes in, 269, 269f in chronic obstructive pulmonary disease, 743 pharmacologic causes of, 2514 ventilatory response to, 2593–2594, 2594f age-related changes in, 268 blunted, and development of respiratory failure, 2594–2595, 2594f–2595f normal, 1324, 2736 Hyperchloremic acidosis, 216 Hypereosinophilic syndrome (HES), 317–318 Hyperfractionation, radiation, definition of, 1895 Hyperglycemia control of, and outcomes with community-acquired pneumonia, 2110–2111 in critically ill patients, 2698 Hyper-IgE recurrent infection. See Hyperimmunoglobulin E syndrome Hyper-IgM immunodeficiency, 323 pulmonary infection in, 2235–2236 Hyper-IgM syndrome, 2139 Hyperimmunoglobulin E syndrome, pulmonary infection in, 2239, 2239f Hyperinflation in chronic obstructive pulmonary disease, 713–714, 714f, 731 congenital lobar, 699 respiratory muscle interaction in, 77–78 Hypermetabolism, in critical illness, 2692–2693 Hyperoxia, sequence of pulmonary changes in, 2627, 2627t Hypersensitivity, systemic, drug-induced, 1090t, 1092 Hypersensitivity lung disease aspergillosis and, 2291, 2292t, 2294, 2295t cytotoxic drugs and, 2012, 2012t drug-induced, 1090t

I-54 Index Hypersensitivity pneumonitis, 896, 1106t, 1161–1172, 2012, 2027, 2542t.

See also Extrinsic allergic alveolitis acute, 1162, 1167–1168 bird-associated, clinical features of, 1162 bronchoalveolar lavage cellular profile in, 1121t chronic, 1162, 1168 clinical features of, 1118t, 1162 computed tomography of, 1112, 1113f, 1115t, 1118t diagnosis of, 1167–1168 methods for, advantages and disadvantages of, 1168, 1169t differential diagnosis of, 1162 drug-induced, 1092, 1110t–1111t epidemiology of, 1161–1162 etiology of, 1161–1162, 1163t–1164t exposures associated with, 1109t fever with, 420 histopathology of, 1118t, 1168–1169, 1170f–1171f imaging of, 2022 immunopathogenesis of, 1169–1171 impairment due to, evaluation of, 684 laboratory findings in, 1165–1167 occupational, 934t occupational exposures and, 935t onset of, 422 pathophysiology of, 375, 375f prevalence of, 1162 probability of, predictors of, 1168, 1170t prognosis for, 1171–1172 radiographic features of, 482, 485, 1162–1165, 1166f, 1167f subacute, 1162, 1167–1168 treatment of, 1118t, 1171–1172 Hypersensitivity reaction(s), drug-induced, 2010, 2012t Hypertension, sleep apnea and, 1711–1712 Hypertrophic osteoarthropathy, 415–418, 417f, 453 Hyperventilation, 404 physiological, in pregnancy, 255, 255f Hyperventilation syndrome, 394 Hypobromous acid, 310t, 314, 315 Hypocapnia, 207, 208t, 595–596 Hypochlorous acid, formation of, 359–360, 360f Hypogammaglobulinemia, 2139 and bronchiectasis, 2188 management of, 2112 thymoma and, 1600–1601, 1601t Hypokalemia, 217–218 Hyponatremia, in tuberculosis, 2470 Hyponatremia of malignancy, 1929, 1930t, 1932–1933 Hypopharynx, 2647 Hypophase, 56

Hypotension, in respiratory failure, 2518t, 2519 Hypothermia, in pneumonia, 2099 Hypoventilation, pathophysiology of, 177 Hypoventilation syndrome(s), ventilatory impairment in, 1668t Hypovolemic shock, oxygen therapy in, 2619 Hypoxemia in acute exacerbations of chronic obstructive pulmonary disease, 741, 742t, 2117f acute reversible, in systemic lupus erythematosus, 1198–1199 air travel-related, testing for, 596, 596f in ALI/ARDS, 2536, 2536t arterial, 2616–2617 causes of, 2616, 2616t tissue hypoxia with, oxygen therapy for, 2618–2619, 2619t causes of extrapulmonary, 177 intrapulmonary, 177 in croup, 2379 in Pneumocystis pneumonia, 2361 postoperative, 664–665 Hypoxia acute and dyspnea, 397 and pulmonary vasomotor control, 1343–1344, 1345f airway occlusion pressure response to, age-related changes in, 269, 269f cellular causes of, 2617 chronic, and pulmonary vasomotor control, 1344–1345 chronic continuous, ventilatory adaptations to, 167 circulatory, 2616t, 2617 demand, 2617 fetal, 1354 intermittent, ventilatory adaptations to, 167 mechanisms of, 2615–2617 tissue with arterial hypoxemia, oxygen therapy for, 2618–2619, 2619t causes of, 2616, 2616t clinical manifestations of, 2617–2618, 2618t laboratory studies of, 2618 with normal PaO2 , oxygen therapy for, 2619 ventilatory response to, 597–598, 598f, 2593 acute, 1037–1038, 1038f age-related changes in, 268, 269f blunted, and development of respiratory failure, 2594–2595, 2594f–2595f chronic, 1039, 1039f factors affecting, 598, 599t

in hepatic cirrhosis, 447–448 normal, 598, 1324, 2736 Hypoxia-inducible transcription factor-1α, 163, 1039, 1039f Hypoxia-inducible transcription factor-2α, 87 Hypoxia inhalation testing, 596 Hysteresis, 150 I I-309, 340t IA. See Aspergillosis, invasive IALT. See International Adjuvant Lung Cancer Trial IBA. See Aspergillosis, invasive bronchial Ibn An Nafis, 4, 5t Ibsen, Bjorn, 2675 Ibuprofen and aspirin-induced asthma, 802t for cystic fibrosis patient, 2179 IC. See Inspiratory capacity ICU. See Intensive care unit Idiopathic hypereosinophilic syndrome, 1227–1229 cardiac involvement in, 1227 clinical features of, 1231t diagnosis of, 1228 differential diagnosis of, 1228, 1231t epidemiology of, 1227 historical perspective on, 1227 laboratory findings in, 1228 neurologic involvement in, 1227–1228 pathophysiology of, 1228 prognosis for, 1228–1229 respiratory involvement in, 1227 treatment of, 1228–1229 Idiopathic interstitial pneumonia, 1144, 1145 in bone marrow and stem cell transplant recipients, 2226 Idiopathic pneumonia syndrome, in bone marrow and stem cell transplant recipients, 2225–2227, 2225t causes of, 2225–2227, 2225t clinical presentation of, 2226 diagnosis of, 2226–2227 laboratory testing in, 2225–2227, 2226t mortality rate for, 2226 Idiopathic pulmonary arterial hypertension, 1347, 1378–1380 classification of, 1360, 1362t definition of, 1360 epidemiology of, 1378–1379 histopathology of, 1364, 1364f lung transplantation for, 1391 prognosis for, 1379–1380, 1380f Idiopathic pulmonary fibrosis, 330, 492f, 1106t, 1143–1159 acute exacerbations of, 1153, 1156 age of onset, 1143 angiogenesis in, 1154–1155

I-55 Index angiostasis in, 1154–1155 basement membrane injury and, 1154 bronchoalveolar lavage cellular profile in, 1121t bronchoalveolar lavage in, 1149–1150 classification of, 1144–1145 clinical features of, 1116t, 1143 in collagen vascular disease, 1193 complement in, 349 computed tomography of, 1112, 1114f, 1116t, 1146–1147, 1148–1149, 1149f cytokines in, 337, 1154 definition of, 1145 diagnosis of, 1146–1151 definite, 1151 delay in, 1143 probable or likely, 1151 diagnostic criteria for, 1151 in absence of lung biopsy, 1120–1122, 1122t differential diagnosis of, 1146–1147 eosinophils in, 318 epidemiology of, 1145–1146 epithelial cell apoptosis and, 1153–1154 epithelial-mesenchymal transition in, 1156 exercise testing in, 1148 extracellular matrix in, 1155 familial, 1146 fibroblasts in, 1155–1156 and gastroesophageal reflux disease, 1156 genetics of, 1146 growth factors and, 1154 histology of, 1116t historical perspective on, 1144–1145 history-taking in, 1147 host defense and, 1156 incidence of, 1145–1146 inflammation and, 1153 interleukin-1 receptor antagonist and, 336 laboratory evaluation in, 1147 lung transplantation in, 1774t, 1775–1777 mortality rate for, 1145–1146 multiple-hit hypothesis of, 1156 natural history of, 1151–1152 progression through pathological patterns in, 1156 occupational exposures and, 935t oxygen supplementation in, 1159 pathogenesis of, 1144–1145, 1153–1156 pathology of, 1150–1151 pharmacotherapy for, 1156–1158 physical examination in, 1147 prevalence of, 1145–1146 prognosis for, 1151–1152 composite scoring system for, 1152–1153 pathologic predictors of, 1152

physiological predictors of, 1152 radiographic predictors of, 1152 pulmonary function testing in, 1147–1148 pulmonary rehabilitation in, 1159 radiographic features of, 483–485, 1146, 1147f, 1148–1149, 1149f risk factors for, 1146 scintigraphy in, 558, 559 TGF-β in, 339 treatment of, 1116t, 1156–1159 Idiopathic pulmonary hemosiderosis, 1242, 1242f, 1281 clinical course of, 1295–1296 clinical features of, 1295 diagnosis of, 1295 epidemiology of, 1295 histopathology of, 1296, 1296f pathogenesis of, 1296 pathology of, 1285t radiographic findings in, 1296, 1296f serology of, 1285t treatment of, 1296–1297 Ifosfamide, pulmonary effects of, 1073, 1074t, 1075–1076 IHS. See Idiopathic hypereosinophilic syndrome IIP. See Idiopathic interstitial pneumonia ILD. See Interstitial lung disease Ileus, in respiratory failure, 2518t, 2519 ILK. See Inhibitory-κB kinase ILO. See International Labor Organization Iloprost, for pulmonary arterial hypertension, 1388, 1390 IL-1Ra. See Interleukin-1 receptor antagonist Image-guided drainage of air/fluid collections, 535–538 Image-guided needle procedures (in thorax), 534–535 complications of, 534–535 diagnostic, 534 postprocedure care in, 535 results, 534 techniques for, 534 tools for, 534 Imaging modalities, 2017–2018, 2018f in evaluation of impairment/disability, 680 Imatinib mesylate for hypereosinophilic syndrome, 318 for idiopathic pulmonary fibrosis, 1158 α-Imidazole regulation, 214 Imipenem for hospital-acquired pneumonia, 2061, 2061t, 2062 indications for, 2157 interactions with immunosuppressive agents, 2503t for melioidosis, 2440 for nontuberculous mycobacteria, 2505

pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2056 Immobility and nosocomial pneumonia, 2196 and venous thromboembolism, 1425 Immobilization, postoperative, and risk of pulmonary complications, 670 Immune defect(s) in cancer patients, 2215–2216 chemotherapy-related, 2216 infections associated with, 1982–1983, 1983t and microbial virulence, 2207 primary immunologic work-up of, 2233, 2234t pulmonary infection in, 2232–2239 Immune defense(s), 2077–2078 pulmonary. See Pulmonary host (immune) defense(s) Immune-mediated tissue injury type I, 330 type II, 330 type III, 330 type IV:, 330 Immune recognition, innate, 1970–1971 Immune reconstitution inflammatory syndrome, in HIV-infected (AIDS) patients, 2211, 2261, 2330, 2494–2495 and antituberculosis therapy, 2491 Immune reconstitution syndrome. See Immune reconstitution inflammatory syndrome Immunity/immune response(s), 286f acquired, 280 adaptive, 280, 1973–1979 afferent, 1974–1976, 1975f, 2041–2042, 2043f antibody-mediated, 323–324, 330 cell-mediated, 330 efferent, 1976, 1977f, 2041–2042, 2043f B cell-mediated, in lung, 1977–1978, 1977f T cell-mediated, in lung, 1976–1977 innate, 280, 1970–1973, 1970f, 1971f, 2293 Immunocompromised host(s) antibiotic therapy for, difficulties of, 2204 clinical management of, 2203–2204 definition of, 2203 diffuse alveolar hemorrhage in, 1293–1294 epidemiologic exposures, 2204–2205 infection in concomitant processes in, 2207–2208 prevention of, 2207–2208, 2209 and recognition of new syndromes, 2207

I-56 Index Immunocompromised host(s), infection in (Cont.) risk of cumulative, 2205 factors affecting, 2204–2205 progressive, 2205 time-limited, 2205 timetable of, 2205–2207 treatment of, 2209–2210 net state of immunosuppression, 2205 factors affecting, 2204, 2204t Immunocytochemistry, 514 of lung tumors, 531 Immunodeficiency cell-mediated, in children, 2139 in granulocyte disorders, in children, 2138–2139 humoral, in children, 2138 hyper-IgM, pulmonary infection in, 2235–2236 primary definition of, 2232–2233 immunologic work-up of, 2233, 2234t pulmonary infection in, 2232–2239 Immunoglobulin(s), 280f, 321–322, 1978 FcR binding, 325t Fc receptors, 325t Fc region, 325 function, 325–328, 325t heavy chain, 322–323, 325t D (diversity) gene, 322–323, 322t J (junctional) gene, 322–323, 322t V (variable) gene, 322–323, 322t in human lung, measurement of, 329 IgA, 280f, 1979, 1983 deficiency, 332 and bronchiectasis, 2188 combined with IgG subclass deficiency, 332 definition of, 332 management of, 332 pathophysiology of, 332 prevalence of, 332 pulmonary infection in, 2235 in human lung, measurement of, 329 respiratory tract, 329–330 secretory, 280, 326, 327f in airways, 281 in mouth, 281 in nasal secretions, 281 structure and function, 325t, 326–327, 328f subclasses of, 325t, 326 IgA1, 325t, 326 IgA2, 325t, 326 IgD, structure and function, 325, 325t IgE, 1976, 1979 in allergic bronchopulmonary aspergillosis, 838–840, 840t, 2295, 2296–2297, 2300 in allergy, 792–793 in aspergillosis-related asthma, 2295

in asthma, 778, 819 monoclonal antibody to. See also Omalizumab for asthma, 823t, 829t, 830, 2641 in nasal secretions, 281 NSAID-specific, 802 receptors, 309–310 high-affinity, 307, 309–310, 327 low-affinity, 309–310, 327–328 respiratory tract, 330 structure and function, 325t, 327–328 IgG, 280, 1979, 1983 in allergic bronchopulmonary aspergillosis, 838–840, 2295, 2296–2297 in alveolar fluid, 282 in coccidioidomycosis, 2344 Fc domain of, 283, 1972 in human lung, measurement of, 329 in nasal secretions, 281 respiratory tract, 330 structure and function, 325t, 326 subclass deficiency, 331 and bronchiectasis, 2188 clinical presentation of, 332 combined with IgA deficiency, 332 pulmonary infection in, 2235 subclasses, 325t, 326 IgG1, 325t, 326 deficiency, 332 IgG2, 325t, 326 deficiency, 332 IgG3, 325t, 326 deficiency, 332 IgG4, 325t, 326 deficiency, 332 IgM, 323, 1979 in coccidioidomycosis, 2343–2344 in human lung, measurement of, 329 structure and function, 325, 325t isotype switching, 323–324 light chain, 322–323 J gene, 322–323, 322t V gene, 322–323, 322t molecular weight of, 325, 325t in nasal secretions, 281 pooled, 2639 production of, 321–322, 322t respiratory tract, 329–330 fate of, 328 origins of, 328 pathology induced by, 330 in saliva, 281 serum levels, 325t structure of, 325–328, 325t switch regions, 323–324 Immunoglobulin/albumin ratio(s), 329 BAL fluid, 329 serum, 329 Immunoglobulin gene superfamily, proteins, in inflammation, 783

Immunohistochemical technique(s), 2039, 2042t Immunologic test(s), for rheumatic disease, 1111, 1112t Immunonutrition, 2697 Immunoreceptor tyrosine-based activation motifs, 310 Immunoreceptor tyrosine-based inhibition motifs, 326 Immunosuppression net state of, 2205 factors in, 2204, 2204t and risk of infection, 2317, 2318 Immunosuppressive therapy for idiopathic pulmonary fibrosis, 1157 in organ transplant recipient, and pulmonary infection, 2230 for sarcoidosis, 1140t, 1141 Immunotherapy, for chronic stable asthma, 822 Impairment. See also Disability classification of, in AMA Guides, 681–682, 682t definition of, 677 in AMA Guides, 681 evaluation of, 677–678 American Thoracic Society criteria for, 684–685 arterial blood gas analysis in, 681 bronchoprovocation testing in, 681 cardiopulmonary exercise testing in, 681 imaging in, 680 medical history in, 678–679 methods for, 678–681 physical examination in, 680 pulmonary function testing in, 680 occupation-related, workers’ compensation programs for federal, 688–690 state, 687–688 permanent, evaluation of, American Medical Association guidelines for, 681–682, 682t Inborn errors of metabolism. See also specific disorder characteristics of, 1266 pulmonary involvement in, 1265–1277 Incentive spirometry, postoperative, 673t, 674 Indirect Fick method, 2667–2668 Indomethacin, and aspirin-induced asthma, 802t Infant(s), susceptibility to air pollution, 1032t Infantile respiratory distress syndrome pathogenesis of, 131f, 132–133 surfactant in, 125, 131f, 132–133 Infarction, pulmonary, 414f, 2014, 2104 CT angiography of, 462, 462f cytopathology of, 524–525, 525f hemoptysis caused by, 414

I-57 Index presenting as solitary pulmonary nodule, 1817 pulmonary embolism and, 1428, 1428f radiographic features of, 462f, 477 Infection(s) and acute lung injury, 2527 after bronchoscopy, 644 and atopic dermatitis, 428 bronchoscopy in, 1120t in bulla, 918, 921f, 922f, 923–925 treatment of, 926 in cancer patients, 2215–2219 in common variable immunodeficiency, 331 cutaneous manifestations of, 430–431 in cystic fibrosis patient, 880–881 cytopathology of, 518–524 deep cervical space clinical presentation of, 852 complications of, 853 microbiology of, 852 risk factors for, 852 treatment of, 853 upper airway obstruction caused by, 852–853 diagnosis of, 422–423, 422f dyspnea in, 403 of ear, 2091–2094 fever in, 420 head and neck, 2163t, 2164t and mediastinitis, 2163t, 2164t, 2165, 2166t hemoptysis in, 410, 413–414, 413t in IgG subclass deficiency, 332 immune defects and, 286–288, 287t lower respiratory tract, in childhood, and chronic obstructive pulmonary disease, 710 in lung transplant recipient, 1790–1791 of mastoid, 2094 mediastinal, 1591–1595 and mediastinitis, 2163t, 2164t, 2165, 2166t non-head and neck, and mediastinitis, 2163t, 2165 occupational, 934t opportunistic, 2204 of oral cavity, 2086–2087 orbital, 2090, 2090f and parapneumonic effusions, 1488–1489 pathogenesis of, 2077 pathophysiology of, 2077–2078 pelvic, and anaerobic pleuropulmonary infections, 2145t peritoneal, and anaerobic pleuropulmonary infections, 2145t pulmonary. See also Pneumonia bacterial. See Bacterial infection(s) and bronchiectasis, 2185–2186, 2185t in Chediak-Higashi syndrome, 2238

chronic, severity of, Social Security Listings for, 687 computed tomography of, 1115t in cystic fibrosis. See Cystic fibrosis diagnosis of in HIV-infected (AIDS) patients, 2031, 2032 invasive procedures for, 2002–2004 molecular testing for, 2002 noninvasive studies for, 1997–2002 serologic testing for, 2001–2002 skin tests for, 2002 work-up for, 2032, 2033f fungal. See Fungal infection(s) histopathology of, 2033–2034, 2034f in immunocompromised host, 2203–2239 mechanisms of, 2078–2079, 2078t molecular factors and processes in, 2078t, 2079–2080 noninfectious processes mimicking, 2010–2014, 2011t, 2020, 2022, 2024 parasitic. See Parasitic infestation(s) pathogenesis of, 1987–1995, 2078–2079, 2078t pathology of, 1987–1995, 2031–2050 patterns of injury in, 2039–2050 in primary immune defects, 2232–2239 pulmonary alveolar proteinosis complicated by, 2014 radiology of, 18, 1982t, 1985, 1986f, 1987f, 1988t, 1995–1997, 2017–2029 tissue response to, 2042, 2043t vaccination against, 2065–2074.

See also specific vaccine viral. See Viral infection(s) in X-linked hypogammaglobulinemia, 331 in pulmonary alveolar proteinosis, 1319 pulmonary hypertension and, 1376 radiographic features of, 483 respiratory, antecedent to surgery, and postoperative pulmonary complications, 669 in respiratory failure, 2518t, 2519 retropharyngeal, 1309, 1310 and sarcoidosis, 1126–1127 in silicosis, 976, 977 spinal, radiographic features of, 499–500, 503f in Stevens-Johnson syndrome, 436 transmission of, in indoor air, 1031–1032 upper airway obstruction caused by, 852–854 upper respiratory tract, 2085–2091.

See also specific infection

Infection control in prevention of nosocomial pneumonia, 2288–2289, 2288t in pulmonary function testing, 601–602 Infectious agent(s), pulmonary clearance of, 1969–1980 Infectious mononucleosis. See also Epstein-Barr virus (EBV) and pharyngitis, 2086 radiographic features of, 498 Infiltrate diffuse in bone marrow and stem cell transplant recipients, 2224, 2224f in HIV-infected (AIDS) patients, 2214–2215, 2214t diffuse interstitial, in HIV-infected (AIDS) patients, 2248, 2249t focal in bone marrow and stem cell transplant recipients, 2225 in HIV-infected (AIDS) patients, 2214t, 2215, 2248, 2249t interstitial in cancer patient, 2220–2221, 2221t in organ transplant recipient, 2231, 2233t nodular. See also Pneumonia, with nodular infiltrates in cancer patient, 2220–2221, 2221t in organ transplant recipient, 2231, 2233t in organ transplant recipient, 2231 peribronchovascular. See also Pneumonia, interstitial in organ transplant recipient, 2231, 2233t pulmonary, 1091 drug-induced, 1110t–1111t with eosinophilia, 2013 in stem cell transplant recipient, diagnostic approach to, 2223f Infiltration, leukemic, 2542t Inflammation/inflammatory response(s), 280, 2042, 2043t, 2079–2080.

See also Systemic inflammatory response syndrome (SIRS) and acute lung injury, 2527–2528 and bronchiectasis, 2185t, 2187–2188 cell adhesion molecules in, 782–783 chemotactic cytokines and, 339, 340t chronic, lobar atelectasis in, 486f and chronic obstructive pulmonary disease, 715 and exercise-induced asthma, 809 exudative, causes of, 2043t granulomatous, causes of, 2043t, 2048–2049 histiocytic, causes of, 2043t and idiopathic pulmonary fibrosis, 1153 impairment of, 287t

I-58 Index Inflammation/inflammatory response(s) (Cont.) interstitial, causes of, 2043t in lung injury, 337, 338f necrotizing, causes of, 2043t pattern of, and diagnosis of infection, 2034, 2034f physiology of, 1973, 1974f pulmonary, 335 chemokines in, 339–343, 372–374, 373f cytokines in, 337, 338f leukocyte migration in, 354–356 smoking and, 752 vascular, 2049f, 2050 Inflammatory bowel disease (IBD) drug treatment of, pulmonary toxicity of, 440 erythema nodosum in, 434 risk of venous thromboembolism in, 1426 upper airway obstruction in, 855 Inflammatory lung disease, noninfectious, scintigraphy in, 558, 559f Inflammatory mediator(s), 280f Inflammatory pseudotumor, 1918–1919 Infliximab pulmonary toxicity of, 440 therapy with, and risk of infection, 2306 Influenza virus, 1992, 2005, 2005t. See also Avian influenza and acute bronchitis, 2097 antigenic shift, 2384–2385 antiviral prophylaxis for, 2388 assays for, 1989t and bronchiolitis, 896, 2382 characteristics of, 2375t and common cold, 2085 and croup, 2087, 2376t, 2379 diagnosis of, 1999 and diffuse alveolar damage, 2042 epidemics, 2384–2385 H5N1, 2384 immune defense against, 1971, 1973 immune response to, 2385 infection (incl. pneumonia), 1985, 2020 in adults, 2389 and asthma, 796, 816 chemokines in, 355 in children, 2130, 2391 clinical features of, 2384 diagnosis of, 2001, 2002, 2386 in early infancy, 2129 epidemiology of, 2004, 2384–2385 hemoptysis in, 413 in HIV-infected (AIDS) patients, 2257–2258 radiographic findings in, 2215, 2249t ICU admission rate for, 2106t in immunocompromised host, 2204

morbidity associated with, in children, 2125 mortality from, in children, 2125 mortality rate for, 2065 pathogenesis of, 1993–1994, 2374, 2385, 2393 pathology of, 1993–1994, 2043 pleural effusion in, 1494 reactive nitrogen species in, 365 seasonal variation in, 2374, 2385 in severe combined immunodeficiency, 2236 treatment of, 2387–2388, 2387t nomenclature for, 2386 pandemics, 2384–2385 and pharyngitis, 2376t, 2378 staining characteristics of, 2035t and tracheobronchitis, 2376t, 2380, 2381 transmission of, 2374, 2385 in indoor air, 1031 type A, 1993–1994, 2385–2386 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t immune response to, 343 infection (incl. pneumonia) diagnosis of, 2106, 2394 hospitalization rate for, 2105t nosocomial, 2280t serotypes of, 2374 type B, 1993–1994, 2385–2386 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t infection (incl. pneumonia) diagnosis of, 2106 hospitalization rate for, 2105t imaging of, 2021f nosocomial, 2280t type C, 1993–1994, 2385–2386 vaccines against, 2070–2072, 2070t, 2111, 2386–2387, 2386t for asthmatic patient, 821–822 in chronic obstructive pulmonary disease, 734 in HIV-infected (AIDS) patients, 2258 INH. See Isoniazid Inhalation challenge tests, 585t, 586–587 Inhalation fever, 1167–1168 Inhalation injury(ies) acute, occupational, 934t adverse effects of, 1011–1012 and bronchiectasis, 2186 classification of, 1054 epidemiology of, 1053 parenchymal, 1059–1060, 1060f toxic, 993–1006 clinical presentation of, 995–998 compounds in, 1053–1055, 1054t definition of, 994t types of, 994t

in conducting airways acute, 996 chronic, 996 determinants of, 993–995 in lower airways and pulmonary parenchyma acute, 996–997, 997f chronic, 998 mechanisms of, 993–995 particle size in, 993–994 pathogenesis of, 993–994, 995–998 in upper airway, 995–996, 1000t water solubility of inhalant and, 994–995, 994t tracheobronchial, 1057–1059, 1058f, 1059f treatment of, 1060–1061 upper airway obstruction caused by, 858 Inhibitory-κB kinase, activation of, 361 Innominate artery, aneurysm, 857 Insect allergen(s) and occupational asthma, 985t, 986 and risk of asthma, 794 Inspection, of chest, 390 Inspiration, duration of, 2592 Inspiratory capacity, 149t, 569, 569f in chronic obstructive pulmonary disease, 711, 714, 731 definition of, 568t, 1326, 2738 measurement of, 571 normal, 1323, 2735 postoperative changes in, 664 Inspiratory flow rate, ventilator setting for, 2681–2682, 2682f Inspiratory muscle(s) pressure generated by, in first 0.1 s of occluded inspiration (P0.1 ), 599 strength, measurement of, in acute respiratory failure, 2673 Inspiratory reserve volume, 569f definition of, 568t, 1326, 2738 Inspiratory vital capacity, definition of, 568t, 1326, 2738 Inspissated bile syndrome, 867 Instantaneous flows, in diagnostic spirometry, minimal recommendations for, 570t Insulin, and surfactant production, 132 Insulin-like growth factor(s) and airway smooth muscle proliferation, in vitro, 118 IGF-1, and B-cell production, 323 Integrated response, 223–226 exercise testing of, 225–226 for oxygen uptake, 224–225, 225f–226f Integrin(s) eosinophil, 315 in inflammation, 782–783 in inflammatory/fibrotic lung disease, 374 in lung development, 94

I-59 Index Intensity modulated radiation therapy, definition of, 1895 Intensive care unit access to, ethical considerations in, 2727–2728, 2729–2730 agitated patient in analgesia for, 2706–2710 sedation for, 2701–2706, 2708–2710 allocation of resources in, 2718, 2722 distributive justice and, 2722 clinical decision making in, severity scoring systems and, 2719–2720 conditions commonly seen in outcomes of, 2714–2716 prognoses for, 2714–2716 decision making in, 2713–2720 end-of-life care in. See also DNAR orders discussion of, with patient and family, 2731 principles of, 2724–2726 ethical conflicts in between patient’s desires and providers’ moral values, 2725–2726, 2729 prevention of, 2733 resolution of, 2733 ethical considerations in, 2718, 2721–2734 intubated patient in communication with, 2728–2729 ethical considerations with, 2728–2729 macroallocation of resources in, 2722 microallocation of resources in, 2722 ethical principles related to, 2726–2728, 2730 mortality prediction in, 2716–2718 palliative care in, 2733 patients in, decision-making capacity of, 2724, 2729 assessment of, 2731–2732, 2731t prognoses for patients in, 2714–2716 quality management in, 2719 severity score use in, 2718–2720 Intercellular cell adhesion molecule (ICAM) ICAM-1, 347, 363 in inflammation, 783 in inflammatory/fibrotic lung disease, 374 and leukocyte adherence and migration, 347–348 ICAM-2, in inflammation, 783 Intercostal muscle(s) actions of, 75–76, 75f external, 72f, 75–76, 75f internal, 72f, 75–76, 75f parasternal, 72f, 75, 75f, 77 Interferon(s) (IFN) IFN-α, 1971, 1973 effects/functions of, 779t

sources of, 779t targets of, 779t therapy with, pulmonary effects of, 1090t, 1100 IFN-α 2 b, pegylated, pulmonary effects of, 1100 IFN-β, 1971, 1973 effects/functions of, 779t sources of, 779t targets of, 779t IFN-γ , 283, 1970, 1971, 1973, 1976, 1978 adjunctive therapy with in invasive pulmonary aspergillosis, 2312 for zygomycosis, 2321 in aspergillosis, 2293 in blood assay for Mycobacterium tuberculosis, 2454, 2462 effects/functions of, 337, 779t expression of, by airway smooth muscle cells, 121, 122t and isotype switching, 324 in lung inflammation and injury, 337, 338f and SIRS/MODS, 2566–2567 sources of, 779t targets of, 779t IFN-γ 1b, therapy with, for idiopathic pulmonary fibrosis, 1158 for SARS, 2394 therapy with, pulmonary effects of, 1089 Interferon-γ -inducible protein, 340t, 341t Interferon-inducible T cell alpha chemoattractant, 340t, 341t Interleukin(s) (IL) IL-1, 1970, 1971, 1973 in disease, 336–337 effects/functions of, 336, 779t and leukocyte adherence and migration, 348 in septic shock syndrome, 449 and SIRS/MODS, 2566–2567 sources of, 779t targets of, 779t IL-1α, 336 IL-1β, 336 in asthma, 118 expression of, by airway smooth muscle cells, 121, 122t IL-2, 1976 effects/functions of, 779t sources of, 779t targets of, 779t therapy with, pulmonary effects of, 1081t, 1082 IL-3, 315 effects/functions of, 779t and eosinophilia, 2414 eosinophils and, 310t, 313, 315

mast cells and, 310t, 312 sources of, 779t targets of, 779t IL-4, 1971, 1976 in allergic bronchopulmonary aspergillosis, 838, 2296 in aspergillosis, 2293 effects/functions of, 779t eosinophils and, 310t, 315 and isotype switching, 324 and leukocyte adherence and migration, 348 in lung inflammation and injury, 337 mast cells and, 310t, 312 sources of, 779t targets of, 779t IL-5, 315, 1971, 1976 in allergic bronchopulmonary aspergillosis, 838, 2296 and asthma, 775, 776 effects/functions of, 779t and eosinophilia, 2414 eosinophils and, 310t, 313, 315 expression of, by airway smooth muscle cells, 121, 122t mast cells and, 310t, 312 monoclonal antibody against, 317, 318 sources of, 779t targets of, 779t IL-6, 1971, 1973, 1976 in asthma, 118 effects/functions of, 780t expression of, by airway smooth muscle cells, 121, 122t, 123 and leukocyte adherence and migration, 348 mast cells and, 310t, 312 and SIRS/MODS, 2566–2567 sources of, 780t targets of, 780t IL-7 and B-cell production, 323 effects/functions of, 780t sources of, 780t targets of, 780t IL-8, 340t, 341t, 1973, 1976, 2116 in allergic bronchopulmonary aspergillosis, 838, 2296 in chronic obstructive pulmonary disease, 715 effects/functions of, 780t expression of, by airway smooth muscle cells, 121, 122t, 123 mast cells and, 310t, 312 sources of, 780t targets of, 780t in Weibel-Palade bodies, 31 IL-9 effects/functions of, 780t sources of, 780t targets of, 780t

I-60 Index Interleukin(s) (IL) (Cont.)

IL-10, 1971, 1976 in aspergillosis, 2293–2294 effects/functions of, 337, 780t and isotype switching, 324 in lung inflammation and injury, 337 sources of, 780t targets of, 780t IL-11 effects/functions of, 780t expression of, by airway smooth muscle cells, 121, 122t sources of, 780t targets of, 780t IL-12, 1971, 1973 in aspergillosis, 2293 effects/functions of, 780t sources of, 780t targets of, 780t Il-12, 1976 IL-13, 1976 in allergic bronchopulmonary aspergillosis, 2296 effects/functions of, 780t and isotype switching, 324 in lung inflammation and injury, 337 mast cells and, 310t, 312 sources of, 780t targets of, 780t IL-14 effects/functions of, 780t sources of, 780t targets of, 780t IL-15 in aspergillosis, 2293 effects/functions of, 780t sources of, 780t targets of, 780t IL-16, 315 effects/functions of, 780t eosinophils and, 315 sources of, 780t targets of, 780t IL-17, 1973, 1976 effects/functions of, 780t sources of, 780t targets of, 780t IL-18 effects/functions of, 780t sources of, 780t targets of, 780t IL-19 effects/functions of, 780t sources of, 780t targets of, 780t IL-20 effects/functions of, 780t sources of, 780t targets of, 780t IL-21 effects/functions of, 781t

sources of, 781t targets of, 781t IL-22 effects/functions of, 781t sources of, 781t targets of, 781t IL-23, 1973, 1976 effects/functions of, 781t sources of, 781t targets of, 781t IL-24 effects/functions of, 781t sources of, 781t targets of, 781t IL-25 effects/functions of, 781t sources of, 781t targets of, 781t IL-26 effects/functions of, 781t sources of, 781t targets of, 781t IL-27 effects/functions of, 781t sources of, 781t targets of, 781t IL-28 effects/functions of, 781t sources of, 781t targets of, 781t IL-29 effects/functions of, 781t sources of, 781t targets of, 781t Interleukin-1 receptor antagonist, 336 Intermittent abdominal pressure ventilator, 1669–1670, 1670f Intermittent mandatory ventilation (IMV), 2677–2678, 2678f Intermittent positive-pressure breathing (IPPB) in neuromuscular disorders, 1660 postoperative, 674 Intermittent positive-pressure ventilation (IPPV) mouth piece/lip seal for, 1670, 1670f in neuromuscular disorders, 1670, 1670f, 1671–1672, 1671f noninvasive vs. tracheostomy, outcomes with, 1673–1674 noninvasive complications of, 1672 in neuromuscular disorders, 1670, 1670f, 1671–1672, 1671f outcomes with, 1673–1674 Internal oblique muscle, 72f, 76–77 International Adjuvant Lung Cancer Trial, 1869–1870, 1869t International Labor Organization, classification system for evaluation of pneumoconiosis, 680

International Labour Office, classification of chest radiographs, 939 Interstitial cells, 33, 33t, 1105 alveolar, 40–41, 40f, 41f of alveolar septum, 51–52, 52f lipid, 41 Interstitial edema, 1234t Interstitial infiltrate(s), 1988t Interstitial lung disease, 371. See also Idiopathic pulmonary fibrosis acute, 1108t age distribution of, 1106–1107 in ankylosing spondylitis, 1211, 1211f approach to patient with, 1107–1123 biopsy in, 1120, 1120t bronchoalveolar lavage cellular profiles in, 1120, 1121t bronchoalveolar lavage in, 1114–1120 bronchoscopy in, 1120, 1120t cardiopulmonary exercise testing in, 625 chest pain in, 1108 chest radiography in, 1112–1113, 1113f–1114f chronic, 1108t classification of, 934, 935t by duration of symptoms, 1108t in collagen vascular disease, 1193–1195 histopathology of, 1195–1196, 1195f–1196f incidence of, 1193, 1194t computed tomography of, 463, 463f, 1112–1113, 1113f–1114f, 1115t, 1116t–1119t connective tissue disorders and, 2013 cough in, 1108 definition of, 1145 diagnosis of, 1107, 1107f clinicopathologic correlation in, 1122–1123 diffuse, 2027 cyanosis in, 415 dyspnea in, 400 types of, 401t drug-induced, 1089, 1090t drugs associated with, 1110t drug use history in, 1109 dyspnea in, 1108 epidemiology of, 1105–1107 exposure history in, 1108–1109, 1109t family history in, 1109 fever in, 1108 histopathology of, 934, 935t, 1364–1365, 1366f history-taking in, 1108–1109 immunoglobulins in, 330 initial assessment of, 421–424 laboratory evaluation in, 1111–1112 linear, 483, 490f medication history in, 1109

I-61 Index in mixed connective tissue disease, 1210 nodular, 483, 490f occupational, computed tomography of, 939 occupational exposures causing, 934, 935t occupational history in, 1108–1109, 1109t physical examination in, 1109–1111 in polymyositis-dermatomyositis, 1208–1209, 1209f pulmonary airway disease and, 2013 pulmonary function testing in, 1113–1114 pulmonary hypertension in, 1396–1399, 1397f, 1398f racial distribution of, 1107 radiographic features of, 483–486, 490f–492f respiratory bronchiolitis-associated.

See Respiratory bronchiolitis interstitial lung disease reticular, 483, 490f, 491f in rheumatoid arthritis, 1204–1206 in scleroderma, 1206–1207, 1207f sex distribution of, 1107 SFTPC mutations and, 128–129, 129f in Sj¨ogren’s syndrome, 1210–1211, 1210f smoking and, 1108 subacute, 1108t in systemic lupus erythematosus, 1200–1201 terminology for, 1106t thoracoscopic biopsy in, 652–653 treatment of, 1116t–1119t, 1123 vasculitis and, 2013 Interstitium, 31 alveolar, 32–33, 33t, 40–41, 40f, 41f, 51–52, 52f Interventional pulmonology, in upper airway obstruction, 861–862 Interventional radiology, 533–544 historical perspective on, 533 for pulmonary embolism, 1440 Intrapulmonary vessels alveolar, 1349, 1349f calibers, interplay of pressures and, 1350, 1350f corner, 1349, 1349f extra-alveolar, 1349–1350, 1349f function of, 1348–1350, 1349f structure of, 1348–1350 types of, 1348, 1349f Intravenous (IV) drug abuser(s), pneumonia in, 2024 Intravenous immunoglobulin(s) (IVIG), 2139 for common variable immunodeficiency, 332

in IgA deficiency, 332 for viral pneumonia, 2395 for X-linked hypogammaglobulinemia, 331 Intubation blood and secretion management in, 2650 in burn patient, 1060 historical perspective on, 2645–2646 and nosocomial pneumonia, 2196, 2274, 2278–2279 and oxygen source, 2650 positioning for, 2649–2650, 2649f preparation of patient for, 2650 and resuscitation equipment, 2650 saliva and, 2650 tracheal, 2651–2657 Invasive pulmonary aspergillosis, 2292t, 2305–2313 clinical features of, 2307–2308 diagnosis of, 2308–2309 differential diagnosis of, 2298–2299, 2323t epidemiology of, 2305–2306 extrapulmonary involvement in, 2307–2308 immune augmentation treatment for, 2312 nonangioinvasive, 2307, 2307f nosocomial, 2306 pathogenesis of, 2306–2307 pathophysiology of, immunosuppression and, 2307, 2307f prevention of, in high-risk patients, 2312–2313 radiographic findings in, 2308, 2308f risk factors for, 2306 subacute, 2292 surgery for, 2312 treatment of, 2309–2312, 2310t, 2311t Inverse ratio ventilation, in ALI/ARDS, 2549–2551, 2552f Iodinated agents, mucolytic/expectorant, 2642 Iodine, and interstitial lung disease, 1110t Iodoquinol, indications for, 2401 Ion transport, epithelial, CFTR and, 2173–2174 IP-10. See Interferon-γ -inducible protein IPA. See Invasive pulmonary aspergillosis IPAH. See Idiopathic pulmonary arterial hypertension IPF. See Idiopathic pulmonary fibrosis Ipratropium adverse effects and side effects of, 826t, 2636 for asthma, 822, 823t, 826t, 2635–2636 for chronic obstructive pulmonary disease, 738t, 739, 2635 dosage and administration of, 826t

for exercise-induced asthma, 812 pharmacology of, 2635 IPS. See Idiopathic pneumonia syndrome IR. See Interventional radiology IRDS. See Infantile respiratory distress syndrome Irinotecan, pulmonary effects of, radiation therapy and, 1181 IRIS. See Immune reconstitution inflammatory syndrome Iron, microbial requirement for, 1970, 2079 Iron chelator therapy, for zygomycosis, 2321 Iron dioxide, bronchiolitis caused by, 895–896 Iron overload, and risk of infection, 2317, 2318 Iron oxide, bronchiolitis caused by, 893t Irritant receptors, 164, 164f IRV. See Inspiratory reserve volume Ischemia-reperfusion injury, and respiratory failure, 2585 Ischemic heart disease, cardiopulmonary exercise testing in, 621 Isocapnic hyperventilation test, 585t, 810–811, 811f, 818 Isocyanates and occupational asthma, 989–990 occupational lung disease caused by, 935t in smoke and inhalation injury, source of, 1054t Isoetharine dosage forms, 2632t receptor activity, 2632t Isoniazid adverse effects and side effects of, 2477, 2483t, 2503 in children, 2135 hepatotoxicity of, 2135, 2455, 2477 interactions with immunosuppressive agents, 2503t for latent tuberculosis infection, 2455–2456, 2455t in HIV-infected (AIDS) patients, 2491 lupus-like syndrome caused by, 2010, 2012t mechanism of action of, 2464 for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t peripheral neuritis caused by, 2477 pharmacology of, 2476–2477 plus phenytoin, 2477 plus rifampin, hepatotoxicity of, 2477, 2478 pulmonary effects of, 1090t resistance to, 2476 mycobacterial, 2451 testing for, 2463

I-62 Index Isoniazid (Cont.) for tuberculosis, 2464, 2476–2477 in children, 2135 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2490 regimens for, 2481t theoretical basis for, 2476 Isoprinosine, for Pneumocystis pneumonia, 2370 Isoproterenol adverse effects and side effects of, 825t for asthma, 823t, 825t dosage and administration of, 825t dosage forms, 2632t and pulmonary circulation, 1347 receptor activity, 2632t Isospora belli, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t Isotype switching, 323–324 ITAC. See Interferon-inducible T cell alpha chemoattractant ITAM. See Immunoreceptor tyrosine-based activation motifs ITIM. See Immunoreceptor tyrosine-based inhibition motifs Ito cell(s), 41 Itraconazole for allergic bronchopulmonary aspergillosis, 842, 2299 for aspergilloma, 2303 for blastomycosis, 2348 for coccidioidomycosis, 2345 for cryptococcosis, 2334 drug interactions with, 2340 for histoplasmosis, 2340 for invasive fungal infections, 2310t, 2311t prophylaxis, 2312–2313 IVC. See Inspiratory vital capacity Ivermectin for ascariasis, 2418t for strongyloidiasis, 2418, 2418t J Jackson, Chevalier, 2646 Jacobaeus, 649 Jacobs, Merkel Henry, 5t, 13 Janeway, 2646 Japanese summer house hypersensitivity pneumonitis, 1161 etiology of, 1165t Jaw thrust maneuver, 2649–2650 Jo-1 antibodies, 429, 1209 Job’s syndrome. See Hyperimmunoglobulin E syndrome J receptors, 164–165, 398, 400

J reflex, 165, 1340 Justice, principle of, 2722 Juxtacapillary receptors, 164–165 K Kanamycin adverse effects and side effects of, 2483t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for tuberculosis, 2479 dosage and administration of, 2482t Kaposi’s sarcoma, 431–432, 432f, 1954–1955, 1964–1965 in HIV-infected (AIDS) patients, 1294, 2213, 2215, 2247, 2258–2259 and pneumothorax, 1523 radiographic findings in, 2214t, 2249t in immunocompromised host, 2209f in lung transplant recipient, 439–440 scintigraphy of, 557 Karatagener’s syndrome, 2138 Karnofsky score, definition of, 1895 Kerley’s lines, 483, 490f, 494 type A, 483 type B, 483 type C, 483 Ketamine, for agitated ICU patient, 2705 Ketoacidosis, 219 Ketoconazole, for allergic bronchopulmonary aspergillosis, 842 Ketolides adverse effects and side effects of, 2056 characteristics of, 2055–2056 for community-acquired pneumonia, 2110 mechanism of action of, 2055 organisms susceptible to, 2056 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2055 Ketones, in indoor air, sources of, 1023t Ketorolac, and aspirin-induced asthma, 802t Ketotifen, 2639 Kidney(s) in acid-base balance, 208–209 adaptation to respiratory alkalosis, 212 and ammonia recycling, 210–211, 210f and bicarbonate reclamation, 209, 209f biopsy, in immune-mediated diffuse alveolar hemorrhage, 1284–1285, 1285f, 1286f function, altitude and, 1040 net acid excretion by, 209–211 Killian, Gustav, 629 Kinocilia, 27 Kirstein, Alfred, 2646

Klebsiella in acute exacerbations of chronic obstructive pulmonary disease, 742t in acute mediastinitis, 2166t colonization, in cystic fibrosis, 866 drug-resistant, 2282 in empyema, 2144 in HIV-infected (AIDS) patients, radiographic findings in, 2215 hypersensitivity pneumonitis caused by, 1164t infection (incl. pneumonia), 2019, 2022 in Chediak-Higashi syndrome, 2238 in chronic granulomatous disease, 2237 diagnosis of, 1998 hemoptysis in, 413 neonatal nosocomial, 2126 nosocomial, 2280, 2281t, 2282, 2289 treatment of, 2285–2288, 2286t in organ transplant recipient, 2231f, 2232 pathology of, 2043 staining characteristics of, 2036 Klebsiella pneumoniae aspiration pneumonia, 2007 immune defense against, 1973 infection (incl. pneumonia) and bronchiectasis, 2186 of deep cervical space, 852 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2106t nosocomial, 2279, 2280t, 2282 pathogenesis of, 2080 pathology of, 2044f in surgery and trauma patients, 2197 in lung abscess, 2144 pneumonia, 1989, 1995, 1996f, 2005, 2008, 2020 radiologic features of, 1986f in stem cell transplant recipient, 2224f vaccine against, 2080 Klebsiella rhinoscleromatis, 853 Klippel-Feil syndrome, 2647 Kluyvera, in acute mediastinitis, 2166t Koch, Robert, 5t, 15–16, 16f Koch postulates, 16 KOH staining, of Blastomyces dermatitidis, 2346, 2348t Kono-Mead diagram, 75f, 77 Koop, C. Everett, 753 Koplik’s spots, 2391 Krabbe’s disease, 1273–1274, 1274f Kremen1, 86 Kremen2, 86 Krogh, August, 5t, 9–10, 10f Krogh, Marie, 5t, 9–10, 10f

I-63 Index Krypton-81m, ventilation scan using, 549, 550 Kuhn, Franz, 2646 Kussmaul breathing, 394, 404 Kveim, Ansgar, 1125–1126 Kveim reaction, 1126 Kyphoscoliosis, 1617–1623 clinical course of, 1621 control of breathing in, 1620–1621 diagnosis of, 1617–1618 etiology of, 1617–1618, 1618t exercise capacity in, 1620 gas exchange in, 1621 and hypercapnic respiratory failure, 2608–2609 pathophysiology of, 1617–1618, 1618f pulmonary complications of, 1395, 1396f, 1397f pulmonary compression in, 400, 402f pulmonary function testing in, 1618–1620, 1620t and respiratory failure, 2514 respiratory mechanics in, 1618–1620, 1619t sleep-disordered breathing in, 1621 surgery for, and postoperative pulmonary complications, 667 treatment of, 1621–1623, 1622t, 1623f ventilatory impairment in, 1668t L Labetalol, pulmonary effects of, 1096–1097 Laboratory worker’s hypersensitivity pneumonitis, etiology of, 1164t Lactate dehydrogenase (LDH) in HIV-infected (AIDS) patients, 2247t, 2248 in Pneumocystis pneumonia, 2361 Lactic acid, measurement of, in acute respiratory failure, 2661 Lactic acidosis, 219 in acute respiratory failure, 2661 Lactobacillus, 2086 in acute mediastinitis, 2166t in empyema, 2144t infection (incl. pneumonia), 2156t Lactoferrin, 1970, 1973 in airway surface liquid, 281 La¨ennec, Ren´e Th´eophile Hyacinthe, 5t, 13–14, 15, 15f, 694, 766 LALN. See Lung-associated lymph node(s) LAM. See Lymphangioleiomyomatosis Lambert-Eaton syndrome, 1936t, 1937–1938 in small cell lung cancer, 1905t, 1906 Lamellar body(ies), 36–38, 36f, 37f, 126, 126f species differences in, 36 Laminar flow, 154, 154f, 175, 176f Laminin, in lung development, 94 Laminography, 458–459

Langerhans’ cell granulomatosis. See also Eosinophilic granuloma of lung; Histiocytosis X clinical features of, 1118t computed tomography of, 1115t, 1118t histology of, 1118t treatment of, 1118t Langerhans’ cell histiocytosis, pulmonary, 1145, 2025 bronchoscopy in, 1120t clinical course of, 1252–1253, 1252f, 1252t clinical features of, 1245 computed tomography of, 1115t diagnostic evaluation of, 1250–1252 epidemiology of, 1245–1246 exercise physiology in, 1248, 1248f histopathology of, 1248–1249, 1249f, 1250f lung transplantation in, 1774t, 1775–1777 and malignancy, 1245 natural history of, 1245 pathogenesis of, 1250, 1251f prognosis for, 1252–1253 pulmonary function testing in, 1247–1248 radiographic features of, 1246–1247, 1246f, 1247f treatment of, 1252–1253 Langerhans’ cells, 1245 Laplace’s law, 54, 150 Large-cell carcinoma, of lung, 1832t, 1838–1839 variants of, 1839–1840 Large cell neuroendocrine carcinoma of lung, 1839–1840, 1839f Large-cell undifferentiated lung cancer, cytopathology of, 530, 530f Laryngeal cancer, smoking and, 751 Laryngeal dysfunction, differential diagnosis of, 819t Laryngeal mask airway, 2651, 2652f Laryngeal papillomatosis, 2088–2089 Laryngeal tube airway, 2651 Laryngitis, acute, viral causes of, 2087 Laryngocele, 851f upper airway obstruction caused by, 857 Laryngoscopy, historical perspective on, 2646 Laryngotracheal injury(ies), upper airway obstruction caused by, 858 Laryngotracheal stenosis postintubation, 854–855 post-tracheotomy, 854–855 Laryngotracheobronchitis acute, 2087–2088 upper airway obstruction in, 853 Larynx infant, 2647 stenosis of, 854–855 Laser surgery, for bullae, 928

Laser therapy, endobronchial, 637 LaSRS. See ARDSNet, Late Steroid Rescue Study Lassa fever, 2378 LAT. See Linker for activation of T cells Lateral position test, preoperative, for lung resection, 672 Latex, and occupational asthma, 985t, 986, 989 Lavoisier, Antoine Laurent, 5t, 7–8, 8f, 9, 2613 LCNEC. See Large cell neuroendocrine carcinoma of lung Lead National Ambient Air Quality Standards for, 1011t in outdoor air exposures to, 1020 health effects of, 1020 sources of, 1011t Lectin(s), C-type, in aspergillosis, 2293 Lef1, 86 Left atrial anastomotic obstruction, in lung transplant recipient, 1788 Left atrial pressure, 1336–1337 Left ventricular end-diastolic pressure, in acute respiratory failure, 2663 Left ventricular failure pulmonary edema in, 2541t, 2542 radiographic features of, 476, 478f, 480f, 494 on portable examination, 508–509 Left ventricular stroke work index, in pregnancy, 257t Legallois, 12 Legionella in acute mediastinitis, 2166t diagnosis of, 2000, 2003 epidemiology of, 1984t, 2004 in hospital environment, 2274–2275 in indoor air, 1030t, 1031 infection (incl. pneumonia), 2005t, 2006, 2022, 2146 in bone marrow and stem cell transplant recipients, 2223 in HIV-infected (AIDS) patients, 2212t, 2252 radiographic findings in, 2214t, 2215, 2249t hospitalization rate for, 2105t immune defect associated with, 1983t, 2210t in immunocompromised host, 2204 nosocomial, 2277, 2280t, 2281t, 2282 treatment of, 2285–2288, 2286t and parapneumonic effusions, 1489 pathology of, 2043t, 2045, 2045f in severe combined immunodeficiency, 2236 signs and symptoms of, 2099 treatment of, 2055

I-64 Index Legionella (Cont.) in lung abscess, 2154t staining characteristics of, 2035t, 2037, 2045, 2045f Legionella bozemanii, infection (incl. pneumonia), nosocomial, 2275 Legionella micdadei infection (incl. pneumonia), pathology of, 2045, 2045f staining characteristics of, 2045, 2045f Legionella pneumophila, 1986, 1996. See also Legionnaires’ disease blood culture for, 2001 diagnosis of, 1999, 2001 infection (incl. pneumonia), 2005t, 2006, 2019, 2019f chest radiograph in, 2103f in children, 2133, 2134 diagnosis of, 2106 differential diagnosis of, 2266 epidemiology of, 2113 history and physical findings in, 2100t–2101t ICU admission rate for, 2106t nosocomial, 2275 pathogenesis of, 2079, 2113 risk factors for, 2113 treatment of, 2053, 2057, 2113 molecular detection of, 2002 serogroups of, 2113 staining characteristics of, 2040f Legionnaires’ disease, 1985. See also Legionella pneumophila in children, 2133, 2134 diagnosis of, 2000, 2001 epidemiology of, 2113 pathogenesis of, 2113 risk factors for, 2098, 2113 treatment of, 2113 Leiomyoma, 1919–1920 mediastinal, 1596 Leishmania, infection (incl. pneumonia), in immunocompromised host, 2209–2210 Leishmania aethiopica, 2409 Leishmania braziliensis, 2409 Leishmania chagasi, 2409 Leishmania donovani, 2409 infection (incl. pneumonia), in immunocompromised host, 2204 Leishmania infantum, 2409 Leishmania major, 2409 Leishmania mexicana complex, 2409 Leishmaniasis, 2409 in cancer patients, 2219 clinical features of, 2409 cutaneous, 2409 epidemiology of, 2409 in HIV-infected (AIDS) patients, 2409 mucocutaneous, 2409

New World, 2409 Old World, 2409 pulmonary involvement in, 2409 treatment of, 2409 visceral, 2409 Leishmania tropica, 2409 Lemierre’s syndrome, 853 Lepirudin, for pulmonary embolism, 1439 Leptin, 452 Leptospirosis, epidemiology of, 1984t Letterer-Siwe disease, 1245 Leucogyrophana pinastr, hypersensitivity pneumonitis caused by, 1164t Leucovorin, for toxoplasmosis, 2402 Leukemia and infection, 2215–2216 risk of venous thromboembolism in, 1426 Leukemia inhibitory factor, expression of, by airway smooth muscle cells, 121, 122t Leukemic infiltration, 2542t pulmonary, 1964, 1964f Leukoagglutinins, pulmonary transfusion reaction to, 2014 Leukocyte(s) adherence, 347–349, 348f chemotaxis, 783, 783f diapedesis, 783, 783f emigration, 373f, 374 extravasation into inflamed tissue, 348f migration, 347–349, 372, 373f, 783, 783f G protein–coupled chemoattractant receptor in, 353, 353f in pulmonary inflammation, 354–356 recruitment, 783, 783f vascular adhesion, 783, 783f Leukocyte adhesion deficiency, pulmonary infection in, 2238–2239, 2239f Leukotriene(s) (LT) and aspirin-induced asthma, 803–804, 803f in asthma, 778 cysteinyl formation of, 2640 physiologic effects of, 2640 receptors for, expression of, by airway smooth muscle cells, 122, 122t and exercise-induced asthma, 809 formation of, 350, 350f, 778, 782f LTA4 , 350, 350f metabolism, 2640 LTB4 , 311, 315, 350–351, 350f, 1973 mast cells and, 310t, 312 LTC4 , 316, 350, 350f and aspirin-induced asthma, 801 eosinophil, 310t, 314 mast cells and, 310t, 312

LTD4 , 350, 350f and airway smooth muscle proliferation, in vitro, 118 LTE4 , 350, 350f and pulmonary vasomotor control, 1341 synthesis of, 2640 Leukotriene pathway inhibitors, 312, 2640–2641 adverse effects and side effects of, 828t for asthma, 823t, 828t, 830 for eosinophilic disorders, 318 for exercise-induced asthma, 811t, 812 mechanism of action of, 828t Leukotriene receptor antagonists, 2640–2641 clinical use of, 2640 drug interactions with, 2641 pulmonary effects of, 1091t, 1092–1093 safety of, 2640–2641 Levalbuterol adverse effects and side effects of, 824t for asthma, 823t, 824t for chronic obstructive pulmonary disease, 738t dosage and administration of, 824t dosage forms, 2632t receptor activity, 2632t structure-activity relationships, 2633 Levamisole, for hookworms, 2418t Levator costae muscle, 75, 75f, 76 Levofloxacin, 2056–2057, 2060 dosage and administration of, 2057 for hospital-acquired pneumonia, 2061, 2061t, 2062 for pasteurellosis, 2430 for tuberculosis, 2480 in children, 2482t dosage and administration of, 2482t Libertarian theory, 2723 Lichtheim, Ludwig, 15 Liddle’s syndrome, 144 Light-chain deposition disease, 1234, 1952 Light wand, flexible, 2654, 2654f Lignac-Fanconi disease, 1276 Liljestrand, G., 16 Limb-girdle dystrophy, respiratory abnormalities in, 1659 Limonene exposure to, 1027t sources of, 1027t Linezolid activity against MRSA, 2058 adverse effects and side effects of, 2058 anti-TB activity, 2464 for cystic fibrosis patient, 875 for hospital-acquired pneumonia, 2061, 2061t, 2062 mechanism of action of, 2055 for nontuberculous mycobacteria, 2505 organisms susceptible to, 2058

I-65 Index penetration into lung, 2053 pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2058 Lingula, 25 Linkage analysis, 793 in asthma, 793–794 Linker for activation of T cells, 310 LIP. See Lymphocytic interstitial pneumonia LIP. See Lymphocytic interstitial pneumonitis LIP. See Lymphoid interstitial pneumonia Lipid(s), in mycobacterial virulence, 2461 Lipid body(ies), 41 Lipids in host defense, produced by macrophages, 1972t in inflammation, produced by macrophages, 1972t Lipoarabinomannan, 1970 Lipofibroblasts, of alveolar septum, 40f, 41 Lipoid pneumonia, 2014 Lipoma, pleural, 505f, 507 Lipomoblastomatosis, mediastinal, 1611 Lipopolysaccharide (LPS), 1970, 1971, 2081 Lipoprotein(s), in alveolar fluid, 282 Liposarcoma, mediastinal, 1611 Lipoteichoic acid, 1970 Lipoxygenase, inhibitors, for asthma, 830 5-Lipoxygenase, 2640 in arachidonic acid metabolism, 350, 350f 5-Lipoxygenase, inhibitors, 312 5-Lipoxygenase activating protein, 312 5-Lipoxygenase inhibitors, 2640 LIS. See Lung Injury Score Listeria, infection (incl. pneumonia) in cell-mediated immunodeficiency, 2236 immune defect associated with, 1983t, 2210t Listeria monocytogenes, infection (incl. pneumonia), in cancer patients, 2216 Lithium dilution technique, in acute respiratory failure, 2668 Liver arteriovenous malformations in, 1477 cirrhosis of circulatory effects of, 448–449 pulmonary hypertension in, 449 ventilatory effects of, 447–448 dysfunction, in SIRS/MODS, 2565, 2568 Liver disease, and pulmonary hypertension, 1381–1382 Liver transplantation, pulmonary hypertension and, 1382 LL-3858 (anti-TB drug), 2464 LMA. See Laryngeal mask airway

Loading, external mechanical, ventilatory response to, 167–168 Lobe(s), 52–53 embryology of, 81, 82f of lung, 24–25, 24f, 26 development of, 95, 95f Lobectomy hemoptysis after, 414 for lung cancer, 1855 pulmonary function testing before, 671 VATS technique, 656–657, 657f Lobule(s) involvement in emphysema, 695–696, 695f secondary, 26 Lobule of Miller, 695 Loeffler, 1213 Loeffler syndrome, 1091, 1213, 1214–1215, 2013, 2045 clinical features of, 1230t differential diagnosis of, 1230t, 2298 L¨ofgren, Sven, 1126 L¨ofgren’s syndrome, 1136 erythema nodosum in, 434 Lomustine pulmonary effects of, 1079t, 1080–1081 therapeutic uses of, 1078 Lorazepam, for agitated ICU patient, 2703, 2704t Lorrain-Smith, 2613 Loss of heterozygosity (LOH), 1804 5q, in lung cancer, 1806 on short arm of chromosome 9 (9p), in lung cancer, 1806 Louis, 15 Low birth weight, and risk of asthma, 794 L¨owen, 2646 Lower, Richard, 5t, 7 Lower esophageal sphincter (LES), 1302, 1304 contraction, in dysphagia, 1306, 1308f incompetence, 1308–1309 Lower motor neuron disease, ventilatory impairment in, 1651–1652 Low-molecular-weight compounds, and occupational asthma, 985t, 986 LPS. See Lipopolysaccharide (LPS) L-selectin, 315 in inflammation, 782 and leukocyte adherence and migration, 347–348 LTA. See Laryngeal tube airway LTBI. See Tuberculosis, latent Ludwig, Karl, 5t Ludwig’s angina, 852, 1309, 2087 and mediastinitis, 2165 Lumsden, Thomas, 5t, 12 Lung(s) adult, dimensions of, 111, 111t age-related changes in mechanical, 264–266 structural, 263–264

anatomy of, related to gas exchange, 173, 174f auscultation of, 392 branching morphogenesis of, 81, 91, 97 integrated model of, 88–89, 88f, 89f bronchopulmonary segments of, 24–25, 24f capillary fusion and differential growth, 104 capillary network of, development of, 101, 103f cell types in, 27 cell volumes in, 33, 33t circadian clock in, 1694 defense system of. See also Pulmonary host (immune) defense(s) structure of, 41–43 development of, 81–83, 91–105 alveolar stage of, 91, 92f, 93t, 94f, 100–101, 102f, 103f canalicular stage of, 91, 92f, 93t, 94f, 96f, 98, 98f cell proliferation in, 101 embryonic stage of, 91–95, 92f, 93t, 94f–95f fetal, 93t, 95–100, 96f–99f growth factor signaling in, 83–84 postnatal, 93t, 100–105, 102f–103f, 105f–107f prenatal, 92–95, 94f–95f pseudoglandular stage of, 91, 92f, 93t, 94f, 96–98, 96f, 97f saccular stage of, 91, 92f, 93t, 94f, 97f, 100 septation in, 101, 102f, 103f species differences in, 93t, 100 stages of, 82, 82f, 91, 92f transition to growth, 106 zones of, 96f, 97–98, 98f distribution of air in, radiographic evaluation of, 473–476 dynamic compliance of. See Dynamic compliance elastic properties of, 149–151, 149f, 575, 576f age-related changes in, 264–266 knowledge of, historical perspective on, 11–12 elastic recoil of, 149–150, 264–266 age-related changes in, 266 embryology of, 81, 82f, 92–95, 94f–95f as endocrine organ, 444–445 as gas exchanger, 57–65 growth of, 93t, 105f, 106–110, 108f–111f injury, in bone marrow and stem cell transplant recipients infectious etiologies, 2228–2229 non-infectious causes of, 2225 innervation of, 32 maturity of, at birth, species differences in, 100

I-66 Index Lung(s) (Cont.) mechanical properties of, age-related changes in, 264–266 microvasculature of growth of, 109f–110f, 110–111 maturation of, 93t, 104–106, 105f–107f as organ, 23–26 organogenesis, 92–95, 94f–95f penetrating injury of, 1764–1765, 1764f physiology, in acute lung injury, 2524–2525 pressure-volume characteristics of, 149–150, 149f, 150f programmed cell death in, 104 radiation tolerance of, 1184–1185 in partial-lung radiation, 1186–1188 in whole-lung radiation, 1185–1186, 1185f, 1185t secondary lobule of, 26 segments of, 24f, 26 shape of, 24 static compliance of. See Static compliance, of lung structural elements of basic, 26–27 interspecies differences of, 27 structural macromolecules of, age-related changes in, 266–267, 266f structure, age-related changes in, 263–264 subsegments of radiographic anatomy of, 477, 479f topographic anatomy of, 477, 479f–481f surface area of, age-related changes in, 266 systemic effects of, 443–444 tissue, physical properties of, 151 tissue organization of, 26–44 transplantation of in bronchiectasis, 2191 and risk of infection, 2306 zones of, 1350–1351, 1351f Lung-associated lymph node(s), 329 Lung cancer air pollution and, 1020 asbestos-related, 1029, 1029t clinical features of, 955 diagnosis of, 955 epidemiology of, 944, 955 pathogenesis of, 955 pathology of, 955 prognosis for, 955–956 radiographic features of, 955 treatment of, 955–956 with bullous lung disease, 922f, 926 and clubbing of digits, 416 computed tomography of, 460f, 461, 461f cutaneous manifestations of, 432–433 cytogenetics of, 1804

doubling time in, 493f early cytopathology of, 527, 528f detection of, 527 embolization therapy for, 1354 endocrinopathy associated with, 390 epidemiology of, 1899 established, cytopathology of, 527–531 extrapulmonary syndromes associated with, 1929–1938 FDG-PET of, 559–561, 561f for staging, 561–563, 562t, 563f genetic susceptibility to, 1802–1804 acquired genetic changes and, 1802–1804 histological classification of, 528, 528t general considerations in, 1832–1833 WHO system, 1831–1832, 1832t in HIV-infected (AIDS) patients, 2259 radiographic findings in, 2249t and hypertrophic osteoarthropathy, 418 impairment due to, evaluation of, 684 intrarterial chemotherapy for, 1354 local invasiveness of, 390, 391f molecular changes in, 1804–1807 non-small cell. See Non-small cell lung cancer occupational exposure and, 934t, 935 PET/CT of, 564 and pleural effusion, 1505, 1506t and pneumonia, 2110 radiation therapy for contraindications to, 1883, 1884t dose, 1884t indications for, 1884t local tumor boosting, 1188 and risk of radiation pneumonitis/fibrosis, 1188 type, 1884t radiofrequency ablation of, 536, 537f radiographic features of, 459f, 484f, 487f, 498f radon and, 1028 risk factors for, 1816 small cell. See Small cell lung cancer smoking and, 751 staging, FDG-PET for, 561–563, 562t, 563f and superior vena cava syndrome, 390, 391f transthoracic needle aspiration and biopsy of, 645 treatment of, molecular genetics of, 1811, 1811f and tuberculosis, 2215–2216 Lung capacity(ies), 568t abbreviations for, 1326, 2738 definition of, 568, 1326, 2738 normal, 1323, 2735 Lung compliance, 149–151, 149f age-related changes in, 151, 265–266 Lung disease, systemic effects of, 451–453, 451t

Lung expansion maneuvers, postoperative, 673t, 674 Lung injury nitrosative, 359 oxidative, 359 reactive nitrogen species in in vivo evidence for, 364–365, 365f therapies to attenuate, 366–368 reactive oxygen species in in vivo evidence for, 364–365, 365f therapies to attenuate, 366–368 ventilator-associated, 2529–2530 ventilator-induced, 2529–2530 Lung Injury Score, 2535 Lung resection. See also Lobectomy; Pneumonectomy air leak after, 1744 alveolar pleural fistula after, 1744 antibiotic administration with, 1743 chest tube drainage after amount of, 1745 high-output states, 1745–1746 chest tube management after, 1745 complications of, 1744–1752 effects on pulmonary function, 2579 electrolyte management for, 1743–1744 extubation for, 1742 fluid management for, 1743–1744 lung function alterations after, 1741–1742 lung function optimization before, 1740–1741 morbidity and mortality with, 1740 nutritional support with, 1743–1744 oral intake after, 1743–1744 pain control for, 1742–1743 patient selection for, 1739–1740 and perioperative factors affecting lung function, 1741–1742 postoperative oxygen supplementation for, 1742 preoperative cardiac stress testing for, 1742 preoperative evaluation for, 670–673, 1740–1741 recommended approach for, 672–673, 672f pulmonary function testing before, 1740 pulmonary rehabilitation after, 771 smoking cessation before, 1740–1741 subcutaneous emphysema after, 1744–1745, 1745f Lung sound(s) adventitious, 392–393 classification of, 392–393, 393t duration of, changes in, 392 intensity of, changes in, 392 quality of, changes in, 392 transmission of, changes in, 392 vesicular, 392

I-67 Index Lung tissue resistance, 583 definition of, 1327, 2739 Lung transplantation and acute graft dysfunction, 1788–1789, 1789t in allergic bronchopulmonary aspergillosis, 843 allograft rejection in, 330, 1786–1788, 1787f, 1787t, 1788f bronchoalveolar lavage cellular profile in, 1121t anesthesia for, 1780–1781 antimicrobial therapy with, 1784–1785 bronchiolitis obliterans after, 908 in chronic obstructive pulmonary disease, 744–745 complications of infectious, 1790–1791 neoplastic, 1791 surgical, 1788–1790 contraindications to, 1771–1773, 1772t, 1773t in cystic fibrosis, complications of, 881–882, 882f diaphragm function after, 78 disease-specific considerations in, 1774t, 1775–1777 donor lung preservation for, 1779–1780 donor selection, 1777–1779, 1778t double-lung, 1782, 1783f fluid management after, 1784 functional outcomes with, 1792 historical perspective on, 1769–1770 for idiopathic pulmonary fibrosis, 1158–1159 immunosuppression after, 1785–1786 indications for, 1770–1771, 1773t disease-specific, 1775, 1775t for lymphangioleiomyomatosis, 1261 nutritional support after, 1785 postoperative management of, 1784–1791 posttransplant therapy with, 1773 primary graft dysfunction after, 2585 procedure for indications for, 1777, 1778t selection of, 1777, 1778t for pulmonary arterial hypertension, 1391 pulmonary capillaritis after, 1464 pulmonary edema after, 2585 pulmonary rehabilitation in posttransplant, 770–771, 770t pretransplant, 770, 770t recipient immunosuppressive therapy in, dermatologic consequences of, 439–440 selection of, 1770–1777, 1771t results, 1792–1793 and retransplantation, 1792–1793 in sarcoidosis, 1142

single-lung, 1781–1782, 1782f, 1783f survival after, 1792 techniques, 1780–1784 ventilation after, 1784 Lung transplant recipient(s), pneumonia in, 2024 Lung volume(s), 148–149, 568–575, 568t abbreviations for, 1326, 2738 age-related changes in, 270–271, 271f in cystic fibrosis, 872 definition of, 1326, 2738 knowledge of, historical perspective on, 11 in neuromuscular disease, 1647 normal, 1323, 2735 postoperative changes in, 664 in pregnancy, 254, 254f and pulmonary vascular resistance, 1335 radiographic assessment of, 574–575 temperature correction factors, 574, 574t Lung volume reduction, VATS technique, 655 Lung volume reduction surgery, 655 in chronic obstructive pulmonary disease, 743–744, 744f physiologic effects of, 78 pulmonary rehabilitation and, 771 Lupus-like syndrome, drug-induced, 2010, 2012t Lupus pleuritis, 1200 Lupus pneumonitis, 2541t acute, 1199, 1199f Lupus vulgaris, 431 Lusk, Graham, 8 LVEDP. See Left ventricular end-diastolic pressure LVRS. See Lung volume reduction surgery Lymphadenitis, mycobacterial, 2460t, 2472 Lymphadenopathy cervical, upper airway obstruction caused by, 857 hilar in HIV-infected (AIDS) patients, 2214t, 2215, 2249t infectious causes, 2028 noninfectious causes, 2028 in interstitial lung disease, 1115t mediastinal causes of, 498 computed tomography of, 461, 461f infectious causes, 2028 noninfectious causes, 2028 radiographic features of, 495–498, 497f upper airway obstruction caused by, 856 with pneumonia, 1988t, 2019, 2020, 2028

Lymphangiography, dye for, pulmonary effects of, 1295 Lymphangioleiomyomatosis, 1145, 1255–1261 clinical presentation of, 1255–1256, 1256t computed tomography of, 1112, 1113f, 1115t diagnosis of, 1259 epidemiology of, 1255 exercise capacity in, 1258, 1259f lung transplantation in, 1774t, 1775–1777 pathogenesis of, 1257–1258 pathology of, 1256–1257, 1257f prognosis for, 1259–1260 pulmonary physiology in, 1258, 1258f radiographic findings in, 1258–1259, 1259f, 1260f survival with, 1259–1260, 1260f treatment of, 1260–1261 Lymphangiomyomatosis clinical features of, 1119t computed tomography of, 1115t, 1119t histology of, 1119t treatment of, 1119t Lymphangitic carcinomatosis bronchoscopy in, 1120t computed tomography of, 1115t and interstitial lung disease, 1397, 1398f radiographic features of, 483, 485, 490f Lymphatic circulation, pulmonary, 42–43, 2040–2041 Lymph node(s), 42–43, 43f intrapulmonary, 1948–1949, 1949f mediastinal, 1557, 1557f tumors of, 1601 pulmonary, 329, 1557, 1557f, 1947–1949 Lymphocyte(s), 42 activation of, 121–122 in airways, 280f in alveolar space, in host (immune) defense, 284–286, 284t, 285f memory, 1974 in pulmonary fibrosis, 374–376 Lymphocytic interstitial pneumonia, 1145, 2013, 2027 in collagen vascular disease, 1194t histopathology of, 1195, 1195f in HIV-infected (AIDS) patients, radiographic findings in, 2249t in Sj¨ogren’s syndrome, 1210, 1210f Lymphocytic interstitial pneumonitis, in HIV-infected (AIDS) patients, 2260, 2260f Lymphoepithelial-like carcinoma, 1840 Lymphoid aggregates in airways, 280f, 282 bronchial-associated, 281 Lymphoid enhancer factor 1, 86 Lymphoid granulomatosis, 433, 433f

I-68 Index Lymphoid interstitial pneumonia, 491f, 1106t, 1144, 1949, 1953–1954, 1953f, 2013, 2027 clinical features of, 1116t in collagen vascular disease, 1194t computed tomography of, 1115t, 1116t drug-induced, 1110t–1111t histology of, 1116t in HIV-infected (AIDS) patients, 1953–1954 treatment of, 1116t Lymphoid lesions, malignant, 1955–1962, 1956t Lymphoid processes, reactive, 1949–1955 diffuse, 1952–1955 localized, 1950–1952 Lymphoma(s) angioimmunoblastic T-cell, 1962 body cavity, in HIV-infected (AIDS) patients, 2259 bronchoalveolar lavage cellular profile in, 1121t computed tomography of, 1115t cytopathology of, 531 diffuse large B-cell, 1957–1958, 1958f diffuse large cell, 1959 extranodal marginal zone B-cell, of MALT type, 1955–1957, 1957f follicle center cell, 1957–1958 in HIV-infected (AIDS) patients, 2213 radiographic findings in, 2214t and infection, 2215–2216 large B-cell, 1923–1924 intravascular, 1960, 1960f lymphadenopathy in, 2028 lymphocytic, 1602 mantle cell, 1957–1958 mediastinal, 1602 pleural, 1964–1965 and pleural effusion, 1505, 1506t presenting as solitary pulmonary nodule, 1816 primary effusion, in HIV-infected (AIDS) patients, 2259 primary pulmonary, 1923–1924 NK/T cell, 1923–1924 pyothorax-associated, 1965, 1965f radiographic features of, 497f, 498 sarcoidosis and, 1136t secondary pulmonary involvement in, 1961–1962 small lymphocytic, 1949 Lymphomatoid granulomatosis, 1923, 1958–1960, 1959f, 1960t Lymphomatosis, intravascular, 1960, 1960f Lymphoproliferative disorders clonality in, 1949 computed tomography of, 1115t histopathology of, 1949 immunophenotyping of, 1949 Lymphotactin, 340t

Lymphotoxin, 1973, 1977 Lysophosphatidic acid, and airway smooth muscle proliferation, in vitro, 118 Lysophospholipase, 310t, 314 Lysosomal hydrolase, and airway smooth muscle proliferation, in vitro, 118 Lysozyme, 1970, 1973 in airway surface liquid, 281 in asthma, 782 in nasal secretions, 281 M MAC. See Mycobacterium avium complex Mace, inhalation injury caused by, 1003–1004 Machine operator’s lung, etiology of, 1165t Macintosh, Robert, 2646 Macintosh blade, 2653–2654, 2654f Macleod’s syndrome, 474 MacLeod syndrome. See Swyer-James syndrome Macroaspiration, 1299 α 2 -Macroglobulin, 1970 in lung parenchyma, 721t Macrolides in asthma treatment, 831 characteristics of, 2055 for cystic fibrosis patient, 875 indications for, 2060, 2157 interactions with immunosuppressive agents, 2503t mechanism of action of, 2055 organisms susceptible to, 2055 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 resistance to, 2055, 2099, 2131 Macrophage(s) airway, 43 in airways, 280f alveolar, 33t, 40f, 41, 43–44, 43f, 47f, 280, 282, 283, 515–516 in asthma, 777 in immune defense, 1971–1973, 1971f, 2042 immune effector role of, 283 phagocytosis of pathogens, 2080 secretory products of, 1971, 1972t, 2042 in asthma, 777 immune effector role of, 283 interstitial, 41–42, 43 of alveolar septum, 40f, 41 intravascular, 43 pink-tailed, 516, 517f in pulmonary fibrosis, 375–376 Macrophage colony-stimulating factor (M-CSF) effects/functions of, 781t

sources of, 781t targets of, 781t therapy with, for Pneumocystis pneumonia, 2370 Macrophage inflammatory protein (MIP) MIP-2, 1976 MIP-1α, 315, 340t, 372 in allergic bronchopulmonary aspergillosis, 2296 in chronic obstructive pulmonary disease, 715 MIP-3α, 340t MIP-1β, 340t MIP-3β, 340t MIP-1δ, 340t Macrophage inhibitory protein (MIP) MIP-2, 1973, 1976 MIP-1α, 1973 MIP-3α, 1975 MIP-1β, 1973 Macrophage mannose receptor, 1970 Macrophage scavenger receptor, 1970 Magill, Ivan, 2646 Magill forceps, 2653, 2654f Magnesium sulfate for asthma, 2637 inhaled, 2637 intravenous, 2637 mechanism of action of, 2637 Magnetic resonance imaging (MRI), 420–421, 463–465, 464f, 465f, 500f, 2018 of chest wall, 502 of diaphragm, 503 gadolinium-enhanced, 464, 465, 466 in Langerhans’ cell histiocytosis, 1247 of mediastinal masses, 1588–1589, 1589f in Pneumocystis pneumonia, 2360–2361 of pulmonary embolism, 1436 time-of-flight, 464f, 465, 465f of upper airway obstruction, 851–852 Magnus, Heinrich Gustav, 5t Magnus-Levy, 8 Maintenance of Wakefulness Test, 1729–1730 Major basic protein, in asthma, 782 Major basic protein (MBP), 310t, 314, 316 Major histocompatibility complex (MHC), 323, 1974–1975 Major surface glycoprotein, Pneumocystis, 2353–2354 Malaria, 2405–2407 chloroquine-resistant, 2407 clinical presentation of, 2405 diagnosis of, 2406–2407 epidemiology of, 2405 pathogenesis of, 2405 pulmonary features of, 2405–2406 in splenectomized patient, 2219 treatment of, 2407 Malic acid, and occupational asthma, 989

I-69 Index Malignancy computed tomography of, 1115t cutaneous, in lung transplant recipient, 439–440 hemoptysis in, 413 history-taking in, 388 ICU patient with outcomes with, 2715 prognosis for, 2715 in IgA deficiency, 332 non-bronchogenic, 1917, 1919t, 1920–1926 occupational exposure and, 934, 934t pleural effusion caused by. See Pleural effusion, malignant pulmonary Langerhans’ cell histiocytosis and, 1245 sarcoidosis and, 1135, 1136t smoking and, 750t, 751 Malignant mesothelioma. See Mesothelioma Malingering, identification of, 680 Mallampati Scale, 2648, 2648t Malnutrition, 2691–2692 in chronic obstructive pulmonary disease, 731, 2605 complications of, 2692 and critical illness, 2692–2693 effects of, 2692–2693 incidence of in advanced lung disease, 2692 in ICU, 2691–2692 pathophysiology of, 2692 and postoperative pulmonary complications, 669 in respiratory failure, 2518t, 2519 Malpighi, Marcello, 5t, 6 MALT. See Mucosa-associated lymphoid tissue Malt worker’s lung, etiology of, 1163t Mannan-binding lectin, 1970 Mannitol, Aspergillus, 2294 Mantoux test, 2135 Manually assisted coughing, 1672 MAPKp38, in G protein–coupled chemoattractant receptor signaling, 353, 353f Maple bark disease, etiology of, 1163t Maple bark stripper’s lung, 2012 Maple syrup urine disease, 1276 ´ Marey, Etienne Jules, 5t, 16 Marfan’s syndrome and bullous emphysema, 917 sarcoidosis and, 1136t Maroteaux-Lamy syndrome, 1275 Mash1, 87 Mass(es), in HIV-infected (AIDS) patients, 2249t Masson bodies, 888, 891 Mast cell(s), 42, 42f, 280f, 307–313 activation, 309 modulators of, 309

of alveolar septum, 40f, 41 anatomic localization of, 308 in asthma, 312–313, 775, 782 and basophils, differences, 307–308 degranulation, morphology of, 308–309 discovery of, 307 and eosinophils, interactions of, 316 in fibrosis, 313 function, 307 pharmacologic modulation of, 312 granule proteins, in asthma, 782 granules, 42, 42f, 308–309, 309f heterogeneity of, 308 human lung, 308 activation, biochemical analysis of, 309–310 mediators, 310–312, 310t chemotactic, 311 in early-phase response, 310, 311f in late-phase response, 310, 311f nonpreformed, 310t, 311–312 preformed, 310–311, 310t morphology of, 308–309, 309f origins of, 308 protease-expressing, 308 in pulmonary disease, 312–313 in pulmonary fibrosis, 376 regranulation, morphology of, 308–309 tryptase-expressing, 308 Mast cell stabilizer(s), 2639–2640. See also Cromolyn sodium; Nedocromil Master Settlement Agreement, 749 Mastoiditis acute, 2094 in Wiskott-Aldrich syndrome, 2237 Matas, Rudolph, 2646 Material safety data sheets, 678, 940–941, 986 Matrix metalloproteinase (MMP) in ECM remodeling, 380–381 in emphysema, 720 membrane-type, in emphysema, 720 MMP-1, 719 in emphysema, 720 MMP-2, in emphysema, 720 MMP-8, in chronic obstructive pulmonary disease, 720 MMP-9, 718t in chronic obstructive pulmonary disease, 720 eosinophil, 314 MMP-12, 718t in chronic obstructive pulmonary disease, 720 MMP-14, in emphysema, 720 Maximal static recoil pressure, 575, 577, 578t Maximum expiratory flow rate. See Forced expiratory flow, between 200 and 1200 ml of forced vital capacity (FEF200−1200 )

Maximum expiratory pressure, 578–579, 579f, 579t, 1643–1644, 1643t, 1644f, 2673 definition of, 1327, 2739 normal, 1323, 2735 reduced, conditions associated with, 603–604, 604t Maximum inspiratory pressure, 578–579, 579f, 579t, 1643–1644, 1643t, 1644f definition of, 1327, 2739 normal, 1323, 2735 reduced, conditions associated with, 603–604, 604t Maximum insufflation capacity, 1670 Maximum mouth pressures, 1643–1644, 1643t, 1644f Maximum oxygen uptake, in AMA Guides classification of impairment, 682t Maximum static expiratory pressure, 2609 Maximum static inspiratory pressure, in ventilatory pump dysfunction, 2609 Maximum voluntary ventilation, 579, 583, 583f, 615 definition of, 1327, 2739 in diagnostic spirometry, minimal recommendations for, 570t and dyspnea, 395–396 in neuromuscular disease, 1647 normal, 1323, 2735 preoperative, and risk of complications, 671 in upper airway obstruction, 846–849 Mayow, John, 5t, 7, 8, 11, 11f MBC, 2052 MBL. See Mannan-binding lectin MC. See Mast cell(s) MCP-1, expression of, by airway smooth muscle cells, 121, 122t MCP-1-4, 1973 MCP-2, expression of, by airway smooth muscle cells, 121, 122t MCP-3, expression of, by airway smooth muscle cells, 121, 122t MCT . See Mast cell(s), tryptase-expressing MCTC . See Mast cell(s), protease-expressing MDC, 340t MDI. See Metered-dose inhaler Mean airway pressure, 2670 Mean arterial pressure, 2660–2661 normal, 1334t Mean linear intercept, 264 Measles virus assays for, 1989t characteristics of, 2375t and croup, 2376t, 2379 and diffuse alveolar damage, 2042

I-70 Index Measles virus (Cont.) infection (incl. pneumonia) in adults, 2389 in children, 2135, 2391 immune defects and, 2139 in DiGeorge’s syndrome, 2236 in immunocompromised host, 2392–2393 prevention of, 2395 in severe combined immunodeficiency, 2236 treatment of, 2395 pneumonia caused by, 2022 staining characteristics of, 2035t transmission of, 2374 vaccine against, 2070t, 2072 Mebendazole for ascariasis, 2418, 2418t for echinococcosis, 2418t for hookworms, 2418, 2418t Mechanically assisted coughing, 1672 Mechanical ventilation. See also Ventilator(s) for acute exacerbations of chronic obstructive pulmonary disease, 741–742, 2119f, 2122, 2122t for acute respiratory distress syndrome, in trauma patient, 1765 aerosolized antibiotic therapy with, dosage and administration of, 2059 in ALI/ARDS acute respiratory acidosis in, contraindications to, 2549, 2551t higher PEEP in, 2547–2548 high-frequency oscillatory ventilation mode, 2551–2552 low vs. traditional tidal volumes in, 2546–2547, 2548t, 2550f, 2551f lung-protective ventilator strategy, 2530, 2531t, 2532, 2546–2549, 2547f adjuncts to, 2552–2558 modes that permit spontaneous breathing, 2551 permissive hypercapnia in, 2552 contraindications to, 2549, 2551t pressure control mode, 2549–2551, 2552f recommended core ventilator management in, 2548–2549 assist-control, 2676–2677 and bronchodilator therapy, 2684–2685 in chronic obstructive pulmonary disease, chronic, 745 complications of, 2685 controlled, 2676 and dyspnea, 403 historical perspective on, 2675 in hypercapnic respiratory failure, 2611 indications for, 2676

intermittent mandatory ventilation, 2677–2678, 2678f low stretch, 2517–2519 lung-protective ventilator strategy, for ALI/ARDS, 2530, 2531t, 2532, 2546–2549, 2547f adjuncts to, 2552–2558 modes of, 2676–2679 definition of, 2676 new, 2679 monitoring during, 2685 in neuromuscular disorders, 1660–1662, 1660t, 1661t and nosocomial pneumonia, 2275–2277, 2276t, 2278–2279 objectives of, 2675, 2676t pneumomediastinum associated with, 1559–1560 pressure-controlled, 2676 pressure-support, 2677f, 2678–2679, 2678f and pulmonary hemodynamics, 1338–1339 in respiratory failure, 2517–2519 device-related complications of, 2518t, 2519 ventilator settings in, 2679–2684 volume-controlled, 2676 weaning from, 2514, 2686–2689 definition of, 2686 and extubation, 2689 failure, causes of, 2686–2687, 2686f, 2687f timing of, 2687–2688 trial of, 2688–2689 Mechanoreceptor(s), 161, 162f knowledge of, historical perspective on, 13 pulmonary, 164–165, 164f Meclofenamate, and aspirin-induced asthma, 802t Meconium ileus, 866 clinical presentation of, by age group, 866, 867t complications of, by age group, 866, 867t Meconium ileus equivalent, 868, 869f Mediastinal adenitis, in histoplasmosis, 2335 treatment of, 2339, 2339t Mediastinal hemorrhage, spontaneous, 1567 Mediastinal mass(es) biochemical markers of, 1590 biopsy of, 1590–1591 computed tomography of, 1588, 1588f diagnosis of, noninvasive procedures, 1588–1590 esophageal lesions mimicking, 1596 evaluation of, radionuclides for, 1589–1590, 1590t investigation of, 1587–1591

magnetic resonance imaging of, 1588–1589, 1589f pulmonary lesions mimicking, 1596–1597 subdiaphragmatic lesions mimicking, 1597 ultrasound of, 1589 upper airway obstruction caused by, 856 VATS procedures for, 658, 658f Mediastinitis acute, 1560–1563, 2161–2169 antibiotic treatment of, 2164t, 2168–2169 causes of, 1560, 1561t, 2161–2162, 2163t clinical presentation of, 2164t, 2166–2168 complications of, 2169 epidemiology of, 2161–2165 esophageal perforation and, 1560–1561, 1561f head and neck infections and, 2163t, 2164t, 2165, 2166t infections and, 2163t, 2164t, 2165, 2166t laboratory findings in, 2164t, 2166–2168 microbiology of, 2164t, 2165–2166, 2166t nuclear scintigraphy in, 2168 pathogenesis of, 2161–2165, 2164t polymicrobial, 2166t prevention of, 2169 prognosis for, 2169 radiologic diagnosis of, 2164t, 2167, 2167f, 2168f risk factors for, 2164t, 2165t secondary esophageal perforation, 1591–1592, 1592f, 2163t, 2164t, 2165, 2166t, 2167, 2167f secondary to cardiothoracic surgery, 1591, 2162–2163, 2163t, 2164t, 2165t, 2166t, 2167, 2168f surgical treatment of, 2164t, 2168–2169 tracheobronchial perforation and, 1561–1562 anatomical considerations in, 2161 anthrax, 1563, 2436–2437 causes of, 2161 chronic, 1563–1566, 1594, 2161, 2169–2171 clinical presentation of, 2170, 2170t fibrosing, 1594–1595, 1594f laboratory diagnosis of, 2170–2171, 2170t microbiology of, 1594, 2169–2171, 2170t pathogenesis of, 2169, 2170t radiologic diagnosis of, 2170, 2170t surgical treatment of, 2170t, 2171

I-71 Index descending necrotizing, 1562, 1592, 1593f from direct extension, 1562 fibrosing, 856, 1564–1566, 1565f–1566f, 1594–1595, 1594f, 2161, 2169 granulomatous, 1563, 2169 in histoplasmosis, 1594, 2335, 2336f poststernotomy, 1562–1563, 1591 sclerosing, 2161, 2169 subacute, 1594 Mediastinoscopy, 657 in staging of NSCLC, 1853–1854, 1853f, 1854f Mediastinum acquired lesions of, 1583–1584 epidemiology of, 1586 histopathology of, 1586, 1587t historical perspective on, 1584–1585 incidence of, 1586 location of, in adults vs. children, 1586 signs and symptoms of, 1586–1587, 1587t anatomy of, 1555–1557, 1583–1584, 1584f, 2161, 2162f anterior compartment of abnormalities of, 495–498 anatomy of, 495, 495f lesions in, 1585, 1585t, 1586f neoplasms in, 1597–1608 nonseminomatous tumors of, 1606t, 1607–1608 structures in, 1585, 1585t VATS procedures in, 657–658, 657f boundaries of, 1555, 1556f compartments of, 494–495, 495f, 1555–1557, 1556f, 1556t, 1583–1584, 1584f, 1585–1586 congenital cysts in, 1571–1572 lesions in, 1585–1586, 1585t structures in, 1585–1586, 1585t disorders of, computed tomography of, 461, 461f esophageal lesions and, 1596 lymphatics of, 1557, 1557f tumors of, 1601 middle compartment of abnormalities of, 497f, 498–499, 498f–501f anatomy of, 495, 495f lesions in, 1585, 1585t, 1586f masses in, 1608–1609 posterior compartment of abnormalities of, 499–500, 502f–503f anatomy of, 495, 495f lesions in, 1585–1586, 1585t, 1586f masses in, 1609–1611 neurogenic tumors in, 1609–1610 tumors of nerve sheath origin in, 1610–1611 VATS procedures in, 658, 658f radiography of, 494–500 repositioning, in postpneumonectomy syndrome, 1567, 1568f

skeletal lesions in, 1596 tumors of endocrine, 1611 lesions mimicking, 1595–1597 vascular lesions in, 1596 VATS procedures in, 657–658, 657f, 658f Medical need, distribution of resources according to, 2718 Medical Research Council Breathlessness/Dyspnea Scale, 679, 679t, 732, 733t Medication history, 389 Medroxyprogesterone, as respiratory stimulant, 2643–2644 Mefenamic acid, and aspirin-induced asthma, 802t Mefloquine, 2407 Melanoma metastases, survival rates for, 1941, 1942t primary pulmonary, 1925 pulmonary metastases, 1943 Melanoptysis, 971 Melatonin, therapy with, for sarcoidosis, 1140 Melioidosis, 2428t clinical features of, 2440 diagnosis of, 2429t, 2440 differential diagnosis of, 2440 epidemiology of, 1984t, 2428t, 2439 pathogenesis of, 2439 pathophysiology of, 2439–2440 radiologic features of, 2440 treatment of, 2429t, 2440 Melkersson-Rosenthal syndrome, sarcoidosis and, 1136t Meloxicam, dose-related airway response to, in aspirin-sensitive asthmatics, 802 Melphalan, pulmonary effects of, 1073, 1074t, 1075–1076 Membrane conductance, 58–59, 58f Membranoproliferative glomerulonephritis, sarcoidosis and, 1136t Mendelson’s syndrome, 2150, 2198 Meningitis in anthrax, 2436–2437 tuberculous, 2474 Meningocele, anterior, 1596 Meningococcal vaccine, 2111, 2444 Meningococcus. See Neisseria meningitidis Meningoencephalitis, amebic, in cancer patients, 2219 Meniscal opacity, 2028 Menstruation, hemoptysis associated with, 414 Meperidine, for agitated ICU patient, 2708, 2709t 6-Mercaptopurine, immunologic effects of, 2216

Mercury, inhalation injury caused by, 1000t, 1003 Meropenem for cystic fibrosis patient, 875 for hospital-acquired pneumonia, 2061, 2061t, 2062 indications for, 2157 for melioidosis, 2440 pharmacology of, 2056 MESA. See Microsurgical epididymal sperm aspiration Mesenchymal tumors, 1611 Mesothelin, 1544 Mesothelioma, 934, 934t, 1535–1546 asbestos exposure and, 1029, 1029t, 1536 CALBG prognostic index for, 1546 chemotherapy for, 1546–1547 clinical course of, 1545 clinical features of, 954, 1542 complications of, 1545 computed tomography of, 462f diagnosis of, 954, 1544 differential diagnosis of, 1544 electron microscopy of, 1541–1542, 1541f EORTC prognostic index for, 1546 epidemiology of, 944, 953, 1536 erionite-induced, 1537 etiology of, 1536–1537 extrapleural pneumonectomy for, 1548 FDG-PET of, 563–564, 564f gene therapy for, 1549–1550 genetics of, 1537 histological patterns of, 952 histopathology of, 1537–1540, 1538f, 1539f immunohistochemistry of, 1540–1541, 1541f immunotherapy for, 1549 incidence of, 953 laboratory findings with, 1543–1544 molecular pathogenesis of, 1536–1537 molecular profiling of, 1542 mortality rate for, 1545 nonpleural forms of, treatment of, 1548–1549 paraneoplastic syndromes with, 1545 pathogenesis of, 953–954 pathology of, 952–953 gross, 1537, 1538f pleural, 506, 506f, 507 and pleural effusion, 1505–1506, 1507, 1508f pleurectomy for, 1548 pleurodesis for, 1547–1548 positron emission tomography of, 1543 prognosis for, 954–955, 1546 radiation therapy for, 1547 radiographic features of, 954, 954f, 1542–1543, 1542f radiologic findings in, 563

I-72 Index Mesothelioma (Cont.) serum markers of, 1544 staging of, 1544, 1545t surgery for, 1547–1548 survival with, 953 targeted therapy for, 1549 treatment of, 954–955, 1546–1548 new approaches for, 1549–1550 ultrastructure of, 953 viral oncogenes in, 1537 Mesothelium, 24 Metabolic acidosis, 207, 208t approach to patient with, 215–217 case example, 219–220 causes of, 216t clinical assessment of, 217 compensatory response in, 208t pathogenesis of, 215–216 respiratory response to, 212–213 ventilatory adaptations to, 167 Metabolic alkalosis, 207, 208t case example, 220 causes of, 217, 217t compensatory response in, 208t generation of, 217–218 maintenance phase of, 218 posthypercapneic, 217, 218–219 respiratory response to, 213 Metabolic disturbances in critical illness, 2692–2693 dyspnea in, 403 hypercapnia in, 2514 ventilatory adaptations to, 167 Metabolism, knowledge of, historical perspective on, 5t, 7–8 Metachromatic leukodystrophy, 1272–1273 Metal(s) inhalation injury caused by, clinical manifestations of acute, 1000t chronic, 1000t lung disease caused by, 934, 934t Metal fume fever, 1005 occupational, 934t Metal salts, and occupational asthma, 990 Metapneumovirus. See Human metapneumovirus Metaproterenol adverse effects and side effects of, 824t for asthma, 823t, 824t for chronic obstructive pulmonary disease, 738t dosage and administration of, 824t dosage forms, 2632t receptor activity, 2632t Metastatic disease computed tomography of, 1115t cytopathology of, 531 hemoptysis in, 413

lymphadenopathy in, 2028 miliary nodules in, 2025 nodules in, 492f presenting as solitary pulmonary nodule, 1816–1817 pulmonary, 1941–1945 disease-free interval and, 1942–1943 histopathology of, 1942–1943 historical perspective on, 1941–1942 isolated lung perfusion for, 1944 mediastinal nodal involvement in evaluation of, 1944 and outcome, 1944 number of metastases and, 1942–1943 pathology of, 1941 prognosis for, 1941, 1942t surgical management of approach to resection, 1943–1944 extent of resection, 1943–1944 operability and, 1942 patient selection for, 1942 resectability and, 1942 survival rates for, by primary site, 1941, 1942t treatment of, 1941–1942 radiographic features of, 483, 485, 490f, 492f Metazoa, staining characteristics of, 2035t Metered dose inhaler, 2633–2634 for ventilated patient, 2685, 2686t drug delivery by, in chronic obstructive pulmonary disease, 738, 738t proper use of, 739 Methacholine inhalational challenge test, 585t, 586, 789–790, 818 in evaluation of permanent impairment in asthma, 683, 683t method for, 586–587, 586t, 587f Methadone pneumonitis caused by, 2012t properties of, 2709t pulmonary effects of, 1088 Methemoglobinemia, 415–416, 2617 clinical manifestations of, 416 Methemoglobin generators, for cyanide poisoning, 1057 Methicillin-resistant Staphylococcus aureus, 2009, 2024f, 2081, 2110, 2270, 2282 in acute mediastinitis, 2166 infection (incl. pneumonia), 2098 in children, 2132 in HIV-infected (AIDS) patients, 2251, 2252 neonatal nosocomial, 2126 in neutropenic host and cancer patient, 2217 nosocomial, 2196 treatment of, 2285–2288, 2287t pathology of, 2044f

post-influenza, 2060 in surgery and trauma patients, 2197 treatment of, 2058, 2061t, 2062, 2112, 2131 Methotrexate, 2639 for asthma treatment, 831–832 immunologic effects of, 2216 and interstitial lung disease, 1110t, 1206 and pleural effusion, 1506t pneumonitis caused by, 1206, 2012, 2012t pulmonary effects of, 389, 440, 1076–1077, 1076t, 1077t, 1090t, 1091t, 1093, 1097–1098, 1206, 1295 for sarcoidosis, 1140t, 1141 for scleroderma, 430 Methyl-CCNU. See Semustine Methyldopa, pulmonary effects of, 1090t Methylene blue, therapy with, for methemoglobinemia, 416 Methylene chloride exposure to, 1027t sources of, 1027t Methylnaltrexone, 2708 Methylprednisolone adverse effects and side effects of, 827t for asthma, 823t, 827t, 2638 dosage and administration of, 827t Methyl sulfate, bronchiolitis caused by, 893t Methylxanthines, 2636–2637. See also Aminophylline; Theophylline adverse effects and side effects of, 828t, 2637 for asthma, 823t, 828t clinical use of, 2636–2637 mechanism of action of, 828t pharmacology of, 2636 as respiratory stimulants, 2643 safety of, 2637 structure-activity relationships, 2636 Metriphonate, indications for, 2418t Metronidazole for cryptosporidiosis, 2404 indications for, 2400–2401 MIC, 2052, 2054 Mica, bronchiolitis caused by, 893t Micafungin, for invasive fungal infections, 2310t Michaelis-Guttmann bodies, 2048f, 2049 Microabscess, eosinophilic, in allergic bronchopulmonary aspergillosis, 842 Microaspiration, 1299 Microbiologic testing, in HIV-infected (AIDS) patients, 2250 Microbiology, historical perspective on, 5t, 14–16 Microcirculation, in SIRS/MODS, 2567

I-73 Index Microfilaria, infestation, cytopathology of, 524 Micropolyspora faeni, 2012 antibody, prevalence of, 1166 hypersensitivity pneumonitis caused by, 1163t, 1164t Microscope(s), historical perspective on, 6 Microscopic polyangiitis, 1281–1282 alveolar hemorrhage in, 1241 clinical features of, 1118t, 1456–1457 computed tomography of, 1118t definition of, 1289 diagnosis of, 1456–1457 histology of, 1118t organ systems affected by, 1452t pathology of, 1285t, 1286f, 1290 serology of, 1285t, 1290 treatment of, 1118t, 1290, 1459–1461 Microscopic polyarteritis. See Microscopic polyangiitis Microsporidia. See Microsporidiosis Microsporidiosis in cancer patients, 2219 diagnosis of, 2410 in HIV-infected (AIDS) patients, 2212t, 2248, 2258, 2410 in immunocompromised host, 2208 pulmonary involvement in, 2410, 2410f treatment of, 2410 Microsporidium. See Microsporidiosis Microsurgical epididymal sperm aspiration, 882–883 Microvilli, 24, 28f of type II alveolar epithelial cells, 36, 36f Microwave popcorn, volatile flavoring agents, and bronchiolitis, 896, 935t Midazolam, for agitated ICU patient, 2703, 2704t Middle lobe syndrome, and bronchiectasis, 2186 Miescher-Ruesch, 12 MIG. See Monokine induced by interferon-γ MIGET. See Multiple inert gas elimination technique Miliary lesion(s), 1987f, 1988t, 1991, 1997, 2024, 2025, 2026f, 2034, 2034f Miller, Robert, 2646 Miller blade, 2653–2654, 2654f Miller’s lung, etiology of, 1164t Miltefosine, for leishmaniasis, 2409 Mimivirus, infection (incl. pneumonia), 2114 Mineral dusts bronchiolitis caused by, 893t, 895–896 lung disease caused by, 934, 934t Mineral fibers, man-made, health risks with, 1030 Mineral oil pneumonia, 1110t–1111t Minocycline and interstitial lung disease, 1110t

for nontuberculous mycobacteria, 2505 pneumonitis caused by, 2012t pulmonary effects of, 1089, 1090t, 1091t, 1092, 1093, 1242 for sarcoidosis, 1140, 1140t and vasculitis, 1464 Minute ventilation, 211, 591, 612 age-related changes in, 268 and dyspnea, 395, 396 in exercise, 612–613, 613f monitoring, in cardiopulmonary exercise testing, 611 normal, 403, 1323, 2735 in pregnancy, 255, 255f Mist(s), 1053 Mitochondria dysfunction, in SIRS/MODS, 2568 in muscle fibers, 72 partial pressure of oxygen in, and generation of ATP, 2614 Mitochondrial myopathy, respiratory abnormalities in, 1659 Mitogen-activated protein kinase(s) (MAPK), 361–362, 716, 716f Mitomycin-C and interstitial lung disease, 1110t and pleural effusion, 1506t pulmonary effects of, 1070t, 1071–1073, 1181 radiation therapy and, 1181 Mitral valve disease, cardiopulmonary exercise testing in, 621–622, 621f, 622f stenosis hemoptysis in, 410, 414 pulmonary venous hypertension in, radiographic evaluation of, 471, 474f Mixed connective tissue disease (MCTD).

See also Collagen vascular disease alveolar hemorrhage in, 1241, 1293 aspiration pneumonia in, 1209–1210 interstitial lung disease in, 1210 pleural disease in, 1209 pulmonary complications of, 1194t, 1209–1210 pulmonary involvement in, 1193 pulmonary vascular disease in, 1209 respiratory muscle dysfunction in, 1210 sarcoidosis and, 1136t Mixed venous blood, blood-gas values, changes, in response to ventilation-perfusion inequality, 182f, 184–185, 185t Mixed venous oxygen saturation, in acute respiratory failure, 2662–2663 MK-886, 312 mKatG, and sarcoidosis, 1127 MMR. See Macrophage mannose receptor Mobilization, postoperative, early, 673t, 674

MODS. See Multiple organ dysfunction syndrome Mold(s) chronic exposure to, 1010 environmental, and diffuse alveolar hemorrhage, 1295 in indoor air, 1030 health effects of, 1031 opportunistic infections, 2291–2324, 2321–2324. See also Aspergillosis; Candidiasis; Fusariosis; Mucormycosis; Scedosporiosis; Zygomycosis differential diagnosis of, 2323t and risk of asthma, 794, 839 toxic, 1030 Mold inhalational challenge test, 585t Molecular diagnostic testing, 2002 Mometasone furoate adverse effects and side effects of, 826t for asthma, 823t, 826t, 2638 dosage and administration of, 826t, 2638 pharmacology of, 2637 Monaldi procedure, 928 Monday morning fever, 981 Monge’s disease, 229 Monoamine oxidase (MAO), 2633 Monobactams penetration into lung, 2053, 2053t pharmacology of, 2056 Monoclonal antibody(ies) (MAb) anti-IgE, for asthma, 823t, 829t, 830, 2641. See also Omalizumab anti-IL-5, 317, 318 Monocyte chemoattractant protein(s) MCP-1, 340t, 372, 1976 in allergic bronchopulmonary aspergillosis, 2296 in chronic obstructive pulmonary disease, 715 MCP-2, 340t MCP-3, 315, 340t MCP-4, 340t Monod’s sign, 2302, 2302f Monokine induced by interferon-γ , 340t, 341t Monokines, 2042 Mononucleosis, 2378 Monosodium glutamate, sensitivity to, in aspirin-sensitive asthmatics, 802 Montelukast adverse effects and side effects of, 828t for asthma, 823t, 828t clinical use of, 2640 contraindications to, 2640 dosage and administration of, 828t safety of, 2640 Moraxella infection (incl. pneumonia), and bronchiectasis, 2186 staining characteristics of, 2442, 2442f

I-74 Index Moraxella catarrhalis, 2007, 2428t, 2441, 2444–2445 in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t in acute otitis media, 2092 acute sinusitis caused by, 2089 bacteriology of, 2428t, 2444 colonization by, in children, 2136 culture of, 2444 infection (incl. pneumonia), 2428t clinical features of, 2444–2445 diagnosis of, 2445, 2445t differential diagnosis of, 2266, 2445 epidemiology of, 2428t, 2444 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2106t pathogenesis of, 2444 pathophysiology of, 2444 radiologic features of, 2444–2445 treatment of, 2055, 2056, 2057, 2131, 2445 in laryngitis, 2087 pneumonia, 2005, 2020 diagnosis of, 1998 in elderly, 2007 nosocomial, 2008 staining characteristics of, 2444 Morgagni, Giovanni Battista, 5t, 13, 14, 15f, 694 Morgan-Murray diagram, 224–225, 225f–226f Morphine, for agitated ICU patient, 2707–2708, 2709t Morquio’s syndrome, 1275 Mortality prediction, 2716–2718 Mortality prediction model, 2718 Motor neuron disease(s). See also Lower motor neuron disease; Upper motor neuron disease ventilatory impairment in, 1668t Motor unit(s) fast-fatiguable, 72 fast-fatigue resistant, 72 in respiratory muscles, 72 slow, 72 Mounier-Kuhn syndrome, 856, 2138 differential diagnosis of, 701t, 702 Mountain sickness acute, 1040–1041 chronic, 1042–1043 Mouse, lung development in, 81, 82f stages of, 82, 82f Mouse allergens, exposure to, 1031 Mouth, in host (immune) defense, 281 Mouth opening ability, clinical significance of, 2647 Moxifloxacin, 2056–2057, 2060 anti-TB activity, 2464

dosage and administration of, 2057 for hospital-acquired pneumonia, 2061t, 2062 for pasteurellosis, 2430 for tuberculosis in children, 2482t dosage and administration of, 2482t MPC. See Mutant prevention concentration MPIF-1, 340t MPIF-2, 340t MPM. See Mortality prediction model MPO. See Myeloperoxidase M protein, 2080 MRSA. See Methicillin-resistant Staphylococcus aureus MSG. See Major surface glycoprotein MSLT. See Multiple sleep latency testing mSpry2, 85 mSpry4, 85 MSR. See Macrophage scavenger receptor MSUD. See Maple syrup urine disease 99m Tc HAM. See Technetium-99m-labeled human albumin microspheres 99m Tc MAA. See Technetium-99m-labeled macroaggregated albumin Mucicarmine, 2035t, 2037–2038, 2041f Mucin(s), respiratory, pathogen binding to, 2080 Mucin stains, 2035t, 2037–2038, 2041f Mucociliary clearance, 143, 280, 281 in cystic fibrosis, 2174–2175, 2174f evaluation of, scintigraphy in, 559 factors affecting, 559 in normal airway, 2174–2175, 2174f postoperative changes in, 665 Mucociliary escalator, 27–29, 1969–1970, 2040 defects in, 2138 Mucocutaneous candidiasis, in purine nucleoside phosphatase deficiency, 2237 Mucoepidermoid carcinoma, 1845–1846, 1847f, 1925 Mucokinetic agents, 2641–2642 Mucolytics for acute exacerbations of chronic obstructive pulmonary disease, 2121–2122 for chronic obstructive pulmonary disease, 740 for cystic fibrosis patient, 876 Mucopolysaccharidosis (MPS) biochemical features of, 1275 definition of, 1275 diagnosis of, 1275 genetics of, 1275 pathology of, 1275 Mucor, 2316t, 2317

hypersensitivity pneumonitis caused by, 1163t infection (incl. pneumonia). See also Mucormycosis hemoptysis in, 413 in neutropenic host and cancer patient, 2217 pathology of, 2050 in invasive fungal sinusitis, 2091 staining characteristics of, 2036f Mucoraceae, 2316, 2316t infection (incl. pneumonia). See also Mucormycosis cavitation in, 2146 in lung abscess, 2154t Mucorales, classification of, 2316t Mucormycosis, 1995. See also Mucor; Mucoraceae diagnosis of, sputum culture for, 2000 pulmonary, 2316–2321 rhinocerebral, 2091 Mucosa, tracheobronchial, bronchoscopic assessment of, 632–634, 633f Mucosa-associated lymphoid tissue (MALT), 282, 326–327, 1923, 1948 Mucosal addressin cell adhesion molecule, MadCAM-1, in inflammation, 783 Mucositis, in bone marrow and stem cell transplant recipients, 2222 Mucous glands, 27f, 28f, 29 adenoma, 1917 hyperplasia of, 730 Mucous ball(s), 860 Mucous plug, in allergic bronchopulmonary aspergillosis, 842 Mucus, 27–29, 28f, 280f in cystic fibrosis, 2175 hypersecretion of, in chronic obstructive pulmonary disease, 717 Multidrug resistance, 2280–2282 emergence of, 2009, 2010t in plague, 2432 and pneumonia, 2008, 2009, 2196, 2273–2274 risk factors for, 2062 in surgery and trauma patients, 2197 treatment of, 2062 prevalence of, 2099 Multinucleated giant cell(s), 516, 516f in berylliosis, 517, 517f Multiple chemical sensitivity, 1010 Multiple inert gas elimination technique, 713, 713f Multiple myeloma (MM), 1962, 1962f infection in, 2216, 2306

I-75 Index Multiple organ dysfunction syndrome (MODS), 2196. See also Sepsis; Systemic inflammatory response syndrome (SIRS) clinical patterns of, 2562f, 2564–2565 definition of, 2563 diagnostic criteria for, 2562t epidemiology of, 2565 general criteria for, 2563–2564, 2564t historical perspective on, 2561 inotrope therapy in, 2568–2569 management of, 2568–2570 source control in, 2568 metabolic management in, 2570 in miliary tuberculosis, 2475 mortality rate for, 2565 pathogenesis of, 2561–2562, 2562f pathophysiology of, 2565–2566 perfusion management in, 2568 prognosis for, 2715 sepsis-induced, 449–450 underlying basis of, hypotheses of, 2566–2568 vasopressor therapy in, 2568–2569 Multiple sclerosis (MS), ventilatory impairment in, 1649–1651, 1650t, 1668t Multiple sleep latency testing (MSLT), 1729–1730 Multiple sulfate deficiency, 1272 Multivesicular bodies, 36, 37f, 38 Mumps, and bronchiolitis, 2382 Muscarinic receptors, 2635 Muscle fiber(s), 71–72 morphology of, 72 motor units, organization of, 72 type I (slow oxidative), 72 type II (fast-twitch), 72 type IIa (fatigable/glycolytic), 72 type IIa (fatigue-resistant/glycolytic oxidative), 72 Muscular dystrophy and respiratory failure, 2514 ventilatory impairment in, 1668t Musculoskeletal disorders, dyspnea in, 403 Mushroom spores, hypersensitivity pneumonitis caused by, 1163t Mushroom worker’s disease, etiology of, 1163t Mustard gas, bronchiolitis caused by, 894t Mutant prevention concentration, 2052 MVV. See Maximum voluntary ventilation MWT. See Maintenance of Wakefulness Test Myasthenia gravis (MG), 1584–1585, 1599–1600, 1601t and abnormal breathing pattern, 403 and postoperative pulmonary complications, 667 and respiratory failure, 2514 staging of, 1599, 1601t ventilatory impairment in, 1655–1656

Mycetoma, 2301 in sarcoidosis, 1141 as solitary pulmonary nodule, 1817 zygomycetes and, 2319 Mycobacteria, 1987 atypical, 1999 infection (incl. pneumonia) in chronic granulomatous disease, 2237 imaging of, 2021 lymphadenopathy in, 2028 pathology of, 2048–2049 staining characteristics of, 2035t, 2039 cell wall of, 2461 contamination of bronchoscope, 2279 culture of, 2462 in cutaneous disease, species causing, 2460t drug-resistant, 2451 testing for, 2463 drug susceptibility testing, 2463 immune response to, 2460–2461 infection (incl. pneumonia), 2020 in bone marrow and stem cell transplant recipients, 2223 and bronchiectasis, 2189, 2189t, 2190 in cell-mediated immunodeficiency, 2236 in children, immune defects and, 2139 in common variable immunodeficiency, 331–332, 2235 in cystic fibrosis, 880, 2176 cytopathology of, 518, 518f differential diagnosis of, 2266 disseminated in HIV-infected (AIDS) patients, 2247 species causing, 2460t histopathology of, 2034 in HIV-infected (AIDS) patients, 2213, 2242t, 2252–2253, 2487–2496 and pneumothorax, 1523 radiographic findings in, 2214–2215 immune defect associated with, 1983t, 2210t pathogenesis of, 2040 pathology of, 2043t, 2050 pulmonary involvement in, species causing, 2460t severity of, Social Security Listings for, 687 supraglottitis caused by, 853 laryngitis caused by, 2087 in lung abscess, 2154t in lymphadenitis, 2472 species causing, 2460t

multidrug-resistant, 2451 nontuberculous, 2459–2460, 2460t culture of, 2500 drug susceptibility testing, 2500 infection clinical manifestations of, 2500–2501 clinical presentation of, 2502–2503 in cystic fibrosis, 2502 epidemiology of, 2499, 2500 in HIV-infected (AIDS) patients, 2491–2496, 2500 hypersensitivity pneumonitis caused by, 2502 immune response to, 2500–2501 in organ transplant recipients, 2502–2503 pathogenesis of, 2500 treatment of, 2503–2505, 2503t laboratory diagnosis of, 2500 microbiology of, 2499–2500 pulmonary disease, 2501–2502 diagnosis of, bacteriologic criteria for, 2501, 2501t radiographic findings in, 2501, 2501f, 2502, 2502f, 2503, 2504f from respiratory specimens, 2500 staining characteristics of, 2500 pathogenicity of, 2461 sputum culture for, 2000 staining characteristics of, 2037, 2039 virulence factors, 2461 Mycobacterial catalase-peroxidase protein, and sarcoidosis, 1127 Mycobacterium abscessus, 2049, 2500 culture of, 2462 in cutaneous disease, 2460t geographic distribution of, 2460t infection, 2460t, 2505 in cystic fibrosis, 2176 disseminated, 2460t in lymphadenitis, 2460t morphology of, 2460t Mycobacterium africanum, 2459 Mycobacterium asiaticum, infection (incl. pneumonia), 2460t Mycobacterium avium complex, 2459, 2499, 2500 in cutaneous disease, 2460t environmental sources of, 2492 geographic distribution of, 2460t infection (incl. pneumonia), 463f, 2460t bronchiectasis in, 463f, 2190 disseminated, 2460t in HIV-infected (AIDS) patients, 2253, 2491–2496 clinical manifestations of, 2493 epidemiology of, 2491–2492, 2491f pathogenesis of, 2492–2493

I-76 Index Mycobacterium avium complex, infection (Cont.) prevention of, 2493–2496, 2495t radiographic findings in, 2493, 2493f treatment of, 2493–2496, 2494t imaging of, 2022f scintigraphy in, 557 in lymphadenitis, 2460t morphology of, 2460t pulmonary disease, 2503–2505 Mycobacterium avium-intracellulare in HIV-infected (AIDS) patients, 1999, 2000, 2001 infection (incl. pneumonia), 2023–2024 and bronchiectasis, 2186 in cystic fibrosis, 2176 in HIV-infected (AIDS) patients, 2212t, 2215 radiographic findings in, 2249t pathology of, 2048f in lung abscess, 2154t Mycobacterium bovis, 2459, 2467 Mycobacterium canetti, 2459 Mycobacterium celatum, infection (incl. pneumonia), 2460t Mycobacterium chelonae, 2459, 2500 culture of, 2462 in cutaneous disease, 2460t geographic distribution of, 2460t infection, 2505 disseminated, 2460t in lymphadenitis, 2460t morphology of, 2460t Mycobacterium chelonei in acute mediastinitis, 2166t infection, in HIV-infected (AIDS) patients, 2496 Mycobacterium conspicuum, nontuberculous, culture of, 2500 Mycobacterium fortuitum, 2500 in acute mediastinitis, 2166t culture of, 2462 in cutaneous disease, 2460t geographic distribution of, 2460t infection, 2460t, 2505 disseminated, 2460t in HIV-infected (AIDS) patients, 2496 in lymphadenitis, 2460t morphology of, 2460t Mycobacterium genavense culture of, 2500 infection disseminated, 2460t in HIV-infected (AIDS) patients, 2496 Mycobacterium gordonae, 2459, 2500 Mycobacterium haemophilum culture of, 2500 in cutaneous disease, 2460t

geographic distribution of, 2460t infection, 2460t disseminated, 2460t in HIV-infected (AIDS) patients, 2496 in lymphadenitis, 2460t morphology of, 2460t Mycobacterium immunogenum, 2502 Mycobacterium intracellulare, 2499, 2500 Mycobacterium kansasii, 2049, 2459, 2462, 2500 in cutaneous disease, 2460t geographic distribution of, 2460t infection, 2460t, 2505 differential diagnosis of, 2266 disseminated, 2460t in HIV-infected (AIDS) patients, 2496 in lung abscess, 2154t in lymphadenitis, 2460t morphology of, 2460t staining characteristics of, 2039, 2041f Mycobacterium leprae, 2499 staining characteristics of, 2039 Mycobacterium malmoense geographic distribution of, 2460t infection, 2460t disseminated, 2460t in lymphadenitis, 2460t morphology of, 2460t Mycobacterium marinum, 2462 in cutaneous disease, 2460t geographic distribution of, 2460t infection, 2505 morphology of, 2460t Mycobacterium microti, 2459 Mycobacterium nonchromogenicum, in cutaneous disease, 2460t Mycobacterium scrofulaceum, 2499, 2500 geographic distribution of, 2460t in lymphadenitis, 2460t morphology of, 2460t Mycobacterium sherrisii, infection, in HIV-infected (AIDS) patients, 2496 Mycobacterium shimodii, infection, 2460t Mycobacterium simiae, infection, 2460t disseminated, 2460t Mycobacterium smegmatis in cutaneous disease, 2460t infection, 2460t Mycobacterium szulgai, 2462 infection, 2460t Mycobacterium tuberculosis, 1996, 2459–2460, 2467, 2499 Ag85B antigen, 2463 blood assay for, 2454 CFP-10 protein, 2454, 2461, 2462, 2490 contamination of bronchoscope, 2279 culture of, 2462, 2471 diagnosis of, phage technology for, 2462 in empyema, 2144

ESAT-6 protein, 2454, 2461, 2462, 2463, 2490 genotyping of, 2452 in HIV-infected (AIDS) patients. See Tuberculosis, in HIV-infected (AIDS) patients immune response to, 2460–2461, 2463 infection (incl. pneumonia). See Tuberculosis in lung abscess, 2154t molecular detection of, 2002 molecular epidemiology of, 2452 nucleic acid amplification tests for, 2462, 2471 in HIV-infected (AIDS) patients, 2490 staining characteristics of, 2035t, 2039, 2041f strains of, 2460 transmission of, 2451–2452 vaccine against. See Bacille Calmette-Gu´erin (BCG) vaccine Mycobacterium tuberculosis complex, 2459 Mycobacterium ulcerans culture of, 2462 in cutaneous disease, 2460t geographic distribution of, 2460t morphology of, 2460t Mycobacterium xenopi geographic distribution of, 2460t infection, 2460t disseminated, 2460t in HIV-infected (AIDS) patients, 2496 morphology of, 2460t Mycolic acids, 2461 Mycophenolate mofetil, for sarcoidosis, 1140t, 1141 Mycoplasma, infection (incl. pneumonia) and asthma, 816 in bone marrow and stem cell transplant recipients, 2223 in cancer patients, 2221 differential diagnosis of, 2443 pathology of, 2043–2045 systemic effects of, 451–453, 451t treatment of, 831 Mycoplasma pneumoniae, 1983, 1985, 1986, 1992, 1996, 1997 and acute bronchitis, 2097 in acute exacerbations of chronic obstructive pulmonary disease, 2121t and bronchiolitis, 896, 897 and croup, 2087, 2379 epidemiology of, 2004 infection (incl. pneumonia), 2005, 2005t, 2020, 2025 in children, 2133 clinical features of, 2381 in common variable immunodeficiency, 331

I-77 Index diagnosis of, 2001–2002, 2106 differential diagnosis of, 2266 epidemiology of, 2113 extrapulmonary manifestations of, 2113 history and physical findings in, 2101t in HIV-infected (AIDS) patients, radiographic findings in, 2215 hospitalization rate for, 2105t ICU admission rate for, 2106t imaging of, 2021, 2021f signs and symptoms of, 2099 treatment of, 2055, 2057, 2113 in X-linked agammaglobulinemia, 2234 molecular detection of, 2002 pharyngitis caused by, 2086 Mycoses. See Allergic bronchopulmonary mycosis; Fungal infection(s) Mycosis fungoides, 1962 myc proto-oncogenes and cell cycle, 1810–1811 in lung cancer, 1804 MyD88 adapter protein, 355–356 Myelin, tubular, 38, 38f, 39, 56, 126, 126f Myelopathy, ventilatory impairment in, 1668t Myeloperoxidase (MPO), 360, 1973 in asthma, 782 Myeloproliferative disorders, sarcoidosis and, 1136t Myenteric (Auerbach’s) plexus, 1304 Myocardial infarct/infarction acute, oxygen therapy in, 2619 in lung transplant recipient, 1789–1790 in respiratory failure, 2518t, 2519 Myocardial ischemia pain of, 418 in SIRS/MODS, 2568 Myocarditis, 2113 Myoclonus, paraneoplastic, 1937 Myofibril(s), 72 Myofibroblasts, 378–381 of alveolar septum, 40f, 41 expansion, cytokines/growth factors in, 378, 378t in pulmonary fibrosis, 378–379, 379f persistence in active fibrotic site, 380 Myopathy acquired, respiratory abnormalities in, 1656, 1656t, 1659–1660 inflammatory, respiratory abnormalities in, 1659 inherited respiratory abnormalities in, 1656–1659, 1656t ventilatory impairment in, 1668t metabolic, ventilatory impairment in, 1668t

steroid, respiratory abnormalities in, 1659–1660 of systemic disease, ventilatory impairment in, 1668t ventilatory impairment in, 1668t Myosin, 72 Myotonic dystrophy, respiratory abnormalities in, 1658 N NAA. See Nucleic acid amplification NAAQS. See National Ambient Air Quality Standards NAC. See N-Acetylcysteine Nadolol, pulmonary effects of, 1097 NADPH oxidase, 359–360, 360f Naegleria, infection (incl. pneumonia) in cancer patients, 2219 in immunocompromised host, 2210 Nafcillin, 2056 for staphylococcal pneumonia, in children, 2132 NALT. See Nasal-associated lymphoid tissue NAP2, 340t, 341t, 1973 Naproxen and aspirin-induced asthma, 802t pneumonitis caused by, 2012t Narcotics, pneumonitis caused by, 2012t Nasal-associated lymphoid tissue (NALT), 326 Nasal dilators, for obstructive sleep apnea, 1714 Nasal septal deviation, 2647 Nasogastric intubation, and nosocomial pneumonia, 2196, 2278 Nasopharynx, 2646–2647 Nasotracheal intubation, 2650, 2651–2653, 2652f, 2653f National Ambient Air Quality Standards, 1016 for criteria pollutants, 1011f National Cancer Institute (NCI), model for smoking intervention, 753–754 National Emphysema Treatment Trial, 711 National Institute for Occupational Safety and Health (NIOSH), 941–942 Natural killer (NK) cells, in immune defense, 1973 NCIC JBR10 trial, 1869t, 1870 Near syncope, in pulmonary hypertension, 1371, 1371t Nebulized drug solutions, 2633–2634 in chronic obstructive pulmonary disease, 738, 738t Necator americanus, 2414t, 2415, 2416 Neck flexion/extension, assessment of, 2647–2648

soft tissues of, pathology of, upper airway obstruction caused by, 857 Neck muscle(s), actions of, 76 Necrotizing sarcoid granulomatosis, 1464–1465, 1464f Nedocromil adverse effects and side effects of, 827t for asthma, 822, 823t, 827t, 2640 dosage and administration of, 827t for exercise-induced asthma, 811t, 812 mechanism of action of, 2640 pharmacology of, 2640 Needle(s), for transbronchoscopic aspiration and biopsy, 631 Neergaard, K. von. 11, 12 Neisseria, infection (incl. pneumonia), immune defect associated with, 1983t, 2210t Neisseria catarrhalis, pneumonia, 2020 Neisseria gonorrhoeae infection (incl. pneumonia), in complement deficiency, 2236 pharyngitis caused by, 2086 protease, 326 Neisseria meningitidis, 2105, 2428t, 2441–2444 bacteriology of, 2428t, 2442 carriers, 2086 colonization of host, 2079 identification of, in tissue, 2442, 2442f immune response to, 324, 1979 infection (incl. pneumonia), 330–331, 2428t, 2441–2444, 2441f in bone marrow and stem cell transplant recipients, 2224 chemoprophylaxis for, 2444 clinical features of, 2443 in complement deficiency, 2236 diagnosis of, 1998, 2443, 2443t differential diagnosis of, 2443–2444 epidemiology of, 2442 in HIV-infected (AIDS) patients, 2106t immunoprophylaxis for, 2444 pathogenesis of, 2443 pathophysiology of, 2443 prevention of, 2444 radiologic features of, 2443 treatment of, 2444 in X-linked hypogammaglobulinemia, 331 pharyngitis caused by, 2086 protease, 326 serogroups of, 2442 staining characteristics of, 2442, 2442f superinfection, in adenoviral pneumonia, 2389 vaccine against, 2080. See also Meningococcal vaccine

I-78 Index Nematodes, 2413, 2415–2418 infestation, pathology of, 2045 Neoadjuvant, definition of, 1895 Neonate(s), pulmonary circulation in, 1354 Neoplasm(s). See also Malignancy; Tumor(s); specific neoplasm cytopathology of, 527–531 fever with, 420 hemoptysis caused by, 413 lymphangitic spread of and interstitial lung disease, 1397, 1398f radiographic features of, 483, 485, 490f pulmonary, 2014 histological classification of, 528, 528t immunocytochemistry of, 531 systemic effects of, 451–453, 451t. See also Paraneoplastic syndromes Neopterin, assay for, 2107 Nephrogenic fibrosing dermopathy, 437–438, 438f Nephrotic syndrome, risk of venous thromboembolism in, 1426 Nerve(s), pulmonary innervation by, 32 Nerve gas, bronchiolitis caused by, 894t Nerve growth factor, 316 NETT. See National Emphysema Treatment Trial Neurilemmoma, in posterior mediastinum, 1610 Neuroblastoma, 1611 Neuroendocrine cells, 30, 30f. See also Pulmonary neuroendocrine cells Neuroepithelial bodies, 30, 444 Neurofibromatosis (NF), computed tomography of, 1115t Neurogenic tumor(s), radiographic features of, 499–500, 502f Neuroleptic drugs, adverse effects and side effects of, 859 Neuromuscular disorders. See also specific disorder alveolar ventilation in, aids for, 1671–1672 chest wall mobility in, aids for, 1670–1671 clearance of airway secretions in, aids for, 1672 control of breathing in, 1636–1640 extubation in, 1674–1675 protocol for, 1673–1674, 1673t general anesthesia in, 1675 history-taking in, 1640–1641 and hypercapnic respiratory failure, 2608 lung and chest wall mechanics in, 1637–1639, 1639t oximetry feedback respiratory aid protocol for, 1672

physical examination in, 1641 pulmonary compliance in, aids for, 1670–1671 radiographic findings in, 1641–1642 respiratory assessment in, 1640–1643 and respiratory failure, 2514 respiratory mechanics in, 1637–1639, 1639t respiratory muscle dysfunction in, 1636–1637, 1637f respiratory pathophysiology in, 1635–1636 sleep-disordered breathing in, 1639–1640, 1639t upper airway obstruction in, 858–859 ventilatory impairment in, 1635, 1647–1660 levels of, 1635, 1636t pathophysiology of, 1668–1669 preventive therapy for, 1660 treatment of, 1660–1664, 1667–1675 clinical goals for, 1670–1672 principles of, 1660 Neuromuscular junction (NMJ), disorders, ventilatory impairment in, 1655–1656 Neuron(s) inspiratory, 165 pacemaker, 165 phrenic, 166 Neuropathy, ventilatory impairment in, 1668t Neutropenia and acute lung injury, 2528 in bone marrow and stem cell transplant recipients, 2222–2224 in cancer patients, 2216, 2216t causes of, 2216, 2216t cyclic, 2216, 2216t in children, 2138 fever in, empiric antibiotic therapy in, 2220 hereditary, 2216, 2216t in HIV-infected (AIDS) patients, 2243, 2248 iatrogenic, 2216, 2216t immune, 2216, 2216t in children, 2138 infection in, microbiology of, 2216–2219 infection-induced, 2216, 2216t and risk of infection, 2306, 2317 Neutrophil(s) in asthma, 776 cell killing by, defects of associated infections, 1983t, 2210t causes of, 1983t, 2210t chemotaxis, defects of associated infections, 1983t, 2210t causes of, 1983t, 2210t

chemotherapy-related dysfunction, 2216 granule proteins, in asthma, 782 killing, defects of, infections associated with, 1983t in pulmonary fibrosis, 376 Neutrophil-activating protein-2. See NAP2 Neutrophil collagenase. See Matrix metalloproteinase (MMP), MMP-8 Neutrophil elastase, 718t in emphysema, 720 Neutrophilic dermatoses, 434 of dorsal hands, 434, 435f New York Heart Association classification, 614–615, 622 NF-κB, 2116 NICK. See Nuclear factor κB-inducing kinase Nickel airborne, 1020 and occupational asthma, 990 Nicotine addiction to, 747–748 and cigarette consumption rate, 748 dopamine in, 748 epidemiology of, 748 gene-environment interactions and, 748 cravings, management of, 757 dependence, evaluation for, 756–757, 757t in indoor air, sources of, 1022t pharmacology of, 747 replacement, 754–755 combination approach for, 755 inhaler method, 755 nasal spray for, 755 transdermal method, 755 vaccines, 756 withdrawal and depression, 757, 759 management of, 757 symptoms of, 747, 748t, 757 Nicotine polacrilex, 754–755 Nidogen, in lung development, 94 Niemann-Pick disease biochemical features of, 1268 clinical features of, 1266 diagnosis of, 1268 genetics of, 1266 histology of, 1266–1268, 1267f pathology of, 1266 pulmonary involvement in, 1266, 1266f types of, 1266 ultrastructure in, 1268, 1268f Nilutamide, and interstitial lung disease, 1110t Nimesulide, dose-related airway response to, in aspirin-sensitive asthmatics, 802

I-79 Index NIPPV. See Positive-pressure ventilation, noninvasive Nitazoxanide, for cryptosporidiosis, 2404 Nitrates, methemoglobinemia caused by, 416 Nitric oxide amelioration of tissue injury, 366 diffusing capacity for, 195, 195f inhaled, and ARDS, 366 production of, 360–361, 361f and superoxide, interactions of, 2625, 2625f Nitric oxide (NO), 446 in asthma, 122, 778–782 chemical properties of, 1341 exhaled in asthma, 834 in asthma diagnosis, 819 measurement of, 585 expression of, by airway smooth muscle cells, 122, 122t inhaled, 1342 in ALI/ARDS, 2555–2556 pulmonary effects of, 1093 in oxidative injury, 450 protective effect against free radicals, 450–451 in pulmonary hypertension, 1368–1369 and pulmonary vasomotor control, 1341–1342, 1343f in septic shock syndrome, 449–450 synthesis of, 1342, 1343f Nitric oxide synthase (NOS), 360, 361f, 446, 1342, 1343f inducible, 1978 Nitrite, 361, 361f Nitrofurantoin and interstitial lung disease, 1110t lung damage caused by, 389, 389f pneumonitis caused by, 2010, 2012t pulmonary effects of, 1089, 1090t, 1091t, 1092, 1093, 1099–1100 Nitrogenated compounds, in indoor air, sources of, 1021t Nitrogen balance, 2697–2698 Nitrogen dioxide, 360, 1010 bronchiolitis caused by, 893–894, 893t health effects of, 1017 in indoor air, sources of, 1021t inhalation injury caused by, 1001–1002 National Ambient Air Quality Standards for, 1011t occupational lung disease caused by, 935t in outdoor air, exposures to, 1017 pulmonary effects of, acute and chronic, 1024–1025 in smoke and inhalation injury, 1054 sources of, 1011t water solubility of, and site of impact, 995t

Nitrogen mustard derivatives, pulmonary effects of, 1073 Nitrogen oxide(s) inhalation injury caused by, 1000t, 1001–1002, 1054, 1057 water solubility of, and mechanism of lung injury by, 994–995, 994t Nitrogen tetroxide, bronchiolitis caused by, 893 Nitrogen washout, 158, 571, 572, 574, 589–590, 589f Nitroglycerin, methemoglobinemia caused by, 416 Nitrosamines, in indoor air, sources of, 1021t Nitrosoureas and interstitial lung disease, 1111t pulmonary effects of, 1073, 1078–1081, 1079t S-Nitrosylation, 363 Nitroxyl, 360 NLH. See Nodular lymphoid hyperplasia Nocardia, 1985, 1986, 1990, 1996 in acute mediastinitis, 2166t diagnosis of, 1998, 1999 infection (incl. pneumonia) in bone marrow and stem cell transplant recipients, 2223 in cancer patients, 2221, 2221t in chronic granulomatous disease, 2237–2238, 2238f history and physical findings in, 2101t in HIV-infected (AIDS) patients, 2251, 2252 radiographic findings in, 2249t hospitalization rate for, 2105t in immunocompromised host, 2209 pneumonia, 2022 staining characteristics of, 2035t, 2036–2037, 2039, 2039f Nocardia asteroides, 1989 in empyema, 2144 infection (incl. pneumonia), 2146 and bronchiectasis, 2189, 2189t in children, immune defects and, 2139 in HIV-infected (AIDS) patients, 2212t radiographic findings in, 2214t in neutropenic host and cancer patient, 2217, 2218f in organ transplant recipient, 2230, 2232 in lung abscess, 2154t staining characteristics of, 2039f Nocardiosis cytopathology of, 518 in immunocompromised host, 1997 pulmonary alveolar proteinosis complicated by, 2014

Nocturnal oxygen desaturation, in chronic obstructive pulmonary disease, 735 Nodular lymphoid hyperplasia, 1949–1950, 1950f Nodule(s), pulmonary. See also Solitary pulmonary nodule diagnosis of, thoracoscopy in, 655–656 drug-induced, 1110t–1111t excision of, thoracoscopy in, 656, 656f in HIV-infected (AIDS) patients, 2214t, 2215, 2248, 2249t in interstitial lung disease, 1113f, 1115t multiple computed tomography of, 494 disorders associated with, 494 radiography of, 494, 494f parenchymal, in collagen vascular disease, 1194t, 1198, 1198f rheumatoid, 494, 494f Noggin, 85–86, 88f, 89f Noma, 2087 Non-Hodgkin’s lymphoma (NHL), 2014 in HIV-infected (AIDS) patients, 2247, 2259 radiographic findings in, 2249t mediastinal, 1602–1603, 1603f primary pulmonary, 1923–1924, 1955–1957 staging system for, 1602, 1603t Noninvasive positive-pressure ventilation, in hypercapnic respiratory failure, 2611 Nonmaleficence, principle of, 2722–2723 Non-nucleoside reverse transcriptase inhibitors, pharmacology of, 2261 Non-small cell lung cancer, 444 advanced stage anti-angiogenesis therapy for, 1876 chemotherapy for, 1875–1878 first-line, 1876 second-line, 1877–1878, 1877t EGFR inhibitor therapy for, 1877–1878 treatment of, advances in (future directions for), 1878 ancillary studies of, 1847 chemotherapy for, 1867–1878 effectiveness of, 1867–1868 efficacy of, 1867–1868 results of, criteria for reporting, 1867–1868 chest wall resection in, 1859–1860, 1860f cytopathology of, 528–529, 529f diagnosis of, 1851–1853 in asymptomatic patient with abnormal chest radiograph, 1852–1853 in symptomatic patient, 1852

I-80 Index Non-small cell lung cancer (Cont.) early stage, chemotherapy for, 1868–1871 endocrine and hematologic syndromes associated with, 1930t histochemical stains for, 1847–1848 immunohistochemistry of, 1847–1848 inoperable, definition of, 1855 lobectomy for, 1855 localized chemotherapy for, 1868–1871 adjuvant, 1868–1871, 1869t advances in (future directions for), 1871 radiation therapy for, adjuvant, 1871 locally advanced chemotherapy and radiation therapy for concurrent, 1873, 1874t followed by surgery, 1875 chemotherapy for followed by radiation therapy, randomized trials of, 1872–1873 followed by surgery, 1873–1875 definition of, 1857, 1871 radiation therapy for, 1871–1872, 1874t treatment of, 1872, 1873f advances in (future directions for), 1875 locally advanced nonoperative but non-metastatic, treatment of, 1886–1889, 1886f–1887f, 1888t mediastinal involvement in, by direct extension, 1860–1861, 1861f pneumonectomy for, 1856–1857 prognosis after, after resection, 1862–1863, 1863t prognosis for, 1867, 1884 radiation therapy for, 1883–1896 adjuvant, 1871 adjuvant (postoperative), 1883, 1885–1886 definitive, 1883 for locally advanced nonoperative cancer, 1886–1889, 1886f–1887f, 1888t neoadjuvant (preoperative), 1883, 1884–1885 palliative, 1883, 1889–1890, 1889t patient selection for, 1883 recurrence, sites of, 1863 resectability, definition of, 1855 segmental resection of, 1855–1856, 1856f sleeve resection for, 1856–1857, 1856f staging of, 1853–1855, 1853f, 1854f, 1868, 1868f subtypes of, 1831–1832, 1832t surgery for, 1855–1864 advances in (future directions for), 1863–1864 complications of, 1862 follow-up after, 1863

mediastinal lymph node resection in, 1857 morbidity after, 1862 mortality after, 1862 in N2 disease, 1857–1859 palliative, 1862 plus chemotherapy, 1858, 1858f, 1858t prognosis after, 1862–1863, 1863t recurrence after, sites of, 1863 results, 1862–1863 treatment of, 1884 advances in (future directions for), 1863–1864 WHO classification of, 1831, 1832t Nonspecific interstitial pneumonia, 1106t, 1145, 1953 clinical features of, 1116t in collagen vascular disease, 1194t histopathology of, 1195 computed tomography of, 1115t, 1116t histology of, 1116t and idiopathic pulmonary fibrosis, 1156 lung transplantation in, 1774t, 1775–1777 in mixed connective tissue disease, 1210 occupational exposures and, 935t in polymyositis-dermatomyositis, 1208–1209 in rheumatoid arthritis, 1204–1206 in Sj¨ogren’s syndrome, 1211 treatment of, 1116t Nonsteroidal anti-inflammatory drugs (NSAIDs) and airway narrowing, in aspirin-sensitive asthmatics, 802t anaphylactic response to, 802 and aspirin, cross-reactivity of, 801–803 asthma induced by, 313, 799, 801–803, 816 and interstitial lung disease, 1111t pulmonary effects of, 1090t, 1091t, 1092, 1093 tolerated by aspirin-sensitive asthmatics, 802t Norepinephrine, and pulmonary circulation, 1347 Nortriptyline, in smoking cessation, 756 Nose, in host (immune) defense, 280–281 Nosema, 2410 Nosocomial infection, immune defect associated with, 1983t, 2210t NPPV. See Positive-pressure ventilation, nasal NSCLC. See Non-small cell lung cancer NSIP. See Nonspecific interstitial pneumonia NTM. See Mycobacteria, nontuberculous Nuclear factor E2-related factor, 716 Nuclear factor κB, 355–356, 716, 716f activation of, 361

Nuclear factor κB-inducing kinase, 361 Nuclear imaging, in HIV-infected (AIDS) patients, 2247t, 2248–2249 Nuclear magnetic resonance, 463–465 Nucleic acid amplification, for rapid diagnosis of mycobacteria, 2462, 2471 in HIV-infected (AIDS) patients, 2490 Nutrition in acute respiratory failure, 2691–2699 in ICU, 2691–2692 Nutritional status assessment of, 2693–2694 functional, 2693 metabolic, 2693–2694 in chronic obstructive pulmonary disease, 2605, 2692 and postoperative pulmonary complications, 669 Nutritional support in acute respiratory failure, effects of, 2693 administration route, 2694–2695 in advanced lung disease, 2698–2699 arginine in, 2697 basic nutritional prescription in, 2695–2696, 2696t in chronic obstructive pulmonary disease, 735 complications of, 2694–2695, 2695t in cystic fibrosis, 877 energy requirements in, 2696–2697 fat requirements in, 2697 glucose requirements in, 2697 glutamine in, 2697 goals of, 2694 and immunonutrition, 2697 indications for, 2694, 2694t micronutrient requirements in, 2697 monitoring during, 2697–2698 and nitrogen balance, 2697–2698 omega-3 fatty acids in, 2697 preoperative, 669 protein requirements in, 2697 Nystatin, 2299 O O3 . See Ozone Obesity, 1627–1629 abnormal breathing pattern in, 403 and asthma, 795–796, 832–833 control of breathing in, 1628–1629 epidemiology of, 1627 gas exchange in, 1629 and hypercapnic respiratory failure, 2608 and postoperative pulmonary complications, 668–669 pulmonary effects of, 1395 pulmonary function testing in, 1627–1628

I-81 Index respiratory mechanics in, 1627–1628, 1628t respiratory morbidity in, 1627 treatment of, 832–833, 1629 and venous thromboembolism, 1426 Obesity hypoventilation syndrome, 2514, 2608 definition of, 1698–1699 diagnosis of, 1722, 1722t, 1723f management of, 1722 pathophysiology of, 1627–1628, 1628f respiratory mechanics in, 1627–1628, 1628t ventilatory impairment in, 1668t Obstruction, mechanical, and aspiration pneumonia, 2150t, 2151 Obstructive airway disease. See also Bronchitis, chronic; Chronic obstructive pulmonary disease (COPD); Emphysema radiographic evaluation of, 474–476 reversible versus irreversible, 605 Obstructive lung disease, cardiopulmonary exercise testing in, 624–625 Obstructive overinflation, differential diagnosis of, 699 Occupation and asthma, 933–934. See also Asthma, occupational and chronic obstructive pulmonary disease, 708t, 709–710, 933–934 Occupational lung disease. See also Asthma, occupational; Bronchitis, industrial cause of, establishing, 936–937 classification of, 934, 934t clinical approach to patient with, 937–941 diagnostic criteria for, 936 diagnostic testing in, 937–940 epidemiology of, 936–937 exposure assessment in, 940–941 history-taking in, 937, 938t importance of, 936 laboratory diagnosis of, 940 physical examination in, 937 prevention of, 941–942 principles of, 935–936 toxicology of, 936–937 Occupational Safety and Health Administration (OSHA), 941, 942, 1011 Occupation-related disease diagnosis of, 423 workers’ compensation programs for, 687–688 federal, 688–690 state, 687–688 ODTS. See Organic dust toxic syndrome O’Dwyer, Joseph, 2646 Off-label agents, in smoking cessation, 756

Ofloxacin, 2056 adverse effects and side effects of, 2483t for nontuberculous mycobacteria, dosage and administration of, 2504t of lung, 1962, 1962f OH− . See Hydroxyl radical OHS. See Obesity hypoventilation syndrome Oleoresin capsicum, inhalation injury caused by, 1003–1004 Omalizumab adverse effects and side effects of, 829t, 2641 for allergic bronchopulmonary aspergillosis, 842–843 for asthma, 823t, 829t, 830 clinical use of, 2641 dosage and administration of, 829t for eosinophilic disorders, 318 mechanism of action of, 829t pharmacology of, 2641 OME. See Otitis media, with effusion Oncogene(s) dominant, 1802–1803, 1803f in lung cancer, 1804–1805 recessive, 1802, 1803, 1803f Ondine’s curse, 168 Opiate(s) for agitated ICU patient, 2707–2708 properties of, 2709t toxicity of, 2708 pulmonary effects of, 1091t, 1093, 1100 toxicity of, 2708 Opisthorchis, and eosinophilic pneumonia, 1214t Opportunistic infection(s), 2204 fungal, 2321–2324. See also Aspergillosis; Candidiasis differential diagnosis of, 2323t in HIV-infected (AIDS) patients, 2212–2213, 2212t, 2245, 2246–2247 prevention of, 2366 by mold, 2291–2324. See also Aspergillosis; Candidiasis; Fusariosis; Mucormycosis; Scedosporiosis; Zygomycosis differential diagnosis of, 2323t by molds, 2321–2324 Opsoclonus, paraneoplastic, 1937 Opsonins, 1970, 1979, 1983 in alveolar fluid, 282, 283 Optical coherence tomography, 634 Oral appliances, for obstructive sleep apnea, 1718–1720, 1719f Oral cancer, smoking and, 751 Oral cavity bacteria in, 281 in host (immune) defense, 281 infections of, 2086–2087

Oral contraceptives, and venous thromboembolism, 1425–1426 Orbital cellulitis, 2090, 2090f Organic acidosis, 219 Organic antigens, lung disease caused by, 935t Organic compounds airborne health effects of, 1026 sources of, 1026, 1027t in indoor air, health effects of, 1026 Organic dusts, bronchiolitis caused by, 896 Organic dust toxic syndrome, 1006, 1167 Organ transplantation bronchiolitis associated with, 906–909 pulmonary complications of, 906–909 Organ transplant recipient(s) nontuberculous mycobacterial infection in, 2502–2503 pneumonia in, 2024, 2100t and risk of infection, 2317, 2318, 2318f risk of infection in, 2205, 2206f Oropharynx, 2646–2647 in host (immune) defense, 280–281 Orotracheal intubation, 2653–2654, 2654f Orthopnea, 400–401 Ortner syndrome, 1371 Oseltamivir indications for, 2375t for influenza, 2387–2388, 2387t Osler-Weber-Rendu disease. See Rendu-Osler-Weber disease Osmostat, reset, in tuberculosis, 2470 Osteogenesis imperfecta, ventilatory impairment in, 1668t Osteophytes, cervical, 2647–2648 upper airway obstruction caused by, 857 Osteoporosis, smoking and, 752 Otis, A. B., 12 Otitis externa, 2092 acute, 2092 in hyperimmunoglobulin E syndrome, 2239 invasive (malignant), 2092 Otitis media, 281 acute, 2092–2093, 2093f complications of, 2094 in Chediak-Higashi syndrome, 2238 chronic complications of, 2094, 2094f in Wiskott-Aldrich syndrome, 2237 chronic suppurative, 2093–2094, 2093f with cholesteatoma, 2093–2094, 2093f without cholesteatoma, 2093–2094, 2093f common cold and, 2086 in common variable immunodeficiency, 331 complications of, 2094

I-82 Index Otitis media (Cont.) with effusion, 2093 in hyperimmunoglobulin E syndrome, 2239 Ovarian cancer, and pleural effusion, 1505, 1506t Overlap syndrome, 735 Oxacillin, 2056 Oxamniquine, indications for, 2418t Oxazolidinones activity against MRSA, 2058 mechanism of action of, 2058 pharmacokinetics and pharmacodynamics of, 2054 Oxford physiologists, 5t, 6–7, 8, 11 Oxidant(s) inhalation/ingestion, injury caused by, 451 pulmonary injury due to, drug-induced, 1088, 1089 Oxidant-antioxidant imbalance, and chronic obstructive pulmonary disease, 716–717, 716f Oxidative injury, mechanism of, 450 Oxidative phosphorylation, 57, 58, 65 Oxidative stress, 716–717, 716f Oxygen affinity of hemoglobin for, 202, 202f alveolar, 592 alveolar and blood capacitances, and diffusive equilibrium, 192 capillary content of, 415 consumption, 611 in exercise, 65–66, 66f, 67–68 at rest, normal, 1323, 2735 in tissues, 57, 65 diffusing capacity for, 58–61, 58f, 194–195 diffusion of, 47, 48f, 176, 177 knowledge of, historical perspective on, 5t, 9–10 discovery of, 7, 8, 2613 exchange, kinetics of, 205t extraction, 612 calculation of, 612t in exercise, 612–613, 613f flow, through respiratory system, 65–68, 65f intake, decreased, and arterial hypoxemia, 2616–2617, 2616t partial pressures of alveolar, and diffusing capacity, 197 from atmosphere to tissues, 2614, 2615f cascade of, 57–58, 65 secretion of, Bohr’s theory of, 5t, 9–10 supplementation. See also Oxygen therapy effects on ventilatory response to hypercapnia, 2593–2594, 2594f tissue requirements for, 612 transplacental transfer of, 258

transport, 201–203, 611, 2614–2615, 2615f abnormalities, and tissue hypoxia, 2616t, 2617 to alveoli, 47, 48f calculation of, 612t disruption of, 167–187 in exercise, 612–613 pathway, 173–177 resting, 612 uptake, 591–592 in exercise, 235, 235f, 612–613, 613f integrated response for, 224–225, 225f–226f in lung, 57, 65 maximal, 612–613, 613f in classification of cardiac and circulatory failure, 614–615, 615t pathway, 173–177, 174f–176f resting, 612 utilization calculation of, 612t oxygen delivery and, 2615, 2615f Oxygenation, monitoring, in acute respiratory failure, 2668–2669 Oxygen content, of blood, 2511, 2614 Oxygen cost of breathing, 159–160 mechanical ventilation and, 2676, 2677f Oxygen delivery, 1337–1338, 1338f, 2511, 2614–2615, 2615f hyperbaric oxygen therapy and, 1049, 1049f and oxygen utilization, 2615, 2615f reduced, 2616t, 2617 Oxygen dissociation curve, 201, 202f in exercise, 224 historical perspective on, 9 Oxygen equilibrium curve, 201, 202f Oxygen flow rate, 57–58, 65 structure-function relations and, 66–68, 67t, 68t Oxygen therapy acute, delivery systems for, 2621–2623 for acute exacerbations of chronic obstructive pulmonary disease, 741, 742t, 2122 administration of, techniques of, 2620–2624 air-oxygen blenders for, 2623 in ALI/ARDS, 2545–2546 failure of, 2539, 2539f for asthma exacerbations, 835 in chronic obstructive pulmonary disease and air travel, 735–736, 736f long-term, 736–737 delivery systems for, 2620, 2621f in acute setting, 2621–2623 high-flow devices, 2621f, 2622–2623, 2622t

low-flow devices, 2621–2622, 2621f, 2622t Venturi masks for, 2622–2623, 2622t, 2623f historical perspective on, 2613–2614 for idiopathic pulmonary fibrosis, 1159 indications for, 2618–2620 long-term delivery systems for, 2623–2624 indications for, 2620, 2620t nasal cannulae for, 2621, 2622t, 2624 for obstructive sleep apnea, 1714 oxygen masks for, 2621–2622, 2622t partial non-rebreathing, 2622, 2623f partial rebreathing, 2622, 2623f with reservoir bags, 2622, 2622t, 2623f in pulmonary hypertension, 1376 in pulmonary rehabilitation, 767 reservoir nebulizers and humidifiers for, 2623 responses to, in tissue hypoxia, 2616, 2616t short-term, indications for, 2618–2619, 2619t transtracheal catheter for, 2622t, 2624 Oxygen toxicity, 1051, 1051f bronchiolitis caused by, 893t pulmonary, 2624–2626 acute, 2627–2628 biochemical alterations caused by, mechanisms of, 2625–2626, 2626t cellular dysfunction caused by, 2626–2627 mechanisms of, 2625–2626, 2626t cellular mechanisms of, 2624–2625 chronic, 2628 clinical syndromes of, 2627–2628 destruction phase of, 2626–2627 diagnosis of, 2628 inflammatory phase of, 2626 initiation phase of, 2626 molecular mechanisms of, 2624–2625 morphology of changes in, 2626–2627 pathophysiology of, 2626–2627 potentiation of, 2628 prevention of, 2628–2629 proliferation and fibrosis phase of, 2627 pulmonary function testing in, 2628 radiographic findings in, 2628 secondary changes in, 2627 sequence of changes in, 2627, 2627t signs and symptoms of, 2628 subacute, 2628 treatment of, 2628–2629

I-83 Index Oxyhemoglobin, 9 Oxytocin, pulmonary effects of, 1093 Ozone bronchiolitis caused by, 893t, 895 exposures to, 1019–1020 health effects of, 1019–1020 inhalation injury caused by, 1000t, 1002 National Ambient Air Quality Standards for, 1011t sources of, 1011t water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995t P P0.1 , 599 PA. See Alveolar pressure PA-824 (anti-TB drug), 2464 Pacemaker(s), 165 Pachydermoperiostosis, 433 Paclitaxel, pulmonary effects of, 1083–1084, 1083t PAE. See Postantibiotic effect Paecilomyces variottii, hypersensitivity pneumonitis caused by, 1164t PAH. See Polycyclic aromatic hydrocarbons Pain of aortic dissection, 420 cardiac, 419–420 chest wall, 418–419 esophageal, 420 musculoskeletal, 418–419 pleuritic, 418 pulmonary, 418 spinal causes of, 420 thoracic, 418–420 PALE. See Postantibiotic leukocyte enhancement Palivizumab, 2128, 2384, 2395 Palliative care, for ICU patients, 2733 Palliative therapy, definition of, 1895 Palpation, of chest, 390–392 PAMPs. See Pathogen-associated molecular patterns Panbronchiolitis computed tomography of, 1115t differential diagnosis of, 703 diffuse, 909–910, 910f in rheumatoid arthritis, 1204 Pancreatic cancer, metastases, survival rates for, 1941, 1942t Pancreatitis, and pleural effusion, 1495 Panton-Valentine leukocidin, 2058, 2081, 2098, 2132 Staphylococcus aureus strains with mortality rate for, 2112 pathology of, 2112 Pao. See Pressure at airway opening Papanicolaou, George, 511

PA–Pbs. See Transthoracic pressure Papillomatosis, respiratory, recurrent, 860 PA–Ppl. See Transpulmonary pressure Para-aminosalicylic acid adverse effects and side effects of, 2483t pneumonitis caused by, 2012t for tuberculosis, 2479–2480 dosage and administration of, 2482t Paracoccidioides, epidemiology of, 1984t Paracoccidioides brasiliensis, 2007 Paracoccidioidomycosis, 2007 Paraffin, and interstitial lung disease, 1111t Paragonimiasis, 1991, 2414t, 2425 and acute mediastinitis, 2166t clinical presentation of, 1495 cytopathology of, 524, 524f pleural effusion due to, 1495 staining characteristics of, 2035t Paragonimus, 2425 infection, pathology of, 2050 Paragonimus westermanii, 1995, 2414t, 2418t and eosinophilic pneumonia, 1214t infection, 1092 infection (incl. pneumonia), 2146 in lung abscess, 2154t pleural effusion due to, 1495 Parainfluenza virus, 1992 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t assays for, 1989t and bronchiolitis, 896, 2382–2383 characteristics of, 2375t and common cold, 2085, 2376, 2376t and croup, 2087–2088, 2376t, 2379 infection (incl. pneumonia) in adults, 2389 and asthma, 796, 816 in bone marrow and stem cell transplant recipients, 2228 chemokines in, 355 in children, 2130, 2391 immune defects and, 2139 cytopathology of, 523, 523f diagnosis of, 1999, 2001, 2002, 2106, 2394 in early infancy, 2129 in HIV-infected (AIDS) patients, 2258 in immunocompromised host, 2204, 2392 pathology of, 2043 seasonal variation in, 2374 and pharyngitis, 2086 staining characteristics of, 2035t type 3, vaccine against, 2380 Paramyxovirus immune response to, 343 serotypes of, 2374 Paraneoplastic pemphigus, 438, 438f

Paraneoplastic syndromes, 444–445, 1929–1938 endocrine, 1929, 1930t in small cell lung cancer, 1906 hematologic, 1935–1936 neurologic, 1936–1937, 1936t in small cell lung cancer, 1905t, 1906 in small cell lung cancer, 1904–1906, 1905t Parapneumonic effusions, 2154 image-guided drainage of, 535–536 management of, 2157–2158 Paraquat, pulmonary effects of, 1089 Parasitic infestation(s), 1990–1991, 1995, 2013. See also Helminthic disease(s) in cancer patients, 2219 cytopathology of, 523–524, 524f and diffuse alveolar damage, 2042 and eosinophilic pneumonia, 1214, 1214t, 1215–1216 in HIV-infected (AIDS) patients, 2242t, 2258 immune defect associated with, 1983t, 2210t and lung abscess, 2154t pathology of, 2045–2047, 2050 pleural, 1494–1495 staining characteristics of, 2035t Paraspinal line(s), 503f posterior, 459f, 500, 503f Parathyroid adenomas, 1611 Parathyroid hormone-related peptide (PTHrP), ectopic production of, 1930–1932, 1930t, 1931f Parenchyma, pulmonary age-related changes in, 264, 264t, 265f alveolar, 174f biomechanics of, 53–56 cells of morphometric characteristics of, 33t volume of, 33, 33t design of, 50–57 diseases affecting radiographic features of, 476–494 thoracoscopy in, 652–655 internal support of, 51–53 late alveolarization in, 97f, 105f, 106–108, 108f smoke and inhalation injury to, 1059–1060, 1060f unit of, 26 Parenteral nutrition, 2695 complications of, 2519, 2695, 2695t Parkinson’s disease upper airway obstruction in, 859 ventilatory impairment in, 1649 Paromomycin for cryptosporidiosis, 2404 indications for, 2401 Paronychia, chronic, 416 Parotid gland(s), obstruction, 281

I-84 Index Paroxysmal nocturnal dyspnea, 401–402 Paroxysmal nocturnal hemoglobinuria (PNH), risk of venous thromboembolism in, 1426 Partial liquid ventilation, in ALI/ARDS, 2558 Particulate matter in indoor air, sources of, 1021t in outdoor air exposures to, 1017–1019 health effects of, 1017–1019 PM2.5 , 1018 National Ambient Air Quality Standards for, 1011t sources of, 1011t PM10 , 1018 National Ambient Air Quality Standards for, 1011t sources of, 1011t Particulate soot, in indoor air, sources of, 1021t Parturition, respiratory response during, 256 Parvovirus, B19, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t PAS. See Para-aminosalicylic acid; Periodic acid Schiff (PAS) stain Pasteurella multocida, 1998, 2289, 2428t, 2429–2430. See also Pasteurellosis bacteriology of, 2428t, 2429–2430 culture of, 2429t ecology of, 2430 staining characteristics of, 2429t virulence factors, 2430 Pasteurellosis, 2428t clinical features of, 2430 diagnosis of, 2429t, 2430 differential diagnosis of, 2430 epidemiology of, 1984t, 2428t, 2430 pathogenesis of, 2430 pathophysiology of, 2430 radiologic features of, 2430, 2430f treatment of, 2429t, 2430 Patched, in lung development, 94 Patched 1 (Ptch1), 88f, 89 Patched receptor, 82, 85, 87, 88, 89f Pathogen(s) intracellular, immune response to, 1976f, 1977 isolation of, 2031, 2032t Pathogen-associated molecular patterns, 355, 355f, 1970, 1971 Pathogen recognition receptor(s), 1970, 1971 endocytic, 1970 secreted, 1970 signaling, 1970 PAVM. See Pulmonary arteriovenous malformation(s)

P-BAL. See Protected bronchoalveolar lavage (P-BAL, PTC-BAL) Pbs. See Pressure at body surface Pbx. See Plethysmograph pressure PC20 , in evaluation of permanent impairment in asthma, 683, 683t PCP. See Pneumocystis carinii PD20 . See Provocative dose Peak airway pressure, 2670–2671 Peak expiratory flow age-related changes in, 271–272, 272f in asthma, 833 definition of, 1327, 2739 in diagnostic spirometry, minimal recommendations for, 570t Peak expiratory flow rate, in upper airway obstruction, 846–847 Peclet number, 64–65, 64f Pectoralis major muscle, clavicular head of, actions of, 76 Pectus excavatum, 1624–1625 computed tomography of, 1624, 1624f exercise capacity with, 1624 pulmonary function testing in, 1620t respiratory mechanics in, 1619t, 1624 treatment of, 1624–1625, 1625f PEF. See Peak expiratory flow Pelvic infection, and anaerobic pleuropulmonary infections, 2145t PEmax . See Maximum expiratory pressure Pemphigus, paraneoplastic, 438, 438f Penciclovir, 2394 Penicillamine and interstitial lung disease, 1111t pneumonitis caused by, 2012t pulmonary effects of, 1089, 1091t, 1098, 1242, 1294 and vasculitis, 1464 Penicillin(s) allergy to, 2056, 2061t, 2062 amino-, 2056 for anaerobic infections, 2157, 2157t for anthrax, 2429t anti-pseudomonal, 2056 anti-staphylococcal, 2056 for community-acquired pneumonia, 2109 for meningococcal pneumonia, 2444 natural, 2056 for pasteurellosis, 2429t, 2430 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 pharmacology of, 2056 pneumonitis caused by, 2012t pulmonary effects of, 1090t resistance to, 2056, 2099, 2108 for staphylococcal pneumonia, in children, 2132 for streptococcal pharyngitis, 2086

Penicillin-binding protein 3, 2055 Penicillin G, 2056 Penicillin V, 2056 Penicilliosis, in HIV-infected (AIDS) patients, 2254, 2256 Penicillium contamination of bronchoscope, 2279 hypersensitivity pneumonitis caused by, 1163t, 1164t in indoor air, 1031 infection (incl. pneumonia) in cancer patients, 2217 in HIV-infected (AIDS) patients, 2212t in immunocompromised host, 2208 Penicillium marneffi, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2254, 2256 Pentamidine for acanthamoebiasis, 2401 adverse effects and side effects of, 2367, 2369 aerosol, 2366–2367 for leishmaniasis, 2409 for Pneumocystis pneumonia, 2367–2368, 2368t, 2369 prophylaxis, for Pneumocystis pneumonia, 2366–2367 Pentavalent antimony, for leishmaniasis, 2409 Pentoxifylline, for sarcoidosis, 1140, 1140t Pentraxin, PTX3, in aspergillosis, 2294 Pepper spray, inhalation injury caused by, 1003–1004 Peptic ulcer disease, smoking and, 752 Peptococci, 2007 in acute mediastinitis, 2166, 2166t infection (incl. pneumonia), 2156t nosocomial, 2281t Peptostreptococcus, 2007, 2086, 2142 in acute mediastinitis, 2166, 2166t in empyema, 2144, 2144t infection (incl. pneumonia), 2156, 2156t conditions underlying, 2145t nosocomial, 2281t in lung abscess, 2144 Peptostreptococcus anaerobius, in empyema, 2144t Peptostreptococcus magnus, in empyema, 2144t Peptostreptococcus micros, in empyema, 2144t Percussion of chest, 392 historical perspective on, 14 Percutaneous transluminal angioplasty and stenting, venous, 540 Percutaneous ventilation, 2654–2655 Perflubron, 2558 Perforans, 1977

I-85 Index Peribronchovascular infiltrate. See Pneumonia, interstitial Peribronchovascular space, 53 Pericardial effusion with pneumonia, 2028 radiographic evaluation of, 460 Pericardial fluid, imaging of, 2028 Pericardial window, 658 Pericarditis, 2028 amebic, 2400, 2400f, 2401 in histoplasmosis, 2337 pain of, 419 radiation-induced, 1892 in respiratory failure, 2519 Perichondritis, 2091–2092 Pericyte(s), 39 of alveolar septum, 40f, 41 Periodic acid Schiff (PAS) stain, 2035t, 2037 Periodic breathing, altitude and, 1040 Periodontitis, 2087, 2101t Peripheral nervous system abnormalities, and respiratory failure, 2514 disorders, ventilatory impairment in, 1653–1655 Peristalsis primary, 1304 secondary, 1304 Peritoneal infection, and anaerobic pleuropulmonary infections, 2145t Permissible exposure limits, 941 Peroxynitrite, 360, 2625, 2625f biochemical alterations caused by, 2625–2626, 2626t cellular dysfunction caused by, 2625–2626, 2626t Pertactin, 2069, 2080 Pertechnegas, 549, 551 Pertussis diagnosis of, 1999 differential diagnosis of, 2382 vaccine against, 2066t, 2069 Pertussis toxin, 2069, 2080 PET. See Positron emission tomography Pet(s), and risk of asthma, 794 PET/CT, 547–548, 564–565 applications of, 564–565 attenuation artifacts, 565, 565f of lung cancer, 564 Petriellidium boydii, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t Pfl¨uger, 8 PF ratio, in acute respiratory failure, 2669 p53 gene and cell cycle, 1810–1811 in lung cancer, 1805–1806 Phage technology, for rapid diagnosis of mycobacteria, 2462

Phagocyte(s) defects of immunologic work-up of, 2234t pulmonary infection in, 2237–2239 epithelium and, 143–144 reusable, 283 Phagocytosis, 280, 282, 283, 1972–1973 bacterial resistance to, 2080 phases of, 283 Phagolysosome(s), 42 Phantom tumor, 505 Pharmaceuticals, and occupational asthma, 985t, 986 Pharmacodynamics of antibiotics, 2054–2055 definition of, 2054 Pharmacokinetics of antibiotics, 2054–2055 definition of, 2054 Pharmacotherapy, 2631–2644. See also specific drug for obstructive sleep apnea, 1714 Pharyngeal cancer, and aspiration, 1310 Pharyngeal muscle stimulation, for obstructive sleep apnea, 1715 Pharyngitis, 2086 in Chediak-Higashi syndrome, 2238 clinical features of, 2377–2378 diagnosis of, 2378 differential diagnosis of, 2378 epidemiology of, 2086 exudative, 2086 in HIV-infected (AIDS) patients, 2086 nonexudative, 2086 pathogenesis of, 2378 prevention of, 2378 streptococcal, 2086, 2378 and laryngitis, 2087 treatment of, 2378 viral causes of, 2086, 2376t, 2378 Pharyngoconjunctival fever, 2378 Pharynx anatomy of, 1299, 1300f mucosa, traumatic alteration, and aspiration, 1310 Phenacetin, methemoglobinemia caused by, 416 Phenylephrine and airway smooth muscle proliferation, in vitro, 118 and pulmonary circulation, 1347 Phenytoin and interstitial lung disease, 1111t pneumonitis caused by, 2010, 2012t pulmonary effects of, 1089, 1090t, 1092, 1097 Pheochromocytoma mediastinal, 1611 radiographic features of, 502f Phialophora, infection (incl. pneumonia), in cancer patients, 2217

Phlebotomy, for polycythemia, 1378 Phlogiston, 5t, 7 Phosgene bronchiolitis caused by, 893t, 894 inhalation injury caused by, 1000t, 1002 in smoke and inhalation injury, 1054, 1057 source of, 1054t water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995t Phosphodiesterase inhibitors, for pulmonary arterial hypertension, 1388 Photodynamic therapy, 639 bronchoscopy in, 639 in upper airway obstruction, 862 Phrenic nerve dysfunction in neuromuscular disease, 1653 ventilatory impairment in, 1668t Phrenic nerve injury, 2586–2587 Phrenic nerve stimulation, 1644–1646, 1645f Phrenic neurons, 166 pH-temperature relationship, and acid-base balance, 214 Phthalic acid, and occupational asthma, 989 Phthiocerol dimycoserate, 2461 Physical–chemical synthesis, knowledge of, historical perspective on, 5t, 10–11 Physical examination, of patient with respiratory symptoms, 389–393 Physiological dead space, 592 ratio of, to tidal volume definition of, 1327, 2736, 2739 in Langerhans’ cell histiocytosis, 1248, 1248f in lymphangioleiomyomatosis, 1258, 1258f normal, 1324, 2736 and ventilatory demands of exercise, 235f, 236, 238–241, 239f, 240f Pickwickian syndrome, definition of, 1698 Picornavirus, 1992 and common cold, 2376, 2376t PIE. See Pulmonary infiltrate with eosinophilia Pierre-Robin syndrome, 2647 PIE syndrome, 2013 Pigeon breeder’s disease, 1161–1162, 2012 clinical features of, 1162 etiology of, 1164t prognosis for, 1162, 1171 radiographic features of, 1166f PIIA. See Postinspiratory inspiratory activity PI3K, in G protein–coupled chemoattractant receptor signaling, 353, 353f

I-86 Index Pilmx hypertension, primary, in collagen vascular disease, 1194t Pilus (pl., pili), 2080 PImax . See Maximum inspiratory pressure Pimecrolimus, 428 Pindolol, pulmonary effects of, 1097 a-Pinene exposure to, 1027t sources of, 1027t Pink puffer, 476, 713, 1403–1405, 1406f PIOPED. See Prospective Investigation of Pulmonary Embolism Diagnosis Piperacillin, 2056 for cystic fibrosis patient, 875 Piperacillin/tazobactam, 2056 for hospital-acquired pneumonia, 2061, 2061t, 2062 indications for, 2157 Piperazine, for ascariasis, 2418t Pirbuterol adverse effects and side effects of, 824t for asthma, 823t, 824t for chronic obstructive pulmonary disease, 738t, 739 dosage and administration of, 824t dosage forms, 2632t receptor activity, 2632t structure-activity relationships, 2633 Pirfenidone, for idiopathic pulmonary fibrosis, 1158 Piritrexim, for Pneumocystis pneumonia, 2368t PIRO classification system, 2562–2563, 2563t Piroxicam, and aspirin-induced asthma, 802t PISAPED. See Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis Pituitary snuff taker’s disease, etiology of, 1164t Plague, 2006, 2428t. See also Yersinia pestis bubonic, 2431 clinical presentation of, 2431 diagnosis of, 2429t, 2432 differential diagnosis of, 2432 epidemiology of, 1984t, 2428t, 2431 historical perspective on, 2430–2431 multidrug resistant, 2432 pathogenesis of, 2431 pathophysiology of, 2431 pneumonic, 2430–2431, 2432 prevention of, 2432 radiologic features of, 2431–2432 spread of, 2431 treatment of, 2429t, 2432 vaccine against, 2432 Plain film radiography, 2017, 2018f Plants, and occupational asthma, 985t, 986 Plaque dental, 281

pleural, asbestos-related clinical features of, 945 diagnosis of, 946 epidemiology of, 944–945 natural history of, 944–945 pathogenesis of, 944 pathology of, 944 pathophysiology of, 945 radiographic features of, 945–946, 945f, 947f treatment of, 946 Plasma cell(s), 42, 280f Plasma cell granuloma, 1918–1919, 2014 Plasmacytoma, 1925 of lung, 1962, 1962f Plasmalemmal vesicles, 31, 34 Plasmodium falciparum, 2405–2407, 2406f Plasmodium malariae, 2405 Plasmodium ovale, 2405–2407 Plasmodium vivax, 2405–2407 Plateau pressure, 2670, 2670f, 2671 Platelet-activating factor (PAF), 311, 315, 350 eosinophil, 310t, 314 mast cells and, 310t, 312 Platelet-derived growth factor (PDGF) and airway smooth muscle proliferation, in vitro, 118 effects/functions of, 781t and lung development, 87 sources of, 781t targets of, 781t Platelet-endothelial cell adhesion molecule, PECAM-1, in inflammation, 783 Platelet factor-4, 340t, 341t Platelet inhibitors, and diffuse alveolar hemorrhage, 1295 Platinum, and occupational asthma, 990 Platyhelminths, 2413 Platypnea, 400–401 PLCH. See Langerhans’ cell histiocytosis, pulmonary Pleconaril, 2086 Pleistophora, 2410 Pleomorphic carcinoma, 1840–1841 Plethysmograph(s) pressure, 572–573, 573f pressure-corrected flow, 572–573 volume, 572 Plethysmograph pressure, 584, 584f Plethysmography body, 571, 572–574, 573f definition of, 572 Pleura. See also Pleural thickening biopsy of, 651 development of, 95, 95f lymphomas of, 1964–1965 metastases to, 505f nodules of, radiographic features of, 505f, 507

parietal, 23–24, 24f radiographic evaluation of, 503–508 tumors of. See also Mesothelioma primary, 1550–1552 solitary fibrous, 1550, 1551f visceral, 23–24, 24f Pleural effusion, 392, 2050. See also Benign asbestos pleural effusions and abnormal breathing pattern, 403 acute benign, asbestos-related, 947–948, 947f asbestos-related, 947–948, 947f, 1498–1499 atelectasis with, 480 bilateral, 506 in bone marrow and stem cell transplant recipients, 2225 causes of, 2153 in collagen vascular disease, 1194t drug-induced, 1498 esophageal perforation and, 1495–1496 fungal, 1494 in heart failure, 494 in HIV-infected (AIDS) patients, 1502, 2215 intra-abdominal abscess and, 1496, 1496f laboratory examination of, 2154 loculated, 505–506 in lung transplant recipient, 1789 malignant, 1505–1515 causes of, 1505–1506, 1506t clinical presentation of, 1507–1509 diagnosis of, 1511–1512 fluid characteristics in, 1510–1511 management of, 1513–1515, 1513t pathogenesis of, 1506–1507 prognosis for, 1512 radiographic findings in, 1509–1510, 1509f–1510f thoracoscopic management of, 651–652 management of, 2157–2158 with mediastinitis, 2167 in mixed connective tissue disease, 1209 non-malignant, 1487–1502 causes of, 1487, 1488t differential diagnosis of, 1487, 1488t evaluation of, 1487–1488 exudative, 1487–1488, 1488t transudative, 1487–1488, 1488t pancreatitis and, 1495 paramalignant, 1505 causes of, 1505, 1506t management of, 1513–1515, 1513t parapneumonic, 1488–1489 drainage of, 1490–1491, 1491f thoracostomy for, 1489, 1490t with pneumonia, 2028 in post-cardiac injury syndrome, 1502 postoperative, 1501

I-87 Index pulmonary embolism and, 1495 pulmonary Langerhans’ cell histiocytosis and, 1246 radiation-induced, 1184 radiographic features of, 457–458, 457f, 458f, 503–506, 505f, 506f on portable examination, 508 rheumatoid, 505f in rheumatoid arthritis, 505f, 1202 in sarcoidosis, 1501–1502 in scleroderma, 1206 in staphylococcal pneumonia, in children, 2132 in streptococcal pneumonia, in children, 2133 thoracoscopic management of, 651 in tuberculosis, 2472–2473, 2473f tuberculous, 1493–1494 unilateral, causes of, 506 in uremic pleuritis, 1502 viral, 1494 in yellow nail syndrome, 1502 Pleural fluid cellular composition of, 24 circulation of, 24 homeostasis of, 24 imaging of, 2028 infrapulmonary, 458f, 503–505 laboratory examination of, 2154 loculated, 505–506 subpulmonic, 503 volume of, 24 Pleural friction rub, 393 in pneumonia, 2099 radiation-induced, 1184 Pleural pressure(s), 152, 575, 575f during breathing cycle, 148, 148f in chronic obstructive pulmonary disease, 398 gradients, in upright lungs, 157, 158f measurement of, historical perspective on, 11–12 Pleural thickening, 2028 diffuse asbestos-related clinical features of, 946 diagnosis of, 946–947 pathogenesis of, 946 pathology of, 946 pathophysiology of, 946 radiographic features of, 946, 947f treatment of, 947 radiographic features of, 506 Pleurectomy, for mesothelioma, 1548 Pleurisy in interstitial lung disease, 1108 in mixed connective tissue disease, 1209 in rheumatoid arthritis, 1202 Pleuritic pain, 418 pulmonary Langerhans’ cell histiocytosis and, 1246 radiation-induced, 1184

Pleuritis, 2028, 2050, 2050f lupus, 1200 radiation-induced, 1184 uremic, 1502 Pleurodesis for mesothelioma, 1547–1548 for pneumothorax, 1527–1529 thoracoscopic, 651–652 Pleuroscopy, 649 Plexogenic arteriopathy, 1196 in CREST syndrome, 1207–1208 in rheumatoid arthritis, 1202 in scleroderma, 1207 in systemic lupus erythematosus, 1201 Plugged telescopic catheter sampling, 1987 in nosocomial pneumonia, 2283 PMF. See Progressive massive fibrosis PNA. See Protein nucleotide agglutination PNE. See Pulmonary neuroendocrine cells Pneumatocele, 1989 in hyperimmunoglobulin E syndrome, 2239 Pneumococcal vaccine(s), 2066–2068, 2066t, 2111, 2132 in chronic obstructive pulmonary disease, 734 Pneumococcus, transmission of, in indoor air, 1032 Pneumoconiosis coal worker’s, 2025 computed tomography of, 1115t definition of, in Black Lung Benefit Act, 689 evaluation for, International Labor Organization classification system for, 680 FDG-PET in, 565 fever in, 420 hard metal, 1106t imaging of, 2022 impairment due to, evaluation of, 684 lymphadenopathy in, 2028 metal-induced, exposures associated with, 1109t occupational, 934, 934t radiographic features of, 483 scintigraphy in, 559 severity of, Social Security Listings for, 686 Pneumocystis, infection (incl. pneumonia) bronchoalveolar lavage cellular profile in, 1121t pathology of, 2043t Pneumocystis carinii, 1985, 1986, 1987 attack rates, 2354t cytomorphology of, 521, 521f, 522f drug resistance in, 2366 extrapulmonary disease, 2356f, 2358 growth of, 2353 histologic diagnosis of, 2361–2364, 2363f historical perspective on, 2351–2352

infection (incl. pneumonia), 422f, 1995, 1996, 1997, 2351–2370 in acute lymphoblastic leukemia, 2354t adjunctive therapies for, 2370 in bone marrow and stem cell transplant recipients, 2223, 2224f, 2229 in cancer patients, 2215, 2221, 2221t in cell-mediated immunodeficiency, 2236 with central nervous system tumor, 2354t in children, 2355 in chronic granulomatous disease, 2237 clinical presentation of, 2356–2358 coinfections (dual infections) with, 2358, 2360f in collagen vascular disease, 2354t in common variable immunodeficiency, 331–332, 2235 conditions associated with, 2354, 2354t corticosteroid therapy and, 2355 corticosteroid therapy for, 2370 cytology of, 2357f cytomegalovirus infection and, 2355, 2357f, 2358, 2359, 2360f, 2364 cytopathology of, 520–522, 521f–522f diagnosis of, 1999–2000, 2003, 2358–2365 in DiGeorge’s syndrome, 2236 in early infancy, 2130 epidemiology of, 2354–2356 fiberoptic bronchoscopy in, 2361t, 2364–2365 gallium-67 citrate imaging in, 557, 558f in HIV-infected (AIDS) patients, 2212, 2212t, 2213, 2251, 2252, 2351, 2352, 2354–2355, 2356f clinical presentation of, 2246, 2356–2358 empiric therapy for, 2262, 2262f, 2263f prevention of, 2365–2367 radiographic findings in, 2214–2215, 2214t, 2215, 2248, 2249t, 2359, 2360 in Hodgkin’s disease, 2354t in hyper-IgM immunodeficiency, 2236 immune defect associated with, 1983t, 2210t immune response to, 2355–2356, 2358 in immunocompromised host, 2204, 2208, 2351, 2354, 2354t laboratory findings in, 2361, 2361t lung biopsy in, 2361t, 2365

I-88 Index Pneumocystis carinii (Cont.) in lung transplant recipient clinical presentation of, 2356–2358 radiographic findings in, 2359 in neutropenic host and cancer patient, 2217, 2218, 2355 nosocomial, 2280t nuclear medicine scans in, 2359–2360 in organ transplant recipient, 2230, 2232, 2355, 2356 clinical presentation of, 2356–2358 prevention of, 2367 pathophysiology of, 424 percutaneous needle aspiration in, 2361t, 2365 prophylaxis, 2365–2367 in purine nucleoside phosphatase deficiency, 2237 radiographic findings in, 483, 2356f, 2357f, 2358–2361, 2359f, 2360f in rhabdomyosarcoma, 2354t scintigraphy in, 559 in severe combined immunodeficiency, 2236, 2354t sputum examination in, 2361–2364, 2361t in stem cell transplant recipient, 2224f tracheal aspiration in, 2361t, 2364 transmission of, 2355 treatment of, 2352, 2367–2370, 2368t response to, 2370 in Wegener’s granulomatosis, 2354t in Wiskott-Aldrich syndrome, 2237 in X-linked agammaglobulinemia, 2234 latent infection, reactivation of, 2355 life cycle of, 2352–2353, 2352f in lung abscess, 2154t major surface glycoprotein, 2353–2354 microbiology of, 521 molecular biology of, 2353–2354 molecular detection of, 2002 reinfection, 2355 staining characteristics of, 2356f, 2357f, 2362–2364, 2363f strains of, 2353 structure of, 2352, 2352f taxonomy of, 2353 Pneumocystis jiroveci, 2031, 2351 and diffuse alveolar damage, 2042 infection (incl. pneumonia), 2025, 2027f in children, 2136–2137, 2137f immune defects and, 2139 differential diagnosis of, 2255 epidemiology of, 2098 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2101, 2245, 2253–2254, 2254f hospitalization rate for, 2105t

lymphadenopathy in, 2028 pathology of, 2047, 2047f in pediatric HIV-infected (AIDS) patients, 2139 pneumothorax in, 1523–1524 treatment of, 2054, 2056 Pneumocystosis, pulmonary alveolar proteinosis complicated by, 2014 Pneumolysin, antibody assay, 2106, 2130 Pneumomediastinum, 1557–1560, 2167, 2167f anatomic considerations in, 1557, 1558f–1559f etiology of, 1557, 1560t mechanical ventilation and, 1559–1560 in pregnancy, 259t spontaneous, 1557–1558 Pneumonectomy extrapleural, for mesothelioma, 1548 hemoptysis after, 414 preoperative evaluation for, 670–673 pulmonary edema after, and respiratory failure, 2584 pulmonary function testing before, 671 VATS technique, 656–657 Pneumonia alveolar (airspace), 1995–1996 in anatomic disorders, 1982t ancillary findings in, 2027–2028 approach to patient with, 1981–1987 atypical, 2005–2007, 2005t, 2099 in children, 2133 bacterial, 1988–1991, 2005t, 2006, 2023.

See also Bacterial infection(s); specific bacterium animal product, 2435–2441 in children, 2130–2134 chest radiographs in, 2130, 2131f clinical features of, 2130 etiologic diagnosis of, 2131 laboratory findings in, 2130 microbiology of, 2131 pathogenesis of, 2130 treatment of, 2131 complicating influenza, 2388 in early infancy, 2127–2128, 2127f environmental, 2435–2441 in HIV-infected (AIDS) patients, 2245, 2246, 2248, 2249t, 2250–2253, 2251f, 2252f radiographic findings in, 2249t in lung transplant recipient, 1790 neonatal, 2125–2127 obligate human commensals causing, 2441–2445 pathogenesis of, 1988–1991 pathology of, 1988–1991 in pediatric HIV-infected (AIDS) patients, 2139 secondary to viral infection, in children, 2135 unusual, 2428, 2428t

in bone marrow and stem cell transplant recipients, 2222 broncho-, 1986f, 1995, 1996 in cancer patients, 2216 causes of, 2220, 2221t differential diagnosis of, radiologic findings in, 2220–2221, 2221t cavitating, 2148f in HIV-infected (AIDS) patients, 2214t, 2215 microbiology of, 2146 centrilobular, 2018, 2020–2022 in Chediak-Higashi syndrome, 2238 in children after first 6 months of life, 2130–2134 bacterial, 2130–2134 complicating viral exanthems, 2135 in early infancy, 2127–2130 morbidity associated with, 2125 mortality from, 2125 neonatal, 2125–2127 recurrent, 2137–2139, 2137f viral, 2130 cholesterol, 2014 in chronic granulomatous disease, 2237 classification of, by clinical setting, 1981, 1982t clinical manifestations of, 2099 clinical specimens in, examination of, 1985–1987, 1987f in common variable immunodeficiency, 331 community-acquired, 1982t, 2004–2007 adjunctive therapy for, 2110–2111 anaerobes in, 2143, 2143t in children, 2130 clinical manifestations of, 2099 complicated course in, risk factors for, 2101–2102, 2107t definition of, 2097 diagnostic work-up for, 2104 empiric therapy for, 2108, 2109t epidemiology of, 2004, 2098 etiology of, 2004, 2101, 2104t–2106t in HIV-infected (AIDS) patients, 2098 hospitalization for, admission decision, 2101–2104 hospitalization rate for, 2098 in immunocompromised host, 2098 microbiology of, 2098 mortality from functional status for previous week and, 2103–2104 predictive clinical rules for, 2102, 2107t, 2108t risk factors for, 2101–2102, 2107t mortality rate for, 2005, 2098 in organ transplant recipients, 2098 outcomes with, 2110 timing of treatment and, 2060

I-89 Index pathogens causing, 2059, 2059t prevention of, 2111–2112 requiring hospitalization, etiology of, 2101, 2105t requiring ICU care, etiology of, 2101, 2106t risk factors for, 2098 severity-of-illness scoring system for, 2102, 2107t, 2108t treatment of, 2051–2052, 2059–2061, 2108–2110 failure of, 2110, 2111t initial regimen for, 2059–2060 quality of care measures for, 2112–2114 worsening during treatment, 2110, 2111t consolidation in, 1988t cryptococcal, diagnosis of, 2002 cryptogenic organizing. See Cryptogenic organizing pneumonia in cystic fibrosis, 1982t definition of, 2097 diagnosis of, 1982t, 1985–1987 diffuse in bone marrow and stem cell transplant recipients, 2225 radiographic features of, 482 diffuse lung opacification, 2018 etiology of, 2025 imaging of, 2025, 2027f pathogenesis of, 2025 drug-induced organizing, 1089–1091, 1090t in early infancy, 2127–2130 in elderly, 1982t, 2007 etiology of, 2101 prevention of, 2111 signs and symptoms of, 2099 treatment of, 2110 eosinophilic. See Eosinophilic pneumonia(s) epidemiology of, 1984, 1984t, 2098 etiologic diagnosis of, 2101, 2104t etiology of clues to, in history and physical exam, 2099, 2100t–2101t and imaging, 2018 evaluation of patient with, 1981, 1982t in evolution, 2009 focal opacity in, 1988t fungal, 1990, 1994–1996, 2023, 2025 diagnosis of, 1999, 2002 sputum culture for, 2000 in HIV-infected (AIDS) patients, 2253–2257 imaging of, 2019 in immunocompromised host, 1997 giant cell, in immunocompromised host, 2392–2393

health care–associated, 2007, 2008–2009, 2008f, 2051, 2193, 2273–2274 hemoptysis in, 410, 413 history-taking in, 1982t, 1984–1985 in HIV-infected (AIDS) patients, 1997, 2021, 2023, 2207–2208, 2207f, 2208f etiology of, 2101, 2106t hospital-acquired, 2008–2009, 2008f, 2193, 2273–2274 adequate therapy for, 2061 antibiotic therapy for, 2061–2062, 2061t appropriate therapy for, 2061 definition of, 2097–2098 diagnosis of, 2003 empiric therapy for, 2061–2062, 2061t treatment of, 2051–2052 host defenses and, 1982–1983, 1983t in hyperimmunoglobulin E syndrome, 2239 idiopathic, in bone marrow and stem cell transplant recipients, 2225–2227, 2225t imaging of, ancillary findings in, 2027–2028 in immunocompromised host, 1982t, 1997, 2022, 2023–2024, 2207–2208, 2207f, 2208f differential diagnosis of, 1988t radiographic features of, 1988t institution-acquired, 2098 interstitial, 1995, 1996–1997 acute. See Acute interstitial pneumonia in bone marrow and stem cell transplant recipients, 2225 chronic, of unknown cause, 2013 desquamative. See Desquamative interstitial pneumonia giant cell. See Giant cell interstitial pneumonia idiopathic. See Idiopathic interstitial pneumonia lymphocytic. See Lymphoid interstitial pneumonia lymphoid. See Lymphoid interstitial pneumonia nonspecific. See Nonspecific interstitial pneumonia radiographic features of, 483, 491f usual. See Usual interstitial pneumonia laboratory testing in, 1982t, 1985 lipid, cytopathology of, 524, 525f lipoid, 2014 in allergic bronchopulmonary aspergillosis, 842 computed tomography of, 1115t lobar, 1995–1996, 1996f, 2018

abnormal breathing pattern in, 403 etiology of, 2019 imaging of, 2019–2020, 2019f pathogenesis of, 2018–2019 lymphoid interstitial, in pediatric HIV-infected (AIDS) patients, 2139 macronodular, 2023f, 2024, 2024f differential diagnosis of, 2020 management of antimicrobial therapy for, 1987 guidelines for, 1983–1987 meningococcal, 2428t, 2441–2444. See also Neisseria meningitidis epidemiology of, 2428t microbiology of, 1982t, 1984t, 1985–1987, 2193, 2194 micronodular, 2018 etiology of, 2024, 2025 intermediate, 2024 imaging of, 2025, 2026f miliary, 2018, 2024, 2025, 2026f imaging of, 2025, 2026f mineral oil, 1110t–1111t morbidity associated with, 2065 in children, 2125 mortality from, 2051–2052 in children, 2125 in hospitalized patients, 2110 mortality rate for, 2065, 2098 mycobacterial, 2023 mycoplasmal, differential diagnosis of, 2443 necrotizing, 1988, 1989, 1990f, 2007, 2028, 2141, 2148f, 2153 microbiology of, 2144–2146 in surgery and trauma patients, 2199 neonatal, 2125–2127 nodular, 2018, 2022–2024 etiology of, 2022–2024 imaging of, 2024, 2024f, 2025f noninfectious processes mimicking, 2024 pathogenesis of, 2022 with nodular infiltrates, 1995, 1997 nonresolving, 2008–2009, 2008f nosocomial, 1982t, 2020, 2051, 2193, 2196, 2518t, 2519 anaerobes in, 2143, 2143t approach to, 2274 bacterial, 2008–2009 costs of, 2273 definition of, 2097–2098, 2273 diagnosis of, 2194, 2283–2285, 2284t enteral nutrition and, 1311 epidemiology of, 2273 evaluation of patient for, 2008, 2008f in immunocompromised host, treatment of, 2288 incidence of, 2275–2277, 2276t microbiology of, 2193, 2273, 2279–2283, 2581

I-90 Index Pneumonia, nosocomial (Cont.) mortality rate for, 2273, 2279, 2279t in neonates, 2126–2127 pathogenesis of, 2274–2275, 2275f polymicrobial, 2280, 2281t prevention of, 2273, 2288–2289, 2288t, 2582 and respiratory failure, 2580–2582 risk factors for, 2193–2194, 2277–2278, 2278t, 2580–2581 hospital, 2277–2278 intrinsic (host), 2277, 2278t transmission of pathogens in, 2274 treatment of, 2273, 2285–2288, 2285f, 2286t, 2287t, 2582 in nursing home patients mortality from, 2110 treatment of, 2111 obstructive in cancer patients, 2217, 2217f in neoplasia, 2014 organizing computed tomography of, 1115t drug-induced, 1110t–1111t in organ transplant recipient, 2229–2232 radiologic diagnosis of, 2230–2232, 2231f, 2232f, 2233t outcomes with, factors affecting, 2004, 2004t, 2005 pathogens causing, 1984, 1984t peribronchiolar, 2018, 2020–2022 physical findings in, 1985, 2099, 2100t–2101t plague, 2006 pneumococcal, 1985, 1995, 1996f, 2004.

See also Streptococcus pneumoniae in children, 2131–2132 clinical features of, 452 diagnosis of, 2001, 2106 drug-resistant, 2065 in HIV-infected (AIDS) patients, 2098, 2101 mortality rate for, 2005 in pediatric HIV-infected (AIDS) patients, 2139 penicillin-resistant epidemiology of, 2099 risk factors for, 2099 postantibiotic effect in, 2054 treatment of, 2055, 2056, 2057, 2060–2061, 2108–2110 Pneumocystis. See Pneumocystis carinii; Pneumocystis jiroveci polymicrobial, 2101t hospitalization rate for, 2105t postobstructive, 2110 in cancer patients, 2221, 2221t hospitalization rate for, 2105t postoperative, 2193–2200. See also Pneumonia, nosocomial

after lung resection, 1746–1747 and respiratory failure, 2580–2582 posttraumatic, 2193–2200. See also Pneumonia, nosocomial in pregnancy, 259t prognosis for, 2004, 2004t, 2005 progressive, 2028 radiographic diagnosis of, 2099–2101, 2101f–2103f radiographic features of, 477, 477f radiologic findings in, 1982t, 1985, 1986f, 1987f, 1988t, 1995–1997 radiology of, modalities for, 2017–2018 recurrent, in children, 2137–2139, 2137f in different locations, 2138 focal, 2137–2138, 2137f pulmonary defense defects and, 2138 systemic host defense defects and, 2138–2139 round, 2022–2024 seasonal occurrence of, 2098 spherical, 1995 streptococcal, 2042–2043 pathology of, 2042–2043 in surgery and trauma patients, 2193–2200. See also Pneumonia, nosocomial clinical features of, 2197–2199 complications of, 2198–2199 diagnosis of, 2194, 2197–2199 early-onset, 2197 epidemiology of, 2194 late-onset, 2197 microbiology of, 2193, 2197 mortality rate for, 2194 pathogenesis of, 2196–2197 prevention of, 2194, 2195t, 2199 risk factors for, 2193–2196 operative, 2195, 2195t postinjury, 2195t, 2196 postoperative, 2195t, 2196 preinjury, 2194–2195, 2195t trauma-related, 2195–2196, 2195t treatment of, 2194, 2199–2200 systemic effects of, 451–453, 451t tuberculous, hemoptysis in, 413 tularemic, 2006. See also Tularemia typical, 2099 unresolving, in immunocompromised host, 2009–2010 ventilator-associated, 2008–2009, 2008f, 2020, 2193, 2273–2274 costs of, 2273 definition of, 2197 diagnosis of, 2197, 2198t incidence of, 2275–2277, 2276t invasive diagnostic testing in, 2003 microbiology of, 2196, 2282 mortality rate for, 2276t risk factors for, 2277–2278, 2278t treatment of, 2051–2052, 2058–2059 viral, 2025, 2027f, 2388–2395

in adults, 2388, 2389–2390 causes of, 2376t and bacterial superinfection, 2388 in bone marrow and stem cell transplant recipients, 2228 causes of, 2376t, 2388–2393 in children, 2135, 2388, 2391 causes of, 2376t chest radiographs in, 2130, 2131f differential diagnosis of, 2394 clinical features of, 2388 diagnosis of, 2393–2394 differential diagnosis of, 2388–2393 in DiGeorge’s syndrome, 2236 in HIV-infected (AIDS) patients, 2257–2258 in immunocompromised host, 2391–2393 causes of, 2376t pathogenesis of, 2393 prevention of, 2394–2395 treatment of, 2394–2395 Pneumonia Severity Index, 2028 Pneumonitis aspiration, 2198. See also Aspiration pneumonia chemical, 2150–2151, 2150t chronic, in Wiskott-Aldrich syndrome, 2237 drug-induced, 2010–2011, 2011t, 2542t in cancer patient, 2221, 2221t in immunocompromised host, 1997 hypersensitivity, 330, 2012 aspergillosis and, 2294, 2295t in nontuberculous mycobacterial infection, 2502 Rhizopus and, 2319 interstitial, 896 in allergic bronchopulmonary aspergillosis, 842 desquamative, radiographic features of, 482 in scleroderma, 430 lupus, 2541t lymphocytic interstitial, in HIV-infected (AIDS) patients, 2214t, 2215, 2260, 2260f noninfectious, in cancer patient, 2221 pathogenesis of, 283 post-obstructive, 2020 radiation. See Radiation pneumonitis Pneumopericardium, 1560 Pneumoperitoneum, 2167 diagnostic, 469 in respiratory failure, 2519 Pneumotachography, 569–570, 569f Pneumotaxic center, 12 Pneumothorax, 24, 2028 and abnormal breathing pattern, 403 after needle biopsy, 534–535 aspiration of, 1526–1527, 1528f bronchoscopy-related, 644–645

I-91 Index with bulla, 925 in bullous lung disease, 918, 920f catamenial, 1523 in chronic obstructive pulmonary disease, 742–743 treatment guidelines for, 1530–1531 clinical features of, 1524 complications of, 1531–1533 in cystic fibrosis, 1521–1522, 2176 treatment guidelines for, 1531 diagnostic, 469 in HIV-infected (AIDS) patients, 1523–1524 treatment guidelines for, 1531 iatrogenic, 1517 treatment guidelines for, 1531 in interstitial lung disease, 1115t in lung transplant recipient, 1789 observational management of, 1526 and open chest wound, in trauma patient, emergency department interventions for, 1758 operative therapy for, 1529–1530 pathophysiology of, 1517–1518, 1518f with percutaneous aspiration of solitary pulmonary nodule, 1824, 1825f pleurodesis for, 1527–1529 pulmonary barotrauma and, 1047 pulmonary Langerhans’ cell histiocytosis and, 1246 radiographic features of, 507–508, 507f, 1524–1526, 1525f, 1526f reabsorption of, 1518–1519, 1519f secondary, VATS management of, 654 simple, in trauma patient, emergency department interventions for, 1758 size of, calculation of, 1525, 1526f spontaneous, 1517 primary, 1517 epidemiology of, 1519 etiology of, 1519–1520 incidence of, 1519 treatment guidelines for, 1530, 1531t secondary, 1517 epidemiology of, 1520 etiology of, 1520–1521, 1521t incidence of, 1520 treatment guidelines for, 1530–1531 smoking and, 751 VATS management of, 653–654, 653f tension, 1531–1532 in trauma patient, emergency department interventions for, 1758, 1758f treatment guidelines for, 1531 thoracoscopy for, 1530 with transthoracic needle aspiration and biopsy, 647 traumatic, 1517, 1522–1523 treatment guidelines for, 1531

treatment of, 1526–1531 tuberculous, 2469, 2470f PNP. See Paraneoplastic pemphigus Pod1, 87 Poikiloderma, photodistributed, 428–429, 429f Poiseuille’s law, 570 Poliomyelitis, ventilatory impairment in, 1651, 1668t Pollen(s) in indoor air, 1030t sources of, 1022t and risk of asthma, 794 Pollen inhalational challenge test, 585t Pollutant(s), environmental, 795 Polyangiitis overlap syndrome, 2013.

See also Microscopic polyangiitis Polyarteritis nodosa, 2013 classic, 1461 cutaneous manifestations of, 435 Polychlorinated biphenyls exposure to, 1027t sources of, 1027t Polycyclic aromatic hydrocarbons, 1020 exposure to, 1027t sources of, 1027t Polycythemia, 1378 adaptation to, 230 cyanosis due to, 415 Polycythemia vera, risk of venous thromboembolism in, 1426 Polymerase chain reaction (PCR), 2002, 2033 in detection of Aspergillus, 2308–2309 in diagnosis of coccidioidomycosis, 2344 in diagnosis of histoplasmosis, 2338 multiplex, 2106–2107, 2130 Polymer fume fever, 1005–1006 occupational, 934t Polymorphonuclear leukocytes, 280, 282, 283, 1973 Polymyositis-dermatomyositis, 428–429, 428f, 429, 429f. See also Collagen vascular disease alveolar hemorrhage in, 1293 aspiration pneumonia in, 1208 BOOP in, 905 clinical features of, 1117t computed tomography of, 1117t histology of, 1117t interstitial lung disease in, 1208–1209, 1209f pulmonary complications of, 1193, 1194t, 1208–1209 pulmonary involvement in, 2013 and respiratory failure, 2514 respiratory muscle dysfunction in, 1208 treatment of, 1117t

Polymyxin, aerosolized, 2059 Polyp(s), nasal, 807, 2647 Pompe’s disease, 1275–1276, 1276f Pontiac fever, 2113 Pores of Kohn, 35f, 36, 37, 51f, 104, 107f, 151, 695 in emphysematous lungs, 719, 719f Porphyria cutanea tarda, sarcoidosis and, 1136t Porphyromonas, 2007 Porphyromonas gingivalis, 2087 Portable chest examination, 508–509, 508f Portal-pulmonary hypertension, 449 Portopulmonary hypertension, 1381–1382 PORT Severity Index (PSI), 2004, 2102, 2107t Posaconazole for blastomycosis, 2348 for coccidioidomycosis, 2345 for cryptococcosis, 2334 for fusariosis, 2322 for histoplasmosis, 2340 prophylaxis, 2313 for zygomycosis, 2320 Positional cloning, 710–711 Position therapy, for obstructive sleep apnea, 1714–1715 Positive airway pressure, bilevel, in neuromuscular disorders, 1667, 1671 Positive end-expiratory pressure, 2670, 2671 in ALI/ARDS, 2545, 2683–2684, 2683t higher levels, as lung-protective strategy, 2547–2548, 2684, 2684f intrinsic, 2676, 2683 in acute respiratory failure, 2670, 2671, 2672f in chronic obstructive pulmonary disease, 78, 2678, 2681, 2682f and pulmonary hemodynamics, 1338–1339 Positive-pressure ventilation complications of, 2645 historical perspective on, 2645 nasal for acute exacerbations of chronic obstructive pulmonary disease, 2119f, 2122, 2122t in hypercapnic respiratory failure, 2611 noninvasive in hypercapnic respiratory failure, 2611 for respiratory failure, 2588 and pulmonary hemodynamics, 1338–1339

I-92 Index Positron emission tomography (PET), 420–421, 547–548 and computed tomography, integrated.

See PET/CT F-18 fluorodeoxyglucose in chronic obstructive pulmonary disease, 565f, 566 indications for, 559 of lung cancer, 559–561, 561f for staging, 561–563, 562t, 563f of mesothelioma, 563–564, 564f metabolic considerations in, 559, 560f in pneumoconiosis, 565 in sarcoidosis, 565–566, 1136, 1138f of solitary pulmonary nodule, 559–560, 560f, 561t standard uptake value for, 560 with F-18 fluorodeoxyglucose, 2018, 2018f in HIV-infected (AIDS) patients, 2248–2249 of mesothelioma, 1543 in small cell lung cancer, 1903 of solitary pulmonary nodule, 1819–1820 Postantibiotic effect, 2054, 2057 Postantibiotic leukocyte enhancement, 2054 Post-cardiac injury syndrome, 1502 Postcommissurotomy syndrome, 419–420 Postinspiratory inspiratory activity, 2592 Postnasal drip, and chronic cough, 410 Postpericardiotomy syndrome, 419–420 Postpneumonectomy syndrome, 860 mediastinal repositioning in, 1567, 1568f Posttransplant lymphoproliferative disorder (PTLD), 1791, 1962–1964, 1963f, 1963t in bone marrow and stem cell transplant recipients, 2224 Posttussive syncope, 409–410 Potassium channels, in pulmonary hypertension, 1369–1370 Potassium sulfite, sensitivity to, in aspirin-sensitive asthmatics, 802 Potato riddler’s lung, etiology of, 1163t Potocytosis, 31 Pott, Percival, 2473 Pott’s disease, 2473 Pott’s puffy tumor, 2090, 2090f PPD. See Purified protein derivative (PPD) test Ppl. See Pleural pressure(s) Ppl–Pbs. See Chest wall, pressure difference across PPV. See Positive-pressure ventilation Practolol, and interstitial lung disease, 1111t p21ras, and airway smooth muscle proliferation, in vitro, 120, 120f

Praziquantel, indications for, 2418t Prealbumin, serum, in nutritional assessment, 2694 Prednisolone adverse effects and side effects of, 827t for asthma, 823t, 827t dosage and administration of, 827t for hypersensitivity pneumonitis, 1171 Prednisone adverse effects and side effects of, 827t for allergic bronchopulmonary aspergillosis, 842, 2299 for asthma, 823t, 827t, 2638 for chronic obstructive pulmonary disease, 2638 dosage and administration of, 827t for hypersensitivity pneumonitis, 1171 for idiopathic pulmonary fibrosis, 1157 for sarcoidosis, 1139–1140, 1140t Preeclampsia, pulmonary edema in, 259t Pregnancy, 253–260 acute respiratory distress syndrome in, 258–259, 259t and airway management, 2648 anatomic changes of, 253–254 asthma in, 259, 259t cardiovascular physiology in, 256–258 and cystic fibrosis, 260 cystic fibrosis and, 882–883 dyspnea in, 258, 403 erythema nodosum in, 434 exercise in, respiratory response during, 256 hemodynamic changes in, 256, 257t lung volumes in, 254, 254f physiological anemia of, 256 physiological changes of, 254–258 and pulmonary arteriovenous malformations, 1468, 1469f pulmonary hypertension in, 260, 1392 respiratory diseases in, 259–260, 259t respiratory physiology in, 254–256 sarcoidosis and, 1135, 1141 sleep-disordered breathing in, 260 sleep disturbances in, 256 venous thromboembolism in, 259–260, 259t, 1425 ventilatory changes in, 254–256, 255f Prematurity and risk of asthma, 794 and risk of infection, 2306 Pressure at airway opening, 575, 575f during breathing cycle, 148, 148f Pressure at body surface, 152, 575f Pressure control ventilation, in ALI/ARDS, 2549–2551, 2552f Pressure-flow curve(s), isovolume, 155–156, 156f Pressure-flow relationships, 154–155 Pressure-volume curve(s) in acute respiratory failure, 2672, 2672f

in emphysema, 265, 265f of lung, 149–150, 149f, 150f normal in elderly, 265, 265f in young persons, 265, 265f relaxation, 152–153, 152f Prevotella, 2086 in empyema, 2144, 2144t nonpigmented, infection (incl. pneumonia), 2156t pigmented, infection (incl. pneumonia), 2156t Prevotella buccae, in empyema, 2144t Prevotella denticola-melaninogenica group, in empyema, 2144t Prevotella intermedia, 2087 Prevotella intermedia-nigrescens group, in empyema, 2144t Prevotella melaninogenica, 2007, 2142, 2146f infection (incl. pneumonia), 2156 Prevotella oralis, in empyema, 2144t Prevotella oris, in empyema, 2144t Priestley, Joseph, 5t, 7, 8, 9, 9f, 12, 2613 Primaquine, 2407 methemoglobinemia caused by, 416 Primary biliary cirrhosis (PBC), sarcoidosis and, 1135, 1136t Primary ciliary dyskinesia and bronchiectasis, 2185t, 2187 diagnosis of, 2187 genetics of, 2187 Primary effusion lymphoma, 1964–1965, 1965f Primary sclerosing cholangitis (PSC), sarcoidosis and, 1136t Primum non nocere, 2722 Procainamide lupus-like syndrome caused by, 2010, 2012t pulmonary effects of, 1090t pulmonary toxicity of, 1096 Procalcitonin, serum, assay for, 2107–2108 Procarbazine and pleural effusion, 1506t pneumonitis caused by, 2012, 2012t pulmonary effects of, 1083, 1083t Progesterone, dyspnea caused by, 403 Progressive massive fibrosis in coal workers clinical features of, 971 complicated, 970–971 management of, 973–974 mortality rate for, 970 pathology of, 970–971 radiographic findings in, 969, 971–972 in silicosis, 975–976, 976f Progressive multifocal leukoencephalopathy (PML), sarcoidosis and, 1136t

I-93 Index Progressive systemic sclerosis, 429–430.

See also Scleroderma pulmonary complications of, 905 Proguanil, 2407 for Pneumocystis pneumonia, 2370 Proopiomelanocortin (POMC), 1933, 1934f Properdin factor B, in alveolar fluid, 282–283 Prophylactic radiation therapy, definition of, 1895 Propionibacteria, infection (incl. pneumonia), 2156t Propionibacterium acnes in empyema, 2144t and sarcoidosis, 1126–1127 Propionic acids, and aspirin-induced asthma, 802t Propofol, for agitated ICU patient, 2703–2704, 2706t Propoxyphene pneumonitis caused by, 2012t pulmonary effects of, 1088 Propranolol, pulmonary effects of, 1096–1097 Propylthiouracil (PTU) and interstitial lung disease, 1111t pulmonary effects of, 1091t, 1092, 1242, 1294–1295 and vasculitis, 1464 Prospective Investigation of Pulmonary Embolism Diagnosis, 552–554, 553t, 554t, 555f, 1428–1429, 1432–1433, 1433t, 1434t Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis, 552 Prostacyclin pulmonary effects of, 1091t in pulmonary hypertension, 1368–1369, 1369f and pulmonary vasomotor control, 1340–1341, 1341f Prostacyclin analog(s), for pulmonary arterial hypertension, 1388 Prostaglandin(s) (PG) biologic effects of, 1341 formation of, 778, 782f PGD2 , 316 in asthma, 778 mast cells and, 310t, 312 PGE2 , 1976 and aspirin-induced asthma, 803–804, 803f expression of, by airway smooth muscle cells, 122, 122t, 123 and pulmonary vasomotor control, 1341 Prostanoids in asthma, 778 formation of, 778, 782f

Protease(s), 1979 bacterial, 326 mast cell, 308, 310t, 311 Protease inhibitors interactions with antituberculosis therapy, 2490 pharmacology of, 2261 Protected bronchoalveolar lavage (P-BAL, PTC-BAL), 1987 Protected-specimen brush, 636 Protected specimen brushing, 1987 in nosocomial pneumonia, 2283 Protein(s) altered, hypersensitivity pneumonitis caused by, 1164t handling, in lungs, 2523–2524 Proteinase(s) in asthma, 782 cysteine, in emphysema, 720–721 elastolytic, 718, 718t in emphysema, 719–721 Proteinase 3, 718t Proteinase-antiproteinase imbalance and chronic obstructive pulmonary disease, 715–716 and emphysema, 717–718 Proteinase inhibitor(s), in chronic obstructive pulmonary disease, 721–722, 721t Protein kinase, cGMP-dependent, activation of, 361 Protein kinase C (PKC), 361–362 Protein nucleotide agglutination, 2039 Proteoglycans, 53 mast cell, 310–311, 310t Proteus in acute mediastinitis, 2166t aspiration pneumonia, 2007 in empyema, 2144t infection (incl. pneumonia) in Chediak-Higashi syndrome, 2238 nosocomial, 2280, 2281t, 2282, 2289 treatment of, 2285–2288, 2286t in invasive (malignant) otitis externa, 2092 Proteus mirabilis, immune response to, 1979 Prothrombin, mutation, and risk of venous thromboembolism, 1427 Proton beam radiotherapy, definition of, 1896 Proto-oncogenes, 1802–1803 Protozoa, in indoor air, sources of, 1022t Protozoan infection(s), 2397–2410. See also Amebiasis; Babesiosis; Cyclosporiasis; Leishmaniasis; Malaria; Microsporidiosis; Trypanosomiasis in cancer patients, 2215 in cell-mediated immunodeficiency, 2236

ciliated, 2409–2410 flagellates, 2410 in HIV-infected (AIDS) patients, 2212t nosocomial infection, 2280t staining characteristics of, 2035t Protriptyline, as respiratory stimulant, 2644 Provocative dose, 789 PRRs. See Pathogen recognition receptor(s) PRSP. See Streptococcus pneumoniae, penicillin-resistant Pruritus, 435 PSB. See Protected specimen brushing P-selectin, 315, 347, 363 in inflammation, 782 and leukocyte adherence and migration, 347–348 in Weibel-Palade bodies, 31 Pseudallescheria fungus ball, 2049 identification of, in tissue, 2035, 2038t infection, pathology of, 2045, 2050 staining characteristics of, 2035t Pseudallescheria boydii, 2293, 2323 in allergic bronchopulmonary mycosis, 837 identification of, in tissue, 2050 infection (incl. pneumonia) in cancer patients, 2217 pathology of, 2046f Pseudo-abdominal paradox, 2609 Pseudoaneurysm aortic, computed tomography of, 466, 470f traumatic, CT angiography of, 462–463 Pseudolymphoma, in Sj¨ogren’s syndrome, 1210 Pseudomonas and acute lung injury, 2527 in acute mediastinitis, 2166t drug-resistant, 2282 exoenzyme U, 2527, 2528 hypersensitivity pneumonitis caused by, 1165t infection (incl. pneumonia) in Chediak-Higashi syndrome, 2238 in chronic granulomatous disease, 2237 in cystic fibrosis, 880, 883–884 immune defect associated with, 1983t, 2210t in immunocompromised host, 2209 in organ transplant recipient, 2230, 2232 and parapneumonic effusions, 1489 Pseudomonas aeruginosa, 1988, 1997, 2001 in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t and acute lung injury, 2527 in acute mastoiditis, 2094

I-94 Index Pseudomonas aeruginosa (Cont.) in acute otitis externa, 2092 in bronchiectasis, 2184 in chronic suppurative otitis media, 2094 colonization, in cystic fibrosis, 866–867, 872–873, 874, 880–881 contamination of bronchoscope, 2279 in empyema, 2144 immune defense against, 1973 immune response to, 1979 infection (incl. pneumonia), 2020 and bronchiectasis, 2186, 2189, 2189t, 2190 in children, immune defects and, 2138 in cystic fibrosis, 880, 883–884, 2081–2082, 2175–2176 treatment of, 875–876, 883–884, 2178–2179 in elderly, 2007 history and physical findings in, 2100t, 2101t in HIV-infected (AIDS) patients, 2106t, 2251, 2252 radiographic findings in, 2249t mortality rate for, 2005 neonatal nosocomial pneumonia caused by, 2126 in neutropenic host and cancer patient, 2217 nosocomial, 2196, 2277, 2279–2280, 2280t, 2281t, 2581–2582 clinical features of, 2282–2283 diagnosis of, 2282–2283 epidemiology of, 2282 microbiology of, 2282 prevention of, 2283 treatment of, 2283, 2285–2288, 2286t, 2287t pathogenesis of, 2080 pathology of, 2049f risk factors for, 2059–2060 in surgery and trauma patients, 2197 treatment of, 2054, 2055, 2056, 2057, 2058, 2061t, 2062 in X-linked agammaglobulinemia, 2233–2234 in invasive (malignant) otitis externa, 2092 in lung abscess, 2144, 2152f, 2154t pathogenicity of, 282 in perichondritis, 2091 quorum sensing by, 2080–2081 septic emboli, 2152f toxin produced by, 2081 vaccine against, 2080 Pseudomonas cepacia. See Burkholderia cepacia Pseudomonas fluorescens-putida, contamination of bronchoscope, 2279

Pseudomonas oryzihabitans, colonization, in cystic fibrosis, 881 Pseudomonas pseudomallei. See Burkholderia pseudomallei Pseudotumor, 1817, 1818f PSI. See PORT Severity Index (PSI) Psittacosis, 1987, 2005t, 2006. See also Chlamydophila psittaci diagnosis of, 2001 Psoriasis, drug treatment of, pulmonary toxicity of, 440 Pst. See Static pulmonary pressure Psychomotor Vigilance Task, 1730 PTC. See Plugged telescopic catheter sampling Ptc, 82, 85, 87, 89f PTC-BAL. See Protected bronchoalveolar lavage (P-BAL, PTC-BAL) PTEN, in G protein–coupled chemoattractant receptor signaling, 353, 353f PU.1, and eosinophil development, 313 Pulmonary alveolar proteinosis, 1313–1320, 2014, 2027, 2541t acquired, pathophysiology of, 43 animal models of, 1314–1315, 1316f bronchoalveolar lavage in, 1120, 1122f, 1318, 1318f bronchoscopy in, 1120t, 1318 clinical features of, 1118t, 1317–1319 computed tomography of, 1112, 1113f, 1115t, 1118t congenital, 1313, 1317 diagnosis of, 1319 epidemiology of, 1317 experimental therapies for, 1320 histology of, 1118t and infections, 1319 laboratory findings in, 1317 natural history of, 1319 occupational exposures and, 935t pathogenesis of, 1313–1317 pathology of, 1318, 1319f primary (acquired, idiopathic), 1313 ultrastructure of, 1314, 1315f pulmonary function testing in, 1318 radiographic features of, 482, 489f radiographic findings in, 1317, 1318f secondary, 1313, 1316 severity, classification of, 1319, 1319t therapeutic bronchoscopy for, 643 treatment of, 1118t, 1319–1320 whole lung lavage in, 1320 Pulmonary arterial hypertension. See also Idiopathic pulmonary arterial hypertension acute cor pulmonale in, 1408–1409 and acute hemodynamic instability, clinical presentation of, 1408, 1408t associated with other diseases, 1360, 1362t, 1381–1384

cardiopulmonary exercise testing in, 623–624, 623t, 624f classification of, 1360, 1362t in collagen vascular disease, 1381 in CREST syndrome, 1381 definition of, 1359–1360 epidemiology of, 1378, 1378t extracellular matrix in, 1370–1371 familial, 1360, 1362t, 1380–1381 growth factors and, 1370 histopathology of, 1364, 1366f in HIV-infected (AIDS) patients, 1381 idiopathic, 1196 lung transplantation in, 1774t, 1775–1777 in mixed connective tissue disease, 1381 molecular genetics of, 1370 portal hypertension and, 1381–1382 radiographic evaluation of, 471, 474f respiratory failure in, 1408–1409 in rheumatoid arthritis, 1381 risk factors for, 1378, 1378t in scleroderma, 1381, 1381f in situ thrombosis of small vessels in, 1364, 1366f, 1370, 1423 in Sj¨ogren’s syndrome, 1381 in systemic lupus erythematosus, 1381 treatment of, 1386–1392 anticoagulation in, 1391 combination therapy for, 1390–1391 surgical, 1391–1392 Pulmonary arteriovenous malformation(s) causes of, 1468 clinical presentation of, 1469–1470 complications of, 1475–1477 central nervous system, 1476–1477, 1476f–1477f pulmonary, 1475 diagnosis of, 1470–1475 diseases associated with, 1468 embolization of, 466, 538–540, 542f, 1477–1479, 1478f complications of, 540 results, 540 genetics of, 1468–1469 hemoptysis in, 410, 413, 1475 and hemothorax, 1475 historical perspective on, 1467 location of, 1468 management of, algorithm for, 540, 541f number of, 1468 pathophysiology of, 1467–1468 pregnancy and, 1468, 1469f presenting as solitary pulmonary nodule, 1817 prognosis for, 1479 and pulmonary hypertension, 1475 radiographic features of, 459f, 487, 1470, 1471f–1475f

I-95 Index and screening of probands or relatives, 1473–1475 size of, 1468 structure of, 1467–1468 treatment of, 1477–1479 Pulmonary artery(ies), 47f, 174f, 175 anatomy of, 25, 25f branches of, 25, 25f diameter of, 49, 50f chronic obstructive pulmonary disease and, 703–704, 704f connective tissue support of, 53 embolization, for treatment of arteriovenous malformation, 466 interspecies variations in, 1332, 1333f postoperative obstruction, in lung transplant recipient, 1788 radiographic evaluation of, 465f, 469–472, 471f–475f relationship to lung parenchymal units, 25f, 26 resistance profile of, 49 thrombectomy, 542–543 wall structure of, 31–32, 31f Pulmonary artery catheter, in ALI/ARDS, 2554, 2554t Pulmonary artery catheter/catheterization, in acute respiratory failure, 2663–2666 noninvasive alternatives to, 2666–2668 outcome studies, 2663–2664 precautions with, 2664–2666 Pulmonary artery occlusion pressure in acute respiratory failure, 2663–2666, 2664f–2666f in ALI/ARDS, 2536 clinical significance of, 2543–2544 Pulmonary artery pressure, 1334, 1334f, 1336 diastolic, normal, 1334t mean, normal, 1334t normal, 1334t systolic, normal, 1334t with unilateral pulmonary artery occlusion, preoperative, for lung resection, 672 Pulmonary artery sling, 857 Pulmonary artery steal, 2585 Pulmonary artery systolic/diastolic pressure, normal, 1324, 2736 Pulmonary barotrauma, in respiratory failure, 2517, 2518t Pulmonary blood flow distribution of, radiographic evaluation of, 469–473, 472f–475f normal, 1324, 2736 topographic distribution of (zones), 1350–1351, 1351f Pulmonary blood volume, 1338

Pulmonary capillary(ies). See also Capillaritis alveolar, 41f, 53, 174f fibrous support of, 51f, 52 network of, 49–50, 50f, 51f, 174f, 175 distention of, 1352 oxygen content of, 415 recruitment of, 1352 Pulmonary capillary blood volume, 1348 age-related changes in, 273 definition of, 1328, 2740 measurement of, 196–197 normal, 1324, 2736 Pulmonary capillary hemangiomatosis, 1386 Pulmonary capillary wedge pressure clinical significance of, 2543–2544 normal, 1324, 2736 in pregnancy, 257t Pulmonary circulation, 443–444, 2040.

See also Pulmonary vasculature age-related changes in, 270 altitude and, 1040 and atherosclerosis, 446 in bullous lung disease, 923 distribution of, and gas exchange, 1348 fetal, 1354 gravity and, 178, 178f, 470, 471, 472f, 473, 475f, 1335, 1350, 1350f in zones of lung, 1350–1352, 1351f initial tone of, 1339–1340, 1339f, 1340f lung inflation and, 1352 neonatal, 1354 neural mediators of, 1340 nonrespiratory functions of, 1332 physiology of, knowledge of, historical perspective on, 4–6, 5t, 16–17 reflex effects on, 1340 systemic artery communication with, 1355–1356 topographic distribution of (zones), 1350–1352, 1351f vasculogenesis of, 95, 95f vasoconstrictor mediators of, 1339–1340, 1339f, 1340f vasodilator mediators of, 1339–1340, 1339f, 1340f Pulmonary compliance. See Lung compliance Pulmonary complications, postoperative factors associated with, 666, 666t intraoperative risk factors for, 666t, 669–670 postoperative prophylaxis for, 673–674, 673t postoperative risk factors for, 666t, 670 preoperative risk factors for, 666–669, 666t with thoracic surgery, 666, 666t Pulmonary edema, 2027 in acute lung injury, pathophysiology of, 2523–2525

after lung resection, 1748 alveolar-capillary leak, 2020 in bone marrow and stem cell transplant recipients, 2222, 2227 in cancer patients, 2221, 2221t cardiogenic, 2541t, 2542, 2543 drug-induced, 2542t in heart failure, 494 high-altitude, 1041–1042 hydrostatic, 2020 in immunocompromised host, 1997 increased permeability, 2524 increased pressure, 2524 interstitial, radiographic features of, 485, 490f, 492f noncardiogenic, 2524, 2541t drug-induced, 1091t, 1093 in lung transplant recipient, 2585 postpneumonectomy, 1749, 1749f, 1750f and respiratory failure, 2584 in preeclampsia, 259t radiographic features of, 478f, 482 re-expansion, 1532–1533 tocolytic, 259t Pulmonary embolectomy, 1440 Pulmonary embolism acute, diagnosis of, lung scanning in, 551–556, 556f acute major, 2542t angiography of, 466, 468f, 1436, 1436f in cancer patients, 2221, 2221t clinical assessment of, 1429–1430 clinical presentation of, 1429, 1430t CT angiography of, 462, 462f D-dimer testing with, 1431–1432 diagnosis of, 1428–1438 approach to, 1436–1438, 1437f computed tomographic angiography in, 554–556, 556f ECG findings with, 1430, 1433f echocardiography with, 1433 hemoptysis in, 410 incidence of, 1423, 1424f interventional radiology for, 1440 laboratory findings with, 1430 long-term management of, 1440–1442 lower extremity evaluation with, 1433–1436 magnetic resonance imaging of, 464f, 465, 1436 mortality rate for, 551, 1423, 1424f pleural effusion caused by, 1495 prediction scoring systems for, 1429–1430, 1431t–1432t prophylaxis, 1442–1443, 1442t and pulmonary infarction, 1428, 1428f radiographic features of, 472, 475f, 1430–1431 and respiratory failure, 2587 in respiratory failure, 2517, 2518t sources of, 1424, 1424f

I-96 Index Pulmonary embolism (Cont.) treatment of, 551, 1438–1443 long-term, 1440–1442 ventilation-perfusion lung scanning of, 549, 549f, 1432–1433, 1433t, 1434f, 1435f Pulmonary endocrine cells, 444 Pulmonary function, postoperative changes in, 663–665, 664t Pulmonary function testing, 567–608 abnormal gas transfer on, 602 age and, 270–273 in AMA Guides classification of impairment, 681–682, 682t in asbestosis, 950 in asthma, 603, 604t, 605, 606t, 817–818 in bone marrow and stem cell transplant recipients, 2229 in bronchiectasis, 2188–2189 in bullous lung disease, 921–922, 925t, 926t, 927t in cancer patients, 1068–1069 in chemotherapy patient, 1068–1069 combined obstructive-restrictive pattern on, 602, 607 in cystic fibrosis, 871–872 in dyspnea, 404–405, 405t in elderly, interpretation of, 276 in environmental lung disease, 939–940 in evaluation of impairment/disability, 680 historical perspective on, 11, 11f, 568 in HIV-infected (AIDS) patients, 2249 in idiopathic pulmonary fibrosis, 1147–1148 indications for, 424 infection control in, 601–602 interpretation of, 602–608 in elderly, 276 sequence of test review for, 602, 603f in interstitial lung disease, 1113–1114 in kyphoscoliosis, 1618–1620, 1620t in Langerhans’ cell histiocytosis, 1247–1248 in lymphangioleiomyomatosis, 1258, 1258f in obesity, 1627–1628 obstructive pattern on, 602, 603f, 604–606, 604t, 608t in occupational asthma, 986–987 in occupational lung disease, 939–940 in oxygen toxicity, 2628 in Pneumocystis pneumonia, 2361 preoperative, 670 for lung resection, 671 in pulmonary alveolar proteinosis, 1318 quality control in, 600–602 analytical factors and, 601 costs of, 601 nonanalytical factors and, 600–601 responsibility for, 601 and test results, 601

restrictive pattern on, 602, 606–607, 608t causes of, 606–607, 607t in sarcoidosis, 1133 test selection in, 424 Pulmonary hemodynamics, 1332–1339 exercise and, 1334t, 1339 induced changes in, 1338–1339 mechanical ventilation and, 1338–1339 normal, 1324, 2736 Pulmonary herniation, after lung resection, 1752 Pulmonary host (immune) defense(s), 279–288, 1969, 1970f, 2039–2042, 2079–2080 alveolar macrophages in, 1971–1973, 1971f, 2042 antibody-mediated, 321–332 antigen-specific, 328–329 components of, 279–280 defects in in children, 2138 and pulmonary disease, 287t, 288 and respiratory infections, 286–288, 287t epithelium and, 143–144 in HIV-infected (AIDS) patients, 2243–2244 integrated action of, 279–280, 280f mechanical, 1969–1970, 1971f mechanisms nonspecific, 279–280 specific, 280 and microbes, interactions of, 1979–1980, 1979t nasal, 280–281 oropharyngeal, 280–281 and pneumonia, 1982–1983, 1983t postoperative changes in, 665 specialized regional, 280–286 structure of, 41–43 Pulmonary hypertension acidosis and, 1366–1367 in alveolar hypoventilation, 1395, 1396f, 1397f anatomic alterations caused by, 1360–1362 associated with extrinsic restriction of pulmonary venous blood flow, 1392–1393 associated with hypoxemia, 1362t, 1393–1399 associated with left heart disease, 1392–1393 cardiopulmonary exercise testing in, 623–624, 623t, 624f in chronic obstructive pulmonary disease, 1393–1395, 1394f chronic thromboembolic, 1362t, 1400–1402, 1400f, 1401f clinical classification of, 1360, 1362t

clinical manifestations of, 1371, 1371t complex lesions of, 1364, 1364f constrictive lesions of, 1363 in CREST syndrome, 430 definition of, 1359 diagnostic testing in, 1373t, 1374–1376 dietary, 446–447, 1382 dilation lesion of, 1364, 1364f drug-induced, 1091t, 1382–1384 evaluation of patients with, 1373t exercise in, 1376 fluid management in, 1376–1377 in hepatic cirrhosis, 449 histopathology of, 1363–1365, 1363f, 1364f history-taking in, 1371–1372 in HIV-infected (AIDS) patients, 2259–2260 hypercapnia and, 1366–1367 hypoxia and, 1366–1367 idiopathic, radiographic findings in, 1372f infectious complications of, 1376 in interstitial lung disease, 1396–1399, 1397f, 1398f intimal thickening in, 1363, 1363f management of, 1376–1378 mechanisms of hyperkinetic, 1365, 1367t idiopathic, 1366, 1367–1371, 1367t, 1368f obliterative, 1365, 1367t obstructive, 1365, 1367t passive, 1365, 1367t vasoconstrictive, 1365–1367, 1367t, 1368f medial hypertrophy in, 1363, 1363f miscellaneous causes of, 1362t in mixed connective tissue disease, 1209 in obstructive sleep apnea, 1395–1396 oxygen therapy in, 1376 pain in, 418 pathogenesis of, 1365–1366, 1367f, 1367t pathology of, 703–704, 1360–1371. See also Cor pulmonale physical examination in, 1372–1374 plexiform lesion of, 1364, 1364f in pregnancy, 260 primary, 1360 in collagen vascular disease, 1196 lung transplantation in, 1777 radiographic features of, 471, 472, 474f, 476, 1374–1375, 1374f radiographic findings in, 1371, 1372f rehabilitation in, 1376 in sarcoidosis, 1133 in scleroderma, 1207 secondary, 1360 sleep apnea and, 1713 in systemic lupus erythematosus, 1201 toxin-induced, 1382–1384

I-97 Index vasoactive mediators and, 1368–1370, 1369f vasodilator testing in, 1376, 1386–1387, 1387f vasodilator therapy in, 1377–1378 ventilation-perfusion lung scan in, 556 World Health Organization functional classification of, 1379, 1379t Pulmonary infiltrate with eosinophilia, 1213, 2013 diseases associated with, 1213, 1214t Pulmonary insufficiency, after lung resection, 1750 Pulmonary Langerhans’ cell histiocytosis.

See Langerhans’ cell histiocytosis Pulmonary ligament, 24, 24f Pulmonary mechanics, 147–160 in acute lung injury, 2524–2525 in bullous lung disease, 922–923, 927t Pulmonary medicine, scientific, historical perspective on, 13–17 Pulmonary microvasculopathy, 1364, 1365f Pulmonary nervous plexus, 32 Pulmonary neuroendocrine cells, 30, 30f, 87, 444 primary diffuse hyperplasia of, 910 Pulmonary occlusive venopathy, 1364, 1365f Pulmonary renal syndromes, ANCA-associated clinical features of, 1290–1291 and diffuse alveolar hemorrhage, 1288–1290 treatment of, 1292 Pulmonary resistance, 583 normal, 1323, 2735 Pulmonary stretch receptor(s), 164–165, 164f Pulmonary sulcus tumor, 419f pain of, 419 Pulmonary torsion, after lung resection, 1751, 1751f Pulmonary vascular communication(s) abnormal, 1355–1357 systemic artery-, 1355–1356 acquired, 1355 congenital, 1355 Pulmonary vascular disease in collagen vascular disease, histopathology of, 1196–1197 in mixed connective tissue disease, 1209 obliterative, 424 and postoperative pulmonary complications, 668 in rheumatoid arthritis, 1202 in scleroderma, 1207–1208 in systemic lupus erythematosus, 1201 Pulmonary vascular pressure(s), 1330f, 1335–1337

Pulmonary vascular resistance, 1332–1335 alternative approaches to, 1334–1335, 1335f calculation of, 1332–1334 in exercise, 616, 1334–1335, 1334t, 1335f lung inflation and, 1352 normal, 1334t passive modifiers of, 1335 in pregnancy, 257t at rest, 1334–1335, 1334t, 1335f Pulmonary vasculature. See also Intrapulmonary vessels incorporation into pulmonary parenchyma, 1331, 1332f passive influences on, 1331 radiographic evaluation of, 465f, 469–472, 471f–475f in erect position, 470, 472f gravity and, 470, 471, 472f, 475f in supine position, 470, 472f in upside-down position, 470, 472f Pulmonary vasomotor control, 1339–1348 Pulmonary vein(s), 174f, 175 anatomy of, 25–26, 25f branches of, 25, 25f, 49, 50f connective tissue support of, 53 radiographic evaluation of, 465f, 469–472, 471f–475f relationship to lung parenchymal units, 25f, 26 wall structure of, 31–32 Pulmonary veno-occlusive disease, 1384–1386, 1385f in bone marrow and stem cell transplant recipients, 2228 Pulmonary venous hypertension, 623 classification of, 1362t in heart disease, radiographic evaluation of, 471, 474f Pulmonary vessels, radiographic evaluation of, 465f, 469–472, 471f–475f Pulmonary wedge pressure (s), 1334t, 1336–1337, 1337f. See also Pulmonary capillary wedge pressure Pulse contour analysis, in acute respiratory failure, 2668 Pulse oximetry, 2104 in acute respiratory failure, 2668–2669 Pulse pressure, 2661 Pulularia, hypersensitivity pneumonitis caused by, 1163t Pure large cell carcinoma with rhabdoid phenotype, 1840 Purified protein derivative (PPD), 2462, 2470, 2471t Purified protein derivative (PPD) test intermediate, 2002 second-strength, 2002

Purine nucleoside phosphatase deficiency, pulmonary infection in, 2236–2237 PVOD. See Pulmonary veno-occlusive disease PVR. See Pulmonary vascular resistance Pw . See Pulmonary wedge pressure (s) Pyoderma gangrenosum, 434, 435f sarcoidosis and, 1136t Pyopneumothorax, 2153 Pyorrhea, and anaerobic pleuropulmonary infections, 2145t Pyothorax-associated lymphoma(s), 1965, 1965f Pyrantel for ascariasis, 2418t for hookworms, 2418t Pyrazinamide adverse effects and side effects of, 2478, 2483t hepatotoxicity of, 2478, 2491 for latent tuberculosis infection, 2455–2456 in HIV-infected (AIDS) patients, 2491 mechanism of action of, 2464 pharmacology of, 2478 for tuberculosis, 2464, 2478 in children, 2135 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2490 regimens for, 2481t theoretical basis for, 2476 Pyridoxine, isoniazid and, 2477 Pyrimethamine prophylactic, for Pneumocystis pneumonia, 2367 and sulfadiazine, for Pneumocystis pneumonia, 2368t, 2370 for toxoplasmosis, 2402 Pyrogen(s), 452 Pythagoras, 4 PZA. See Pyrazinamide Q Q fever, 1985, 1987, 1995, 2005–2006, 2005t, 2427. See also Coxiella burnetii chest radiograph in, 2101f diagnosis of, 2002 epidemiology of, 1984t pneumonia, 2022 QFT-G. See QuantiFERON-TB Gold test Quadriplegia, respiratory muscle action in, 75, 75f, 76, 77 Quality of life, 2726. See also Health-related quality of life QuantiFERON-TB Gold test, 2454, 2462, 2471

I-98 Index QuantiFERON-TB test, 2471 in HIV-infected (AIDS) patients, 2490 Quinghaosu, for Pneumocystis pneumonia, 2370 Quinidine, pulmonary effects of, 1089 Quinidine gluconate, 2407 Quinine dihydrochloride, 2407 Quinine sulfate, 2407 Quinolones for cystic fibrosis patient, 2178–2179 penetration into lung, 2053, 2053t Quinsy, 2086 Quinupristin, 2058 pharmacokinetics and pharmacodynamics of, 2054 Quorum sensing, 2055, 2080–2081 R R. See Resistance; Respiratory gas exchange ratio R207910 (anti-TB drug), 2464 R. bronchialis, and acute mediastinitis, 2166t RA. See Rheumatoid arthritis rad (unit), 1177 definition of, 1896 Radiation absorption, measurement of, 1177 dose, units for, 1177 dosimetry, 1173, 1175–1177 equivalent dose, 1177 exposure, measurement of, 1177 external beam, in upper airway obstruction, 862 immunologic effects of, 2216 lung disease caused by, 935t pulmonary toxicity of, 1173–1174.

See also Radiation fibrosis; Radiation pneumonitis acute manifestations of, 1181 clinical syndromes of, 1181–1184 cytopathology of, 526–527 late manifestations of, 1181–1184 pathophysiology of, 1179–1181 tissue effects of, 1173–1174 Radiation fibrosis, 1176f, 1184, 2014 Radiation oncology, historical perspective on, 1173 Radiation pneumonitis, 1890–1892, 2014 bronchoalveolar lavage cellular profile in, 1121t in cancer patient, 2221, 2221t clinical manifestations of, 1182–1184 computed tomography of, 1115t grading system for, 1181, 1182t in immunocompromised host, 1997 pathogenesis of, 1174, 1176f pathophysiology of, 1179–1181 prevention of, advances in (future directions for), 1190 prognostic assays for, 1189–1190

radiographic features of, 1176f, 1182, 1183f–1184f risk of assessment of, with partial-lung radiation, 1186–1188, 1187f chemotherapy and, 1181 Radiation recall, 1181 Radiation therapy accelerated treatment, 1893 advances in, 1173–1174, 1189, 1893–1894 and cell survival, 1178, 1178f combined modality, 1894 delivery of, advances in, 1893–1894, 1893f, 1894f dose-volume histogram, 1174, 1175f, 1894 fractionated, 1173, 1178–1179, 1178f and cell survival, 1178–1179, 1178f historical perspective on, 1173 hyperfractionation, 1893 for lung cancer definitive medically inoperable, 1884t definitive unresectable (with chemotherapy), 1884t dose, 1884t indications for, 1884t palliative unresectable, 1884t postoperative, 1884t preoperative (with chemotherapy), 1884t type, 1884t for mesothelioma, 1547 for non-small cell lung cancer, 1883–1896 planning, 1173–1174, 1175f prevalence of, 1174 pulmonary toxicity of. See also Radiation fibrosis; Radiation pneumonitis clinical syndromes of, 1181–1184 radiation dose-fractionation modulation, 1893 radiobiology of, 1177–1179 radiosensitizers and, 1894 for small cell lung cancer, 1884t prophylactic cranial, 1890, 1909 thoracic, 1890, 1909 technical planning for, 1893–1894, 1893f terminology for, 1895–1896 therapeutic ratio for, 1178–1179, 1179f thoracic acute pulmonary complications of, 1890–1892, 1891f cardiac complications of, 1892 esophageal complications of, 1892 late pulmonary complications of, 1892, 1892f toxicity of, 1890–1892 V20 , 1174, 1175f

Radiation Therapy Oncology Group (RTOG), definition of, 1896 Radiation tolerance, of lungs, 1184–1185 in partial-lung radiation, 1186–1188 in whole-lung radiation, 1185–1186, 1185f, 1185t Radiofrequency ablation, of lung cancer, 536, 537f Radiology, 420–421, 455–509. See also Interventional radiology; specific modality air contrast studies, 469 contrast examinations, 465–466, 466f–468f historical perspective on, 18 physics of, 1174–1177 portable chest examination, 508–509, 508f of pulmonary infections, 18, 1982t, 1985, 1986f, 1987f, 1988t, 1995–1997, 2017–2029 Radionuclides, for evaluation of mediastinal masses, 1589–1590, 1590t Radiopharmaceuticals historical perspective on, 547 in ventilation-perfusion lung scanning, 548–551 Radioprotector(s), 1190 Radiosensitizers, 1894 definition of, 1896 Radon, 1010 in coal mines, 967 decay products of, 1026, 1028 exposure to, reduction of, 1028 health effects of, 1026–1028 in indoor air, 1026–1028 management of, 1028 sources of, 1022t–1023t sources of, 1026–1028 RADS. See Reactive airway dysfunction syndrome RADT. See Rapid antigen detection test Rahn, H., 12, 13 Raldh2, and lung development, 82 Rales, 393, 393t in asbestosis, 950 Ramsay Hunt syndrome, 2092 RANTES, 315, 316, 340t, 1973 expression of, by airway smooth muscle cells, 121, 122t, 123 Rapeseed oil contaminant(s) and pulmonary hypertension, 1383–1384 pulmonary hypertension caused by, 1093 Rapid antigen detection test, for streptococcal pharyngitis, 2086 Rapidly adapting (irritant) receptors, 164–165, 164f Rasmussen’s aneurysm, 1468, 2470 hemoptysis from, 413

I-99 Index ras protein, in lung cancer, 1805 ras proto-oncogenes, in lung cancer, 1804–1805 Rationing, 2727 Rat urine proteins, hypersensitivity pneumonitis caused by, 1164t Ravuconazole, for cryptococcosis, 2334 Raw. See Airway resistance Raynaud’s disease, 415 Raynaud’s phenomenon, 423f in rheumatoid arthritis, 1202 in scleroderma, 429, 430f RB-ILD. See Respiratory bronchiolitis interstitial lung disease Rds, definition of, 1327, 2739 Re. See Reynolds number Reactive airway dysfunction syndrome clinical presentation of, 996 management of, 996 occupational, 934t pathogenesis of, 996 toxins causing, 996, 1000t Reactive airways viral syndrome, differential diagnosis of, 819t Reactive dermatoses, 433–436 Reactive nitrogen intermediates byproducts of, 363 produced by macrophages, 1972t, 1978 Reactive nitrogen species actions of, 360, 362t in lung injury in vivo evidence for, 364–365, 365f therapies to attenuate, 366–368 production of, 360–361, 361f Reactive oxygen intermediates, 2624–2625, 2625f biochemical alterations caused by, 2625–2626, 2626t byproducts of, 363 cellular dysfunction caused by, 2625–2626, 2626t eosinophils and, 310t, 315 generation of, 450–451, 450f injury caused by, 450–451 produced by macrophages, 1972t, 1973, 1978 Reactive oxygen-nitrogen species, 359–361 as signaling molecules, 361, 362t Reactive oxygen species (ROS) formation of, 359–360, 360f in lung injury in vivo evidence for, 364–365, 365f therapies to attenuate, 366–368 Reactive upper airway dysfunction syndrome, 996 Recoil force, of lungs, 575, 576f Recommended exposure limits, 941–942 Recruitment maneuvers, in ALI/ARDS, 2555 Rectus abdominis muscle, 72f, 76–77 Recurrent laryngeal nerve(s) anatomy of, 391f

course of, 1751, 1752f injury, in lung resection, 1751–1752 Recurrent respiratory papillomatosis, 1917–1918, 2088–2089 Red-cell aplasia, 1600, 1601t Red man syndrome, 2169 Reduction pneumoplasty, for bullae, 928 Redwood dust, hypersensitivity pneumonitis caused by, 1163t Reflux laryngitis, 1308 Regional enteritis, erythema nodosum in, 434 Rehabilitation, pulmonary, 763–764 advances in (future directions for), 771 benefits of, 768–769, 769t breathing retraining techniques in, 766–767 bronchial hygiene in, 766 in chronic obstructive pulmonary disease, 734–735 definition of, 764 diagnostic testing for, 765 effects on health care utilization, 769, 770f exercise in, 767–768 exercise testing before, 765 goals of, 766 for idiopathic pulmonary fibrosis, 1159 individualization of, 764 and lung resection, 771 and lung surgery, 769–771 in lung transplant recipient, 770–771, 770t and lung volume reduction surgery, 771 medical evaluation for, 765 multidisciplinary aspects of, 764 oxygen therapy in, 767 patient education in, 766 patient evaluation for, 764–766, 765t patient interview for, 765 patient selection for, 764, 764t physical and social aspects of, 764 psychosocial assessment for, 765–766 psychosocial support in, 768 respiratory and chest physiotherapy techniques in, 766 successful, characteristics of, 764 Rehabilitation program, content, 765t, 766–768 Relapsing polychondritis and bronchiectasis, 2187 large airway lesions in, differential diagnosis of, 701t, 702 upper airway obstruction in, 855 rem (unit), 1177 Remifentanil, for agitated ICU patient, 2708 Renal cell carcinoma, pulmonary metastases, 1943 magnetic resonance imaging of, 465f

Renal failure acute, in respiratory failure, 2518t, 2519 after lung resection, 1750 and risk of infection, 2317 in SIRS/MODS, 2566, 2568, 2570 Renal replacement therapy, for SIRS/MODS, 2570 Renal tubular acidosis, 217 Rendu-Osler-Weber disease, 1467. See also Hereditary hemorrhagic telangiectasia (HHT) Renin-angiotensin system, 444, 445f, 1332, 1332f Reovirus, 1992 Replacement therapy, 2642–2643 Residual volume, 148–149, 149t, 569, 569f, 582 age-related changes in, 271, 271f in chronic obstructive pulmonary disease, 711 definition of, 568t, 1326, 2738 determination of, 571 normal, 1323, 2735 postoperative changes in, 664 Residual volume/total lung capacity ratio in chronic obstructive pulmonary disease, 711 definition of, 1326, 2738 normal, 1323, 2735 Resistance vessels, 1332 Resorcinols. See also specific drug dosage forms, 2632t receptor activity, 2632t structure-activity relationships, 2632 structure of, 2633f Respiration, knowledge of, historical perspective on, 5t, 7–8 Respirator(s), in prevention of inhalation exposures, 942 Respiratory acidosis, 207, 208t acute, 595t, 596 adaptive response to, 211–212, 212f chronic, 595t compensatory response in, 208t Respiratory alkalosis, 207, 208t, 595–596 acute, 595–596, 595t chronic, 595t, 596 compensatory response in, 208t renal adaptation to, 212 Respiratory bronchiolitis interstitial lung disease, 900, 900f, 901f, 1106t, 1145 clinical features of, 1116t computed tomography of, 1115t, 1116t histology of, 1116t treatment of, 1116t Respiratory center(s) chemical stimulation of, knowledge of, historical perspective on, 12–13 knowledge of, historical perspective on, 5t, 12

I-100 Index Respiratory cycle inspiration phase of, 165 late expiration phase of, 165 postinspiration phase of, 165 Respiratory dead space, normal, 1323, 2735 Respiratory depression, postoperative, 665 Respiratory device(s) care of, in prevention of nosocomial pneumonia, 2288–2289, 2288t and nosocomial pneumonia, 2278–2279 Respiratory distress syndrome, of premature neonates pathophysiology of, 39 treatment of, 39 Respiratory effort-related arousal event, 1698 Respiratory exchange ratio, 591–592 Respiratory failure acute, 2509, 2510, 2510t arterial blood pressure measurement in, 2660–2661 central venous catheterization in, 2661–2663 complications of, 2517–2519, 2518t goal-directed therapy for, 2569, 2569f, 2663 hemodynamic monitoring in indications for, 2659–2660 methods for, 2660–2668 principles of, 2659 history-taking in, 2660 imaging in, 2673 laboratory testing in, 2661 monitoring of patient with, 2517 morbidity and mortality in, 2519–2520 nutritional support in, effects of, 2693 perioperative, 2573–2588 physical examination in, 2660 postoperative, 2573–2588 pulmonary artery catheterization in, 2663–2666 noninvasive alternatives to, 2666–2668 outcome studies, 2663–2664 precautions with, 2664–2666 respiratory monitoring in methods for, 2668–2673 principles of, 2659 signs and symptoms of, 2515, 2516t in surgical patient, 2573–2588 after lung resection, 1750 airway abnormalities and, 2514–2515 airway management in, 2515–2516 in ALI/ARDS, management of, 2545–2558 alveolar abnormalities and, 2515 in amyotrophic lateral sclerosis, 1652 in asbestosis, 950 causes of, identification of, 2517

chest wall abnormalities and, 2514 chronic, 2509, 2510, 2510t classification of, 2510–2511, 2510f clinical presentation of, 2509 CNS abnormalities and, 2513–2514 in cystic fibrosis, 881 device-related complications of, 2518t, 2519 diagnosis of, 2515 hypercapnic, 2510–2511, 2510f asthma and, 2607, 2607f causes of, 2592 chronic obstructive pulmonary disease and, 2605–2607, 2607f compensatory/adaptive mechanisms and, 2592–2598 decompensating/maladaptive responses and, 2598–2605 definition of, 2592 kyphoscoliosis and, 2608–2609 morbidity and mortality in, 2520 neuromuscular disease and, 2608 obesity and, 2608 pathophysiology of, 2511–2512 signs and symptoms of, 2516t treatment of, 2609–2611 treatment of hypercapnia in, 2516–2517 hypoxemic, 2510–2511, 2510f differential diagnosis of, 2540, 2540t morbidity and mortality in, 2519–2520 pathophysiology of, 2511 signs and symptoms of, 2516t treatment of hypoxemia in, 2516–2517 management of, principles of, 2515 neuromuscular, 2514 outcomes of, 2714–2715 pathogenesis of, blunted chemosensitivity and, 2594–2595, 2594f–2595f pathophysiology of, 2510, 2511–2513 PNS abnormalities and, 2514 postoperative, 2573–2588 causes of, 2579–2588, 2579t risk of chronic obstructive pulmonary disease and, 2574–2575 predicting, 2575–2576, 2576t smoking and, 2575 by surgical procedure, 2574, 2574t prognosis for, 2519–2520 in pulmonary arterial hypertension, 1408–1409 treatment of, noninvasive positive-pressure ventilation for, 2588 triage decisions in, 2515 Respiratory Failure Risk Index, 2575–2576, 2576t Respiratory gas exchange ratio, 613

Respiratory load compensatory response to, age-related changes in, 269 heightened, compensatory/adaptive responses to, 2595–2596 Respiratory mechanics assessment of, in acute respiratory failure, 2670–2672 synthesis of, historical perspective on, 12 Respiratory motor output compensatory/adaptive, in response to hypercapnia or hypoxia, 2596–2597 indices of, 2592–2593 Respiratory muscle(s), 71, 72f, 161, 1669.

See also specific muscle accessory in chronic obstructive pulmonary disease, FDG-PET of, 565f, 566 in ventilatory pump dysfunction, 2609 actions of, 74–77 in quadriplegia, 75, 75f, 76, 77 in tetraplegia, 76 adaptations of, 71 age-related changes in, 267–268, 268f during breathing cycle, 147–148 changes in, and ventilation, 2597–2598 coordinated activity of, 165–166 dysfunction, 1669 in collagen vascular disease, 1194t in mixed connective tissue disease, 1210 in neuromuscular disorders, management of, 1667–1675 in polymyositis-dermatomyositis, 1208 in systemic lupus erythematosus, 1201, 1201f in dyspnea, 2596–2597 effort, assessment of, 603–604, 604t expiratory, aids for, 1669–1670 fatigue, 2598–2602 and abnormal breathing pattern, 403 activity and, 2601, 2602f, 2603f blood flow and, 2601–2602 causes of, 2598–2599 central, 2599, 2599t in chronic obstructive pulmonary disease, 2606–2607, 2607f classification of, 2599, 2599t definition of, 2599 detection of, 2599–2601 high-frequency, 2599, 2600f low-frequency, 2599, 2600f pathogenesis of, 2601–2602, 2602f, 2603f peripheral, 2599, 2599t treatment of, 2610–2611, 2610t in weaning from mechanical ventilation, 2514

I-101 Index fiber types in, 71–72 morphology of, 72 force-frequency relationships of, 73, 74f force-length relationships of, 72–73, 73f, 167–168 force-velocity relationships of, 73–74, 74f, 167–168 function, in neuromuscular disorders, 1636–1637 functions of, 72–74 innervation of, 1641t inspiratory, aids for, 1669–1670 interactions of, 77, 165–166 pathological conditions affecting, 77–78 physiological conditions affecting, 77 in quiet breathing, 77, 165–166 knowledge of, historical perspective on, 11 length-tension curves of, 72–73, 73f mechanical costs to, in exercise, 247–248 metabolic costs to, in exercise, 248 motor units organization of, 72 types of, 72 power-frequency relationships of, 73–74 in pregnancy, 254 regulation of, 161, 162f strength of, 578–579, 579f, 579t assessment of, 603–604, 604t evaluation, in neuromuscular disease, 1643–1647 measurement of, in acute respiratory failure, 2673 structure of, 71–72 training in neuromuscular disorders, 1660 in pulmonary rehabilitation, 768 Respiratory patches, 47f Respiratory pattern generator, 165 Respiratory protective equipment, in chronic obstructive pulmonary disease, 734 Respiratory pump, 2511, 2511f Respiratory quotient, 592 Respiratory rate, 2592–2593 abnormal, causes of, 403 monitoring, in cardiopulmonary exercise testing, 611 normal, 403, 1323, 2735 ventilator setting for, 2681, 2681f Respiratory resistance, 583–585 Respiratory rhythm abnormalities, pathophysiology of, 168–170 central neural mechanisms of, 165 Respiratory stimulant(s), 2643–2644 Respiratory structure, changes in, and ventilation, 2597–2598

Respiratory syncytial virus (RSV), 1992 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t assays for, 1989t and bronchiolitis, 896, 897, 2376t, 2382–2384 characteristics of, 2375t and common cold, 2085, 2376, 2376t and croup, 2087, 2379 diagnosis of, 1999 immune response to, 314, 2383 infection (incl. pneumonia), 2020, 2025, 2027f in adults, 2389 and asthma, 774–775, 796, 816 in bone marrow and stem cell transplant recipients, 2228 chemokines in, 355 in children, 2130, 2391, 2391f immune defects and, 2139 cytopathology of, 523 diagnosis of, 2001, 2002, 2106, 2394 in early infancy, 2128–2129 in HIV-infected (AIDS) patients, 2258 in immunocompromised host, 2204, 2392 in lung transplant recipient, 1790 nosocomial, 2280t pathogenesis of, 2393 pathology of, 2043 prevention of, 2395 risk factors for, 2098 seasonal variation in, 2374 staining characteristics of, 2035t transmission of, 2374 vaccine against, 2384 Respiratory system dynamic mechanical properties of, 153–157, 579–585 elastic properties of, 152–153, 576–577, 576f, 577f in health and disease, 577–578, 578f, 578t elastic recoil pressure of, 152 functional components of, 2511, 2511f functional divisions of, age-related changes in, 263, 264t static mechanical properties of, 149, 575–579 Respiratory system compliance, 2670f, 2671 normal, 1323, 2735 Restrictive lung disease abnormal breathing pattern in, 403 cardiopulmonary exercise testing in, 625 causes of, 400, 400t dyspnea in, 400 initial assessment of, 421–424

and postoperative pulmonary complications, 667 severity of, Social Security Listings for, 686, 686t Retinoblastoma gene, in lung cancer, 1805 Retinoic acid, and lung development, 82 Retinoic acid syndrome, 1295 Retinopathy, cancer-associated, 1936t, 1937 Reverse precautions, complete, 2207–2208 Reverse shunt effect, 312 Reverse transcriptase, retroviral, 2242–2243 Reynolds number, 154–155 RFA. See Radiofrequency ablation Rheumatic disease(s), that may cause interstitial lung disease, immunologic tests for, 1111, 1112t Rheumatic fever, 2086 Rheumatoid arthritis. See also Collagen vascular disease airway disease in, 1203–1204, 1203f, 1204f alveolar hemorrhage in, 1241, 1293 and bronchiectasis, 2185t, 2187 bronchiolitis obliterans in, 903–904, 1203–1204 and bronchiolitis obliterans-organizing pneumonia, 904, 1204, 1205f clinical features of, 1117t in coal workers, 972–973 computed tomography of, 1117t constrictive bronchiolitis in, 903–904, 1203–1204 drug treatment of, pulmonary toxicity of, 440, 1205–1206 follicular bronchiolitis in, 904–905, 904f, 905f, 1203–1204, 1204f histology of, 1117t immunologic tests for, 1112t interstitial lung disease in, 1204–1206 pleural effusion in, 505f, 1202, 1496–1497 pulmonary complications of, 1193, 1194t, 1201–1206 pulmonary vascular disease in, 1202 and risk of infection, 2306 sarcoidosis and, 1136t solitary pulmonary nodule in, 1817 treatment of, 1117t Rheumatoid factor, in coal worker’s pneumoconiosis, 972–973 Rheumatoid (necrobiotic) nodules, 1202, 1203f, 2048 in collagen vascular disease, 1198, 1198f, 1202, 1203f Rhinorrhea, immune function of, 280 Rhinoscleroma, 853 Rhinosinusitis chronic, treatment of, 832 differential diagnosis of, 819t

I-102 Index Rhinovirus and acute bronchitis, 2097 and acute exacerbations of chronic obstructive pulmonary disease, 2116, 2116t and bronchiolitis, 2382 characteristics of, 2375t and common cold, 2085, 2376, 2376t and croup, 2087, 2379 infection (incl. pneumonia) and asthma, 774–775, 796, 816 in bone marrow and stem cell transplant recipients, 2229 chemokines in, 355 in children, 2391 diagnosis of, 2106 pathogenesis of, 2085–2086, 2374 seasonal variation in, 2374 and pharyngitis, 2086, 2376t, 2378 pneumonia, 2020 serotypes of, 2085, 2374 and tracheobronchitis, 2376t, 2380, 2381 transmission of, 2374 Rhizomucor, in sinusitis, 2319 Rhizomucor pusillus, 2316t, 2317 Rhizopus hypersensitivity pneumonitis caused by, 1163t, 1165t, 2319 infection (incl. pneumonia), in neutropenic host and cancer patient, 2217 in invasive fungal sinusitis, 2091 Rhizopus arrhizus, 2316, 2316t Rhizopus microsporus, 2316t, 2317 Rhodococcus epidemiology of, 1984t infection (incl. pneumonia) diagnosis of, 2429t in HIV-infected (AIDS) patients, 2215 pathology of, 2043t treatment of, 2429t Rhodococcus equi, 1990, 2428t bacteriology of, 2428t, 2434 culture of, 2429t historical perspective on, 2434 in HIV-infected (AIDS) patients, 2248, 2435 infection (incl. pneumonia) clinical features of, 2435 clinical manifestations of, 2270 diagnosis of, 2270–2271, 2434, 2434t, 2435 differential diagnosis of, 2435 epidemiology of, 2270, 2428t, 2434 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2212t, 2251–2252 radiographic findings in, 2214t, 2249t

in immunocompromised host, 2208 pathogenesis of, 2434 pathology of, 2048f, 2049 pathophysiology of, 2434–2435 radiologic features of, 2435 treatment of, 2271, 2435 microbiology of, 2270 staining characteristics of, 2048f, 2049, 2429t Rhodotorula rubra, contamination of bronchoscope, 2279 Rhonchi, 392–393, 393t Rib(s) fractures, 418. See also Flail chest in trauma patient, 1762 tumors of, metastases, 502, 505f Ribavirin, indications for, 2375t, 2394, 2395 Rib cage, motion, analysis of, 1646 Rich, Arnold, 1144 Richards, Dickinson W., 5t, 16, 17f, 228–229, 229f Rickettsia, infection histopathology of, 2034 pathology of, 2050 Rickettsia helvetica, and sarcoidosis, 1126–1127 Riding school lung, etiology of, 1164t RIF. See Rifabutin Rifabutin adverse effects and side effects of, 2478, 2494, 2503 and antiretroviral therapy, 2490 drug interactions with, 2478, 2503 interactions with immunosuppressive agents, 2503t for Mycobacterium avium complex infection, in HIV-infected (AIDS) patients, 2494, 2494t prophylactic regimen, 2495, 2495t for nontuberculous mycobacteria, dosage and administration of, 2504t pharmacology of, 2478 for tuberculosis, 2478 dosage and administration of, 2482t in HIV-infected (AIDS) patients, 2478 Rifampin adverse effects and side effects of, 2477–2478, 2483t, 2503 for anthrax, 2437 for brucellosis, 2429t, 2438–2439 dosage and administration of, 2477 hepatotoxicity of, 2477–2478, 2491 interactions with antiretroviral therapy, 2490 with immunosuppressive agents, 2503t for latent tuberculosis infection, 2455–2456, 2455t

in HIV-infected (AIDS) patients, 2491 mechanism of action of, 2464, 2477 for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t pharmacology of, 2477 plus isoniazid, hepatotoxicity of, 2477, 2478 resistance to, 2477 testing for, 2463 for Rhodococcus pneumonia, 2429t for tuberculosis, 2464, 2477–2478 in children, 2135 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2490 regimens for, 2481t theoretical basis for, 2476 Rifamycins and antiretroviral therapy, 2490–2491 interactions with clarithromycin, 2503 with immunosuppressive agents, 2503t Rifapentine pharmacology of, 2478 for tuberculosis, 2478 dosage and administration of, 2482t regimens for, 2481t Right atrial pressure, normal, 1334t Right middle lobe syndrome hemoptysis in, 413–414 radiographic features of, 485f Right ventricular end-diastolic pressure, in acute respiratory failure, 2663 Right ventricular failure after lung resection, 1748 bronchial circulation in, 1353, 1354f diuretic therapy for, 1377 in pulmonary hypertension, 1371 Right ventricular systolic pressure, 1374 Rigid spine syndrome, ventilatory impairment in, 1668t Riluzole, for amyotrophic lateral sclerosis, 1652 Rimantadine, for influenza, 2387–2388, 2387t Rimonabant, in smoking cessation, 756 Ring shadows, 1222 in allergic bronchopulmonary aspergillosis, 841 Ritodrine, pulmonary effects of, 1091t Rituximab, pulmonary effects of, 1081t, 1083 RL. See Total pulmonary resistance RMP. See Rifampin RNA (ribonucleic acid), viral double-stranded, 1971 single-stranded, 1971

I-103 Index Rocky Mountain spotted fever, differential diagnosis of, 2444 Roentgen (unit), 1177 Roentgen, Wilhelm Conrad, 18, 1173 Rofecoxib, lack of airway response to, in aspirin-sensitive asthmatics, 801, 802f Rohrer, Fritz, 5t, 12 RONS. See Reactive oxygen-nitrogen species ROS. See Reactive oxygen species (ROS) Roundworms, 2413, 2415–2418 Rowbotham, Stanley, 2646 RPT. See Rifapentine RRP. See Recurrent respiratory papillomatosis Rrs. See Respiratory resistance RSV. See Respiratory syncytial virus Rt. See Transepithelial electrical resistance Rti. See Lung tissue resistance Rubeola, vaccine against, 2070t, 2072 Rubner, Max, 8 RUDS. See Reactive upper airway dysfunction syndrome Rule of rescue, 2724 Rus, definition of, 1327, 2739 Ruysh, 694 RV. See Residual volume RVEDP. See Right ventricular end-diastolic pressure RV/TLC. See Residual volume/total lung capacity ratio Rw. See Chest wall resistance S Saccamanno’s fixative, 514 Saccharomonospora viridis, hypersensitivity pneumonitis caused by, 1163t Saccharomyces cerevisiae in allergic bronchopulmonary mycosis, 837 infection (incl. pneumonia), in cancer patients, 2217 Saccharopolyspora rectivirgula. See Micropolyspora faeni Safety margin, definition of, 1896 Salbuterol, structure-activity relationships, 2632–2633 Salicylate and aspirin-induced asthma, 802t dose-related airway response to, in aspirin-sensitive asthmatics, 801 Saligenins. See also specific drug dosage forms, 2632t receptor activity, 2632t structure-activity relationships, 2632–2633 structure of, 2633f Saline, hypertonic, inhalation therapy, for cystic fibrosis patient, 876 Salivary glands, in immune defense, 281

Salivary gland tumors, 1845–1846, 1925–1926 Salla disease, and bullous emphysema, 917 Salmeterol adverse effects and side effects of, 827t for asthma, 823t, 827t for chronic obstructive pulmonary disease, 738t, 739 dosage and administration of, 827t dosage forms, 2632t plus fluticasone adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t receptor activity, 2632t structure of, 2633f Salmonella, infection (incl. pneumonia) in chronic granulomatous disease, 2237 in HIV-infected (AIDS) patients, 2212t, 2215 immune defect associated with, 1983t, 2210t in immunocompromised host, 2207 in neutropenic host and cancer patient, 2217 Sanfilippo’s syndrome, 1275 SAP. See Serum amyloid protein SAPS. See Simplified acute physiological score Sarcoid-like granulomatous lesions, occupational exposures and, 935t Sarcoidosis, 1125–1142, 2542t abdominal, 1128t, 1131t, 1134 acute, with or without erythema nodosum, 1130, 1132 asymptomatic, 1130, 1131–1132 and autoimmune disease, 1135, 1136t bronchoalveolar lavage cellular profile in, 1121t bronchoscopy in, 1120t and cancer, 1135 cardiac, 1128t, 1131t, 1134 diagnosis of, 1136, 1137f treatment of, 1141 cardiopulmonary exercise testing in, 625 classification of, 1130–1131 clinical assessment in, 1137, 1139t clinical course of, 1137–1139 clinical features of, 1118t, 1128t, 1130–1135 and common variable immunodeficiency, 1135 complement in, 349 computed tomography of, 1112, 1113f, 1115t, 1118t cutaneous, 1128t, 1131t, 1133 cutaneous lesions in, 390, 438, 439f–440f

cytopathology of, 525–526, 526f diagnosis of, 1135–1137, 1137f, 1138f endocrine, 1128t, 1131t, 1134 epidemiology of, 1126 erythema nodosum in, 434 etiology of, 1126–1127 exocrine gland involvement in, 1128t, 1131t, 1134 extrapulmonary, 1128t, 1131t, 1133–1135 FDG-PET in, 565–566 fever in, 420 fibrocystic, 1141 gastrointestinal, 1128t, 1131t, 1134 genetics of, 1127 genitourinary, 1128t, 1131t, 1135 heart transplantation in, 1142 hematologic, 1128t, 1131t, 1134 hepatic, 1128t, 1131t, 1133–1134 histology of, 1118t histoplasmosis and, 2335 differentiation of, 2338–2339 historical perspective on, 1125–1126 in HIV-infected (AIDS) patients, 1135 IFN-α therapy and, 1100 imaging of, 2022, 2025 immunoglobulins in, 330 immunopathology of, 1128–1130, 1130f joint and musculoskeletal involvement in, 1128t, 1131t, 1134 lung transplantation in, 1142, 1774t, 1775–1777 lymphadenopathy in, 2028 mediastinal involvement in, 1604 neurologic involvement in, 1128t, 1131t, 1134 treatment of, 1141 ocular, 1128t, 1131t, 1133 treatment of, 1141 pathogenesis of, 1128–1130, 1130f pathology of, 1127–1128, 1129f pathophysiology of, 1128–1130 pleural effusion in, 1501–1502 and postoperative pulmonary complications, 667 and pregnancy, 1135, 1141 prognosis for, 1137–1139 psychosocial manifestations of, 1128t, 1135 management of, 1141 pulmonary, 1128t, 1130–1131, 1131t, 1132–1133, 1397–1398, 1398f chest imaging in, 1132–1133, 1132f computed tomography of, 1133 necrotizing sarcoid granulomatosis in, 1133 pulmonary function testing in, 1133 pulmonary hypertension in, 1133, 1141 pulmonary lesions of, 1991, 1993f, 2014 and quality of life, 1141

I-104 Index Sarcoidosis (Cont.) radiographic features of, 482, 483, 485, 490f, 497f, 498 radiographic findings in, 423, 423f rare associations with other systemic and organ-specific diseases, 1135, 1136t rare manifestations of, 1131, 1131t renal, 1128t, 1131t, 1134 scintigraphy in, 558, 559, 559f solitary pulmonary nodule in, 1817 Th1 immunity and, 1130, 1135 treatment of, 1118t alternative agents for, 1140–1141, 1140t corticosteroids for, 1139–1140, 1140t indications for, 1139, 1139t systemic, 1139–1140, 1140t upper airway obstruction in, 855 of upper respiratory tract and oral cavity, 1128t, 1131t, 1133 work-up for, exclusion of histoplasmosis in, 2338–2339 Sarcoma presenting as solitary pulmonary nodule, 1816 primary pulmonary, 1926, 1926t pulmonary metastases, 1942 synovial, pleural, 1550, 1552 Sarcomatoid carcinoma, of lung, 1840–1841 variants of, 1840–1841 Sarcomere(s), 72 Sarin, bronchiolitis caused by, 894t SARS. See Severe acute respiratory syndrome Sauna taker’s disease, etiology of, 1164t Sauropus androgynus, bronchiolitis associated with, 906 Sax lung, etiology of, 1165t Scalene muscle(s), 72f actions of, 76, 77 Scedosporiosis, pulmonary, 2323–2324 Scedosporium, infection (incl. pneumonia), 2321 differential diagnosis of, 2322 Scedosporium apiospermum, 2323–2324 Scedosporium prolificans, 2323–2324 Schaumann, Jorgen, 1125 Scheele, Carl Wilhelm, 5t, 7, 8, 9 Scheie’s syndrome, 1275 Schistosoma, 1995 and eosinophilic pneumonia, 1214t infection, 1092 pathology of, 2050 staining characteristics of, 2039 Schistosoma haematobium, 2414t, 2418t, 2423–2425 Schistosoma intercalatum, 2423 Schistosoma japonicum, 2414t, 2418t, 2423, 2425

Schistosoma mansoni, 2414t, 2418t, 2423–2425 immune response to, 314 infection, pathology of, 2049f Schistosoma mekongi, 2423 Schistosomes, 2413 Schistosomiasis, 395, 2414t, 2423–2425, 2424f staining characteristics of, 2035t Schwannoma pleural, thoracoscopic management of, 651, 651f in posterior mediastinum, 1610, 1610f Scintigraphy, historical perspective on, 547 SCLC. See Small cell lung cancer Sclerodactyly, 429, 429f Scleroderma, 429–430, 429f, 430f. See also Collagen vascular disease alveolar hemorrhage in, 1241 aspiration pneumonia in, 1208, 1208f clinical features of, 1117t computed tomography of, 1115t, 1117t diagnosis of, 422–423, 423f diffuse, immunologic tests for, 1112t follicular bronchiolitis in, 905 histology of, 1117t histopathology of, 1364–1365, 1366f with interstitial lung disease, 1206–1207, 1207f computed tomography of, 1115t, 1206, 1207f pigmentary disturbances in, 429, 430f pleural disease in, 1206 pulmonary complications of, 388, 1193, 1194t, 1206–1208 pulmonary vascular disease in, 1207–1208 radiographic features of, 490f sarcoidosis and, 1135, 1136t treatment of, 1117t SCM-1β, 340t Scrofuloderma, 431 SDB. See Sleep-disordered breathing SDF-1. See Stromal cell-derived factor-1 Seafood, and occupational asthma, 985t, 986 Secondhand tobacco smoke, 1010 health effects of, 1025–1026, 1025t Secreted Frizzled-related protein 1, 86 Secreted Frizzled-related protein 2, 86 Secretion(s), aspiration of, therapeutic bronchoscopy for, 643 Secretory component, 280f, 326, 327f in nasal secretions, 281 Secretory leukocyte protease inhibitor, in lung parenchyma, 721, 721t Sedation, for agitated ICU patient, 2701–2706 adequacy of, assessment of, 2702 agent for, selection of, 2702 indications for, 2701–2702

strategies for, 2708–2710 Sedative/hypnotics, pulmonary effects of, 1091t Segmented worms, 2413, 2421–2423 Seizure(s), 2101t Selectins, in inflammation, 782 Selective digestive decontamination, 2582 Selective IgA deficiency, pulmonary infection in, 2235 Selective serotonin reuptake inhibitors (SSRIs), for obstructive sleep apnea, 1714 Self-determination, 2723 Self-expandable metallic stent(s), 639–640, 640f Seminoma, mediastinal, 1604, 1606–1607, 1606t, 1607f Semivolatile chemicals exposure to, 1027t sources of, 1027t SEMS. See Self-expandable metallic stent(s) Semustine pulmonary effects of, 1079t, 1080–1081 therapeutic uses of, 1078 Sepsis. See also Multiple organ dysfunction syndrome (MODS); Systemic inflammatory response syndrome (SIRS) and acute lung injury, 2527 definition of, 2563 diagnostic criteria for, 2562t goal-directed therapy for, 2569, 2569f leukocyte migration in, 354–355 multiple organ failure in, 449–450 outcomes of, 2715 prognosis for, 2715 staging, PIRO classification system for, 2562–2563, 2563t Septata, 2410 Septic emboli, 1444–1445, 2152f, 2154t in HIV-infected (AIDS) patients, 2214t Septic shock cytokines in, 336–337 diagnostic criteria for, 2562t goal-directed therapy for, 2569, 2569f maldistributive hypoxia in, 2617 Sequoisis, etiology of, 1163t Sericulturist’s lung, etiology of, 1164t Serine proteinase(s), inhibitors of, in chronic obstructive pulmonary disease, 721 Serologic tests, 2001–2002 Serosa, of lung, 23–24, 24f Serotonin and airway smooth muscle proliferation, in vitro, 118 gut-liver-lung axis and, 1347–1348, 1348f metabolism of, 444f and pulmonary circulation, 1347–1348 in pulmonary hypertension, 1369

I-105 Index Serotonin receptor(s), 1348 Serous otitis, 2093 Serpula lacrymans, hypersensitivity pneumonitis caused by, 1164t Serratia infection (incl. pneumonia) neonatal nosocomial, 2126 nosocomial, 2280, 2281t, 2282, 2289 pneumonia, 2019, 2022 Serratia marcescens contamination of bronchoscope, 2279 infection (incl. pneumonia) in chronic granulomatous disease, 2237 history and physical findings in, 2101t in HIV-infected (AIDS) patients, 2106t nosocomial, 2279, 2280t treatment of, 2285–2288, 2286t Serum amyloid-associated protein, 1234 Serum amyloid protein, 1970 Servetus, Michael, 4–6, 5t, 6 Severe acute respiratory syndrome (SARS), 1994, 2020, 2390–2391, 2427, 2428 in bone marrow and stem cell transplant recipients, 2229 chemokines in, 355 coronavirus, 1994 assays for, 1989t infection (incl. pneumonia), 2098 clinical presentation of, 2114 treatment of, 2114 pneumonia caused by, 2019 staining characteristics of, 2035t epidemiology of, 1984t historical perspective on, 2114 pathology of, 2044f treatment of, 2394 Severe combined immunodeficiency (SCID), 2139 pulmonary infection in, 2236 and risk of infection, 2306 Severity of illness scoring system(s), 2716–2718 calibration of, 2717, 2717f characteristics of, 2717 development of, 2716–2717 and discrimination, 2717, 2717f use in ICU, 2718–2720 Sexual function, smoking and, 752 SFrp1, 86 SFrp2, 86 SFrp4, 86 SGaw. See Specific conductance Shagreen patches, 438 Shell lung, etiology of, 1164t Shell proteins, hypersensitivity pneumonitis caused by, 1164t

Shh gene, 87, 88 Shigella, infection (incl. pneumonia), in Chediak-Higashi syndrome, 2238 Shivering primary motor center for, 452 in pulmonary disease, 452 Shock, metabolic response to, 2693 Shoulder girdle muscle(s), actions of, 76 Shunt(s) and arterial hypoxemia, 2616–2617, 2616t oxygen therapy for, 2619 and gas transport, 177–178 intracardiac, cyanosis due to, 415 left-to-right, 1354 pathophysiology of, 177–178 physiological, in ventilation-perfusion inequality, 187 pulmonary, symbols for, 1328, 2740 Shuttle-walking test, 600 Shy-Drager syndrome, upper airway obstruction in, 859 SIADH. See Syndrome of inappropriate antidiuretic hormone secretion Sicca syndrome, 281 Sick-building syndrome, 1010, 1032, 1034, 1035f Sickle cell disease and pneumococcal infection, 2131–2132 pneumonia in, 2100t pulmonary embolism in, 1425, 1445–1446 and pulmonary hypertension, 1384 pulmonary thrombosis in, 1445–1446 SID. See Strong ion difference Siderophores, 1970, 2079 Sievert (Sv) (unit), 1177 Sildenafil adverse effects and side effects of, 1388 for pulmonary arterial hypertension, 1388 Silica bronchiolitis caused by, 893t, 895–896 crystalline forms of, 974 as carcinogens, 977 exposure to in coal mines, 968, 968f high-risk occupations for, 974–975 free, 974 lung disease caused by, 934, 934t occupational lung disease caused by, 935t, 974 Silicates, sheet, bronchiolitis caused by, 893t, 895–896 Silicosis, 934, 934t, 2025. See also Progressive massive fibrosis accelerated, 976 acute, 976

bronchoalveolar lavage cellular profile in, 1121t chest radiographs in, 937–938, 938f chronic (classic), 975, 975f clinical features of, 976–977 complications of, 977 treatment of, 978–979 computed tomography of, 1115t definition of, 974 diagnostic issues in, 977 exposures associated with, 1109t forms of, 975–976 infectious complications of, 976, 977 lung function in, 977 lymphadenopathy in, 2028 management of, 978–979 medical screening and surveillance in, 978 pathogenesis of, 976 presenting as solitary pulmonary nodule, 1817 prevalence of, 974 prevention of, 978, 979 radiographic features of, 483, 485, 977 radiographic findings in, 423 risk factors for, 974 and risk of infection, 976 and tuberculosis, 976 Silo-filler’s disease, 423, 892, 895f, 1001, 1341, 2013 incidence of, 892 Siltzbach, Louis, 1126 Silver impregnation, 2035t, 2037 Simian virus-40, 1537 Simon focus, 1990 Simple pulmonary eosinophilia. See Loeffler syndrome Simplified acute physiological score, 2718 Simulation, definition of, 1896 Single nucleotide polymorphisms (SNP), in chronic obstructive pulmonary disease, 711 Sin Nombre virus, 2113 characteristics of, 2375t infection, 1994 Sinonasal cancer, occupational exposure and, 934t Sinus(es) mucociliary transport in, 2089 paranasal, development of, 2089 Sinusitis, 281, 2089–2091 bacterial acute community-acquired, 2089 chronic, 2089–2090 complications of, 2090, 2090f nosocomial, 2089 causes of, 2089 in Chediak-Higashi syndrome, 2238 chronic, and exacerbations of asthma, 807 common cold and, 2086

I-106 Index Sinusitis (Cont.) in common variable immunodeficiency, 331 fungal, 2090–2091 allergic, 2090–2091 in immunocompromised host, 2091 invasive, 2090–2091 risk factors for, 2089 Sirolimus interactions with drugs for nontuberculous mycobacteria, 2503t pneumonitis caused by, 2012t pulmonary effects of, 1099 SIRS. See Systemic inflammatory response syndrome Sitaxsentan, for pulmonary arterial hypertension, 1388 Sitophilus granarius proteins, hypersensitivity pneumonitis caused by, 1164t 6-minute walk test, 225, 599–600 Sj¨ogren’s syndrome. See also Collagen vascular disease airway disease in, 1210 and bronchiectasis, 2187 clinical features of, 1117t, 1210 computed tomography of, 1117t histology of, 1117t immunologic tests for, 1112t interstitial lung disease in, 1210–1211, 1210f obstructive airway disease in, 905 pulmonary complications of, 1194t respiratory complications of, 905 sarcoidosis and, 1135, 1136t secondary, interstitial lung disease in, 1211 treatment of, 1117t Skeletal deformity, and abnormal breathing pattern, 403 Skeletal pathology, and ventilatory impairment, 1668t Skin inspection of, 390 neoplastic disorders involving, 431–433 wrinkling, smoking and, 752–753 Skin cancer, in lung transplant recipient, 439–440 Skin disease, 427–440 drug therapy for, pulmonary toxicity from, 440 paraneoplastic, 445 SLE. See Systemic lupus erythematosus Sleep age and, 1681–1682 age-related changes in, 275–276 arousal during, 1693 autonomic regulation during, 1682–1683

cardiovascular control during, 1689, 1690f characteristics of, 1679–1682 CNS regions governing, 1683–1685, 1684f drugs and, 1732–1733 function of, 1682 non–rapid eye movement (NREM), 1679–1681, 1680f, 1681f light, periodicities of ventilation in, 1693–1694, 1693f stages of, 1679, 1680f oxygen therapy in, 2620, 2620t periodic breathing in, 1040 physiological mechanisms of, 1683–1685, 1684f pulmonary disorders during, 1725 quality of, 1731 quantity of, 1730–1731, 1731f rapid eye movement (REM), 1679, 1680f, 1681 features of, 1685–1686 and respiratory chemosensitivity, 2597 species differences in, 1681 ventilatory responses during, 168, 1690–1693, 1690f–1692f, 2597 altitude and, 1040 Sleep apnea, 169, 1697–1725 central, 169, 1712, 1722–1724, 1723f cardiopulmonary exercise testing in, 622 definition of, 1698 mortality rate for, 622 and chronic obstructive pulmonary disease, 735 conditions associated with, 1707, 1707t consequences of, 1710–1713, 1711f cardiovascular, 1711–1713 neurocognitive, 1711 history-taking in, 2647 obstructive, 169 anatomic considerations in, 1700–1701, 1700f, 1701f apneic event in, 1702 cardiopulmonary exercise testing in, 622 clinical presentation of, 1705–1706, 1705t definition of, 1698 diagnosis of, 1707–1710, 1708f–1710f economic effects of, 1713 epidemiology of, 1702–1703 genetic considerations in, 1705 impairment due to, evaluation of, 684 management of, 2649 neural considerations in, 1701–1702, 1702f pathogenesis of, 1699–1702, 1699f, 1700f pulmonary hypertension in, 1395–1396

and respiratory failure, 2587–2588 risk factors for, 1703–1705, 1704t surgical treatment of, 1720–1722, 1720t treatment of, 1713–1722, 1713t screening for, 1706–1707, 1707f in upper airway obstruction, 846 Sleep-disordered breathing definition of, 1698 historical perspective on, 1697–1698 in kyphoscoliosis, 1621 in neuromuscular disorders, 1639–1640, 1639t in pregnancy, 260 spectrum of, 1699, 1699f ventilatory impairment in, 1668t Sleep disorders, in chronic obstructive pulmonary disease, 735 Sleep disturbances, in pregnancy, 256 Sleepiness. See also Somnolence characteristics of, 1727–1728 daytime, causes of, 1733, 1733t differential diagnosis of, 1733–1734 drugs and, 1732–1733 evaluation of patient with, 1733–1734 excessive daytime, prevalence of, 1733 factors affecting, 1730–1733 objective measures of, 1729–1730 quantifying, 1728–1730 performance tests for, 1730 vigilance tests for, 1730 subjective measures of, 1728–1729 Sling-ring complex, 857 Slow code, 2729 SLPI. See Secretory leukocyte protease inhibitor Sly’s syndrome, 1275 Smad, 338–339 Small-airway disease in cystic fibrosis, 872 pulmonary function testing in, 604t, 605, 606t radiographic features of, 492f Small cell cancer, extrapulmonary, 1906 Small-cell carcinoma, 444 doubling time in, 493f Small cell lung cancer chemotherapy for, 1908–1909 second-line, 1909–1910 clinical presentation of, 1904, 1904f diagnosis of, 1902–1903 endocrine and hematologic syndromes associated with, 1930t epidemiology of, 1899–1900 genetic abnormalities in, 1901–1902, 1901t histopathologic classification of, 1900–1901, 1900f immunohistochemistry of, 1903 late complications of, 1910 limited-stage

I-107 Index prophylactic cranial irradiation for, 1890 thoracic radiation therapy for, 1890 metastases, sites of, 1902, 1902t natural history of, 1902 paraneoplastic phenomena with, 1904–1906, 1905t presenting as solitary pulmonary nodule, 1816 prognosis for, 1906–1907 prophylactic cranial irradiation in, 1909 radiation therapy for, 1884t prophylactic cranial, 1890 thoracic, 1890 radiographic findings in, 1903, 1904, 1904f risk factors for, 1899–1900 stage at presentation, 1902, 1902t staging of, 1902t, 1903–1904 thoracic radiotherapy for, 1909 treatment of, 1907–1910 in patients with poor performance status, 1910 surgical, 1907–1908 tumor biology of, 1901–1902 Small-cell undifferentiated lung cancer, cytopathology of, 530–531, 530f Smog, 1019 Smoke composition of, 1053 definition of, 994t Smoke bombs, inhalation injury caused by, 1003, 1004f Smoke inhalation epidemiology of, 1053 occupational, 934t parenchymal injury in, 1059–1060, 1060f toxic compounds in, 1053–1055, 1054t tracheobronchial injury in, 1057–1059, 1058f, 1059f treatment of, 1060–1061 Smoking. See also Nicotine and asbestosis, 949 and bronchiolitis caused by mineral dusts, 896 and carbon monoxide in blood, 1023–1024 and cardiovascular disease, 751–752 cessation, 753–759 and ability to quit, 756 acupuncture and, 754 aversive conditioning and, 754 behavioral approaches, 753–754 benefits of, 730–731, 730f, 758–759 in chronic obstructive pulmonary disease, 734 coal workers and, 973 cravings during, management of, 757 and depression, 757, 759 educational techniques for, 754 evaluation process, 756–757

by gradual reduction vs. abrupt abstinence, 754 group counseling for, 754 hypnosis and, 754 National Cancer Institute’s model for, 753–754 pharmacologic treatment in, 754–756 and postoperative pulmonary complications, 668 pragmatic approaches, 756 preoperative, 1740–1741 preparing smokers for, 757–758 and reason for quitting, 756 risks of, 759 stages of, 753 and weight gain, 757–758 and chronic obstructive pulmonary disease, 708–709, 708t, 709f, 749–751 as chronic relapsing disease, 759 cultural aspects of, 749 cytological responses to, 516, 517f diseases associated with, 749, 750t and elastic fiber synthesis, 718–719 emphysema due to, pathogenesis of, 722–723, 722f epidemiology of, 708, 753 harm reduction strategies for, 759–760 history of, and postoperative pulmonary complications, 668 indoor air contaminants from, 1021t–1022t and interstitial lung disease, 1108 and Langerhans’ cell histiocytosis, 1245, 1250, 1251f and lung cancer, 1816 and malignancy, 750t, 751 hemoptysis in, 413 and Master Settlement Agreement, 749 maternal, and risk of asthma in children, 794–795 oxidant-produced injury in, 450, 451 and oxidative stress, 716, 716f in pregnancy, adverse effects of, 752 prevention of, 760 as public health problem, 749 and pulmonary vasculature, 703 and risk of postoperative respiratory failure, 2575 and small airways, histopathology of, 702 social aspects of, 749 and susceptibility to air pollution, 1032t toxins inhaled in, 749 trends in, 708 Smoothened (SMO), 89, 89f Smooth muscle. See also Airway smooth muscle of airway wall, 27f, 31 of pulmonary vasculature, 31–32 Smooth muscle cell(s)

airway, in asthma, 777 of alveolar septum, 40f, 41, 41f differentiation of, 96–97, 96f, 97f Smudge cells, 2043, 2045f SNARE proteins, 316 Sniffing position, 2646, 2647, 2648f, 2649–2650, 2649f Sniff nasal inspiratory force. See SNIF test Sniff test, 460, 1642, 2586 SNIF test, in amyotrophic lateral sclerosis, 1652 Social Security disability evaluation under, 685–687 Listings of Impairments, 685 Office of Disability Determination Services, 685 Social Security Act Title II (disability insurance), 685 Title XVI (supplemental security income), 685 Sodium benzoate, sensitivity to, in aspirin-sensitive asthmatics, 802 Sodium bicarbonate, mucolytic effects of, 2642 Sodium channels, 144 Sodium nitrite, for cyanide poisoning, 1057 Sodium sulfite, sensitivity to, in aspirin-sensitive asthmatics, 802 Sodium thiosulfate, for cyanide poisoning, 1057 Sodium transport diseases involving, 144 epithelial, 138 cellular and molecular mechanisms of, 139, 139f Soldering fluxes, and occupational asthma, 985t, 986, 990 Solid organ transplantation pneumonia after, 2229–2232 radiologic diagnosis of, 2230–2232, 2231f, 2232f, 2233t pulmonary infection after, 2229–2232 beyond 6 months posttransplant, 2230, 2232f in first month posttransplant, 2229–2230 1 to 6 months posttransplant, 2230, 2231f timetable of, 2206f, 2229 Solitary fibrous tumors, pleural, 1550, 1551f Solitary pulmonary nodule, 1815–1828 benign, 1817, 1817t benign and malignant differentiation of, 559–560, 561t, 1820–1823 radiographic features of, 486 biopsy of, 1823–1824 bronchoscopy of, 1824, 1824f calcification of, 1820–1822, 1821f calcifications in, 486

I-108 Index Solitary pulmonary nodule (Cont.) causes of, 486 cavitation in, 487–489 computed tomography of, 489–494 definition of, 1815 diagnosis of, 494 thoracoscopy in, 655–656 diagnostic approach for, 1826–1828, 1827f differential diagnosis of, 486, 1817, 1817t doubling time of, 487, 493f, 1822 epidemiology of, 1816 excision of, 656 FDG-PET of, 559–560, 560f, 561t with ground-glass appearance, 560 growth rate, assessment of, 1822 imaging of, 1818–1820 repeat, frequency of, 1822–1823 incidence of, 1816 malignant, 1816–1817, 1817t management of, 656 percutaneous needle aspiration of, 1824 positive bronchus sign with, 1824 prevalence of, 1816 probability of malignancy, estimation of, 1823 radiographic findings with, 456f, 459f, 486–494, 493f shape of, 1820–1822, 1820f, 1821f thoracostomy for, 1824–1826 thoracotomy for, 1824–1826 transthoracic needle aspiration and biopsy of, 645, 645f Soluble amyloid P protein, 1233 Somnolence. See also Sleepiness postoperative, after lung resection, epidural analgesia and, 1747 Sonic hedgehog, 88, 88f, 89, 89f and Fgf10 expression, 85 and lung development, 82–83, 92–94 Sore throat. See Pharyngitis South American blastomycosis, history-taking in, 388, 388f Soybean hull antigens, hypersensitivity pneumonitis caused by, 1163t Soybean lung, etiology of, 1163t Soy sauce brewer’s lung, etiology of, 1164t SP-A. See Surfactant protein(s) Sp-A, and lung development, 83 Spallanzani Lazaro, 8 Sparfloxacin, 2057 Sp-B, and lung development, 82 SP-C. See Surfactant protein(s) Sp-C, and lung development, 82–85, 82f SP-D. See Surfactant protein(s) Specific compliance, definition of, 1328, 2740 Specific conductance, 584 definition of, 1327, 2739 normal, 1323, 2735 Spherulin skin test, 2344

Sphingosine 1-phosphate, and airway smooth muscle proliferation, in vitro, 118 Spider nevi, 449 Spinal cord injury(ies), ventilatory impairment in, 1648–1649, 1668t Spindle cell carcinoma, 1840–1841 Spirochetes, 2142. See also specific spirochete infection, pathology of, 2050 staining characteristics of, 2037, 2040f Spirometer(s), 568–569 dry rolling-seal, 569, 569f flow-type, 569 measurements made by, 568–569, 569f volume-type, 569, 569f water-sealed, 569, 569f Spirometry, 579 abnormal, severity of, grading, based on FEV1 , 603, 603t in asthma, 833 diagnostic, 570–571 minimal standards for, 570, 570t in dyspnea, 404 forced respiratory maneuvers during abbreviations for, 1326–1327, 2738–2739 definition of, 1326–1327, 2738–2739 monitoring, 571 in neuromuscular disease, 1646, 1646f in upper airway obstruction, 846 Splendore-Hoepllei phenomenon, 2037, 2039f Splenectomy associated infections, 1983t, 2210t, 2219 infections associated with, 1983t vaccinations with, 2111 SPN. See Solitary pulmonary nodule Sporothrix, infection (incl. pneumonia), in immunocompromised host, 2207 Sporothrix schenckii, infection (incl. pneumonia), in HIV-infected (AIDS) patients, 2212t Sporotrichosis, 1990 diagnosis of, 2002 Sprouty2, 85, 88f, 89 Spry2, 85, 89f Spry4, 85 Sputum assays, 423, 2031 in HIV-infected (AIDS) patients, 2247t, 2250 bacterial antigen detection in, 2001 bloody, 414 cultures, 2000–2001, 2104 in cystic fibrosis, 872–873 cytologic examination of, 1988f, 1997–1998 Diff-Quik staining, 2000 direct examination of, 1997–2001

direct immunofluorescent microscopy of, 1999 examination of, 819 in Pneumocystis pneumonia, 2361–2364, 2361t in pneumonia, 1985–1987, 1987f fluorochrome-stained, examination of, for bacteria, 1999 foul-smelling, 2101t fungal wet mounts, 1999 Giemsa-stained smears, 1999–2000 Gram-stained smear, examination of, for bacteria, 1998–1999, 1998f, 1999f induced, 512 microscopic examination of, 2000 postbronchoscopy, 513 specimen collection, 2104 spontaneously produced, 512, 512f stain and culture, 2104–2107 Ziehl-Neelsen-stained, examination of, for bacteria, 1999 Squamous cell(s), 514–515 Squamous cell carcinoma, 514, 515f of lung, 1832t, 1833–1835, 1834f, 1835f cytopathology of, 528–529, 529f doubling time in, 493f in lung transplant recipient, 439–440 presenting as solitary pulmonary nodule, 1816 Squamous papilloma, 1917–1918 SS. See Scleroderma Stachybotrys chartarum, 1030–1031 and diffuse alveolar hemorrhage, 1295 Stahl, Georg Erst, 5t, 7 Stain(s), histochemical, 2034–2039, 2035t.

See also specific stain Standard uptake value, for FDG-PET, 560 Staphylococci (Staphylococcus spp.) in acute mediastinitis, 2166t cavitation caused by, 2043 coagulase-negative in acute mediastinitis, 2166 in empyema, 2144t in empyema, 2143 exotoxin A, 2133 in HIV-infected (AIDS) patients, radiographic findings in, 2215 infection (incl. pneumonia) in children, 2132 complicating influenza, 2388 hemoptysis in, 413 lymphadenopathy in, 2028 Staphylococcus aureus, 1985, 1988, 1989, 1996, 2001 and accessory gene regulator (agr) network, 2080–2081 in acute mastoiditis, 2094 in acute otitis externa, 2092 acute sinusitis caused by, 2089 antibiotic resistance in, 2270

I-109 Index and atopic dermatitis, 428 in auricular cellulitis, 2091 bronchopneumonia caused by, 2042 in chronic suppurative otitis media, 2094 colonization, in cystic fibrosis, 866–867, 872–873, 874 drug-resistant, 2131 in empyema, 2144 immune defense against, 1973 infection (incl. pneumonia), 2005, 2020, 2022, 2023f, 2098 in bone marrow and stem cell transplant recipients, 2224 and bronchiectasis, 2186, 2189, 2189t in Chediak-Higashi syndrome, 2238 in children, 2132 immune defects and, 2138 in chronic granulomatous disease, 2237 clinical manifestations of, 2269 in common variable immunodeficiency, 331 complications of, 2112, 2269 in cystic fibrosis, treatment of, 875–876, 2178, 2179 of deep cervical space, 852 diagnosis of, 1998, 1998f, 2269–2270 differential diagnosis of, 2266 in elderly, 2007 and empyema, 1490 epidemiology of, 2269 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2106t, 2251 radiographic findings in, 2249t hospitalization rate for, 2105t in hyperimmunoglobulin E syndrome, 2239 ICU admission rate for, 2106t immune defect associated with, 1983t, 2210t in leukocyte adhesion deficiency, 2238 in neutropenic host and cancer patient, 2217 nosocomial, 2279–2280, 2280t, 2281t, 2282, 2581–2582 treatment of, 2285–2288, 2286t and parapneumonic effusions, 1489 pathogenesis of, 2080, 2269 postinfluenza, 2060 risk factors for, 2112 signs and symptoms of, 2099 supraglottitis caused by, 853 in surgery and trauma patients, 2197 treatment of, 2112, 2270 in X-linked agammaglobulinemia, 331, 2233–2234 in invasive (malignant) otitis externa, 2092 in lung abscess, 2144, 2154t

methicillin-resistant. See Methicillinresistant Staphylococcus aureus microbiology of, 2268–2269 in nosocomial sinusitis, 2089 and orbital complications of sinusitis, 2090 in perichondritis, 2091 PVL-positive, infection (incl. pneumonia) mortality rate for, 2112 pathology of, 2112 in supraglottitis, 2088 toxin produced by, 2081 toxins produced by, 2052, 2055 and tracheitis, 2379 in tracheitis, 853 tracheitis caused by, 2088 vaccine against, 2080 Staphylococcus epidermidis, infection, of deep cervical space, 852 Starling equation, 2523–2524 Starling resistor, 1350, 1350f STAT1, 1976 STAT4, 1976 STAT6, 1976 Static compliance of chest wall, 575–576, 575f, 576f of lung, 575, 576f, 577 age-related changes in, 267, 267f definition of, 1328, 2740 normal, 1323, 2735 of respiratory system, age-related changes in, 267, 267f Static pulmonary pressure, at specified lung volume, definition of, 1328, 2740 Status asthmaticus outcomes of, 2714 prognosis for, 2714 Stavudine, adverse effects and side effects of, with isoniazid, 2490 Steeple sign, 2379 Steiner stain, 2037 Stem cell factor, 308, 316 and B-cell production, 323 effects/functions of, 781t sources of, 781t targets of, 781t Stemphylium languinosum, in allergic bronchopulmonary mycosis, 837 Stenotrophomonas, infection (incl. pneumonia), in organ transplant recipient, 2230 Stenotrophomonas maltophilia infection (incl. pneumonia) in cystic fibrosis, 875, 881 treatment of, 875, 2179 in neutropenic host and cancer patient, 2217 nosocomial, 2196 pneumonia, 2009

Stent(s) airway, 862 complications of, 644 endobronchial, 639–640 self-expandable metallic, 639–640, 640f tube, 639–640 Sternocleidomastoid muscle(s), 72f actions of, 76 Sternotomy, median, pulmonary complications of, 666, 666t Sternum, fracture, in trauma patient, 1763 Steroid(s) inhaled, for bronchiectasis, 2191 interactions with drugs for nontuberculous mycobacteria, 2503t resistance to, 2639 Steroid myopathy, respiratory abnormalities in, 1659–1660 Stethoscope, historical perspective on, 13–14 Stevens-Johnson syndrome, 436, 436f, 2099, 2113, 2207 Stipatosis, etiology of, 1164t Stokes, William, 403 Stomach, pathogens from, and nosocomial pneumonia, 2274 Streptococci (Streptococcus spp.) in acute mediastinitis, 2166t in acute otitis externa, 2092 acute sinusitis caused by, 2089 α-hemolytic in empyema, 2144t and epiglottitis, 2379 in auricular cellulitis, 2091 beta-hemolytic, 2024, 2024f in empyema, 2143, 2144 infection (incl. pneumonia), lymphadenopathy in, 2028 bronchopneumonia caused by, 2042 cavitation caused by, 2043 coagulase-negative, in acute mediastinitis, 2166 in empyema, 2144, 2144t group A in acute mastoiditis, 2094 antiphagocytic factors, 2080 infection (incl. pneumonia), 2271 in Chediak-Higashi syndrome, 2238 in children, 2133 clinical presentation of, 2113 epidemic, 2113 epidemiology of, 2113 invasive, 2113 mortality rate for, 2113 supraglottitis caused by, 853 treatment of, 2113 and orbital complications of sinusitis, 2090

I-110 Index Streptococci (Streptococcus spp.), and orbital complications of (Cont.) pharyngitis, 2079, 2086 in supraglottitis, 2088 tracheitis caused by, 2088 group B in acute otitis media, 2092 infection (incl. pneumonia), 2271 neonatal infection, 2125–2126, 2126f vaccine against, 2080 group C, pharyngitis, 2086 group D, nonenterococcal, in empyema, 2144t group F, infection (incl. pneumonia), 2271 group G infection (incl. pneumonia), 2271 pharyngitis, 2086 immune defense against, 1973 infection (incl. pneumonia) in children, 2133 of deep cervical space, 852 in HIV-infected (AIDS) patients, 2106t hospitalization rate for, 2105t ICU admission rate for, 2106t immune defect associated with, 1983t, 2210t nosocomial, 2280, 2281t in lung abscess, 2154t microaerophilic, 2007, 2147f infection (incl. pneumonia), 2156 conditions underlying, 2145t staining characteristics of, 2036f and tracheitis, 2379 viridans, in acute mediastinitis, 2166 Streptococcus agalactiae, neonatal infection, 2125–2126, 2126f Streptococcus epidermidis in acute mediastinitis, 2166t immune defense against, 1973 infection (incl. pneumonia) hospitalization rate for, 2105t immune defect associated with, 1983t, 2210t Streptococcus intermedius, in empyema, 2144t Streptococcus mitis, 2086 Streptococcus mutans, 2086–2087 Streptococcus pneumoniae, 1989, 1995–1996, 1996f and acute bronchitis, 2097 in acute exacerbations of chronic obstructive pulmonary disease, 742t, 2117, 2121t in acute mastoiditis, 2094 in acute otitis media, 2092 acute sinusitis caused by, 2089 antibiotic resistance in, 2267–2268 bronchopneumonia caused by, 2042 colonization of host, 2079 diagnosis of, 2001

drug-resistant, 2065, 2108, 2131 infection risk factors for, 2059–2060 treatment of, 2056–2057, 2060–2061 infection (incl. pneumonia), epidemiology of, 2099 in empyema, 2143–2144 and H. influenzae, interactions of, 2081 in HIV-infected (AIDS) patients, radiographic findings in, 2215 immune response to, 324 infection (incl. pneumonia), 330–331, 2004, 2005, 2019, 2019f. See also Pneumonia, pneumococcal in bone marrow and stem cell transplant recipients, 2224 and bronchiectasis, 2186, 2189t, 2190 in cancer patients, 2216 chest radiograph in, 2102f in children, 2131–2132 clinical manifestations of, 2266–2267 in common variable immunodeficiency, 331 in complement deficiency, 2236 complicating influenza, 2388 of deep cervical space, 852 diagnosis of, 1998, 2267, 2267f differential diagnosis of, 2266–2267 in elderly, 2007 and empyema, 1490–1493, 1492f epidemiology of, 2004, 2266 history and physical findings in, 2100t in HIV-infected (AIDS) patients, 2106t, 2251, 2252 radiographic findings in, 2214t, 2249t hospitalization rate for, 2105t ICU admission rate for, 2106t immune defect associated with, 1983t, 2210t in immunocompromised host, 2204 in neutropenic host and cancer patient, 2217 nosocomial, 2008, 2277, 2280, 2280t, 2282 treatment of, 2285–2288, 2286t and parapneumonic effusions, 1489 pathogenesis of, 2080, 2081, 2265–2266 in pediatric HIV-infected (AIDS) patients, 2139 prevention of, 2268 risk factors for, 2112 signs and symptoms of, 2099 supraglottitis caused by, 853 in surgery and trauma patients, 2197 treatment of, 2055, 2062, 2112, 2268 in Wiskott-Aldrich syndrome, 2237 in X-linked agammaglobulinemia, 331, 2233–2234

macrolide-resistant, 2108–2110 microbiology of, 2265 MICs for penicillin, 2112 and orbital complications of sinusitis, 2090 and otitis media, 2131 penicillin-resistant, 2109, 2112, 2131 infection (incl. pneumonia), epidemiology of, 2099 protease, 326 quinolone resistance, 2057 and sinusitis, 2131 in sputum, 2104 in supraglottitis, 2088 and tracheitis, 2379 tracheitis caused by, 2088 vaccines against, 2066–2068, 2066t, 2080, 2111, 2132, 2268 virulence factors, 2081 Streptococcus pyogenes infection (incl. pneumonia), 2113, 2271 and empyema, 1490 in lung abscess, 2144 pharyngitis caused by, 2086 pneumonia, 2005 Streptococcus salivarius, 2086 Streptococcus viridans, 2007 infection of deep cervical space, 852 supraglottitis caused by, 853 Streptokinase, 535–536 for pulmonary embolism, 1439–1440 Streptomyces, infection (incl. pneumonia), in immunocompromised host, 2207 Streptomyces albus, hypersensitivity pneumonitis caused by, 1165t Streptomycin adverse effects and side effects of, 2483t, 2503 for brucellosis, 2429t, 2438–2439 interactions with immunosuppressive agents, 2503t for nontuberculous mycobacteria, 2505 dosage and administration of, 2504t for plague, 2429t, 2432 for tuberculosis, 2479 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2490 theoretical basis for, 2476 for tularemia, 2429t, 2434 Stress response, 2561–2562, 2562f Stress ulcer(s) prevention of, 835 in respiratory failure, 2518t, 2519 Stridor, 392–393 causes of infectious, 2379 noninfectious, 2379 inspiratory, in children, 2379 in upper airway obstruction, 846

I-111 Index Stripe sign, 554, 555f Stroke and aspiration, 1307–1308 ventilatory impairment in, 1648 Stromal cell-derived factor-1, 340t, 341t Strong ion difference, 213–214 Strongyloides infection, 1092 infestation immune defect associated with, 1983t, 2210t pathology of, 2045, 2046f Strongyloides stercoralis, 1995, 2013, 2414t, 2415–2418, 2416f biology of, 2414 and eosinophilic pneumonia, 1214t, 1215–1216 in HIV-infected (AIDS) patients, 2248, 2258 hyperinfection syndrome caused by, 2414t, 2415, 2417, 2417f, 2418, 2418t infestation in bone marrow and stem cell transplant recipients, 2223 in cancer patients, 2219 history and physical findings in, 2100t in immunocompromised host, 2204, 2210 in neutropenic host and cancer patient, 2217 pathology of, 2050f in lung abscess, 2154t Strongyloidiasis, 2000, 2414t, 2415–2418, 2417f cytopathology of, 523–524, 524f Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment, 2719–2720 Subacute sensory neuropathy, paraneoplastic, 1936–1937, 1936t Subarachnoid pleural fistula, after lung resection, 1746 Subclavian vein, obstruction of, percutaneous transluminal angioplasty and stenting for, 540 Suberosis, etiology of, 1163t Subglottic stenosis, 855 Submucosal glands, 137 biology of, 141–143 cell types of, 141 development of, 141 electrolyte transport in, 141–142, 142t macromolecular products of, 142–143, 142t physiology of, 141 protein products of, 142–143, 142t structure of, 141, 141f Submucosal (Meissner’s) plexus, 1304

Substance P, and airway smooth muscle proliferation, in vitro, 118 Substituted judgment, 2725 Sudden death, in pulmonary hypertension, 1371–1372 Sudden infant death syndrome (SIDS), maternal smoking and, 752 Sugar cane, moldy, 2012 Sulbactam, 2056 Sulfadiazine for acanthamoebiasis, 2401 for toxoplasmosis, 2402 Sulfa drugs, pneumonitis caused by, 2010, 2012t Sulfamides, and interstitial lung disease, 1111t Sulfasalazine eosinophilic pneumonia caused by, 1216f and interstitial lung disease, 1111t pneumonitis caused by, 2010, 2012t pulmonary effects of, 1089 and vasculitis, 1464 Sulfatase, 2633 Sulfatide lipidosis, 1272–1273 Sulfonamides and interstitial lung disease, 1111t pulmonary effects of, 1090t, 1091t, 1092 Sulfur dioxide bronchiolitis caused by, 893t, 894 health effects of, 1016–1017 in indoor air, sources of, 1021t inhalation injury caused by, 1000t, 1001 National Ambient Air Quality Standards for, 1011t occupational lung disease caused by, 935t in outdoor air, exposures to, 1016–1017 in smoke and inhalation injury, source of, 1054t sources, 1011t water solubility of and mechanism of lung injury by, 994–995, 994t and site of impact, 995t Sulindac, and aspirin-induced asthma, 802t Superior vena cava obstruction of, percutaneous transluminal angioplasty and stenting for, 540 venography of, 467–469, 471f Superior vena cava syndrome, 390, 1564, 1566f, 1611–1612, 1903 Superoxide anion, 2624–2625 eosinophils and, 310t, 315 formation of, 359–360, 360f Superoxide dismutase, 360, 360f, 2625, 2626 Aspergillus, 2294 SUPPORT, 2719–2720

Supraglottitis, 2088 treatment of, 853 upper airway obstruction in, 853 Supraventricular tachyarrhythmias, in chronic obstructive pulmonary disease, 743 Surface forces, 125–126 and micromechanics of alveolar septum, 56–57, 56f, 57f and stabilization of lung structure, 54–56, 150–151, 151f Surfactant, 56, 125, 282 in airways, 39 apoproteins of, 36, 37f, 38f, 39, 41 mutations of, 39 biophysical activity of, assessment of, 39 catabolism, 126f, 131–132, 1314, 1314f by alveolar macrophages, 43, 126f composition of, 36, 126–127 damage to, 39 deficiency of, 39 degradation of, 38 discovery of, 12 distribution of, in lung, 39 dysfunction, 39 exogenous, in ALI/ARDS, 2557–2558 functions of, 36, 39, 151, 151f homeostasis, 1314, 1314f inactivation by plasma proteins, 134 inhibition of, in respiratory distress syndrome, 133–134 intraalveolar, 38 intracellular storage form of, 37–38, 37f phospholipids, 126 recycling and catabolism of, 126f, 131–132 synthesis of, regulation of, 132 production of, 1314, 1314f reduction, in respiratory distress syndrome, 134 regulation of, 132 recycling of, 38, 38f, 1314, 1314f replacement therapy with, 39, 2642–2643 reuptake of, by type II cells, 38 SA/LA ratio, 39 secretion of, 38, 38f species differences in, 36, 37f, 39 and stabilization of lung structure, 54, 54f, 55f subtypes of, 36, 37f, 38, 38f synthesis of, 37f, 38, 38f, 39f, 41 reduction, in respiratory distress syndrome, 134 Surfactant protein(s) function of, 127–130 recycling and catabolism of, 126f, 131–132 SP-A, 126–127, 130–131, 282, 1973, 1983 in aspergillosis, 838, 2293 functions of, 127

I-112 Index Surfactant protein(s), SP-A (Cont.) nitration of, 363 structure of, 127f SP-B, 126–127, 126f deficiency of, and respiratory failure at birth, 129–130 functions of, 129 gene for (SFTPB), 129 mutations of, disorders associated with, 129f, 130 structure of, 128f, 129 SP-C, 87, 89f, 126–127, 126f functions of, 127–128 gene for (SFTPC), 127 mutations of, and interstitial lung disease, 128–129, 129f and lung development, 84 structure of, 127–128, 128f SP-D, 126–127, 282, 1973, 1983 in aspergillosis, 838, 2293 functions of, 127, 131, 131t structure of, 127f structure of, 127–130 synthesis of reduction, in respiratory distress syndrome, 134 regulation of, 132 Surgery cardiac, effects on pulmonary function, 2578–2579 effects on pulmonary function, 2577–2579 pulmonary complications of, 666, 666t upper abdominal, effects on pulmonary function, 2577–2578 Surgical incision, type of, and postoperative pulmonary complications, 669–670 Surgical patient(s) acute respiratory failure in, 2573–2588 risk factors for, 2574–2575 risk of, predicting, 2575–2576, 2576t pneumonia in, 2193–2200. See also Pneumonia, nosocomial postoperative interventions for ineffective, 674 and prevention of pulmonary complications, 673–674, 673t postoperative pulmonary complications in, 2573. See also Pulmonary complications preoperative evaluation of, 670, 671f arterial blood gas analysis in, 670 chest radiography in, 670 history-taking in, 670 physical examination in, 670 pulmonary function testing in, 670 preoperative pulmonary preparation, 673, 673t pulmonary function testing in, preoperative, 670

pulmonary rehabilitation for, 769–771 risk assessment in, cardiopulmonary exercise testing in, 626–628 Surgical procedure, and risk of postoperative respiratory failure, 2574, 2574t Surgical site, and postoperative pulmonary complications, 669 Surrogate decision makers, 2725, 2729 and best interests of patient, 2725 identification of, 2732 role of, 2732 and substituted judgment, 2725 Survival, meaningful, 2726 Swallowing difficulty. See Dysphagia muscles involved in, 1299, 1301t–1302t phases of, 1299–1304, 1303f muscles involved in, 1301t–1302t and ventilation, integration of, 1304 Swallowing center(s), 1304 Sweating, in pulmonary disease, 452 Sweat test, in diagnosis of cystic fibrosis, 870, 870f Sweet syndrome, 434, 434f Swimmer’s ear, 2092 Swyer-James syndrome, 474, 897 Symmorphosis, 66–68, 68t Sympathectomy, VATS procedure, 658–659, 659f Sympathomimetics. See Beta-adrenergic agonists Syncope posttussive, 409–410 in pulmonary hypertension, 1371, 1371t, 1392, 1392f Syndrome of inappropriate antidiuretic hormone secretion (SIADH), 390, 444–445, 1932–1933 in small cell lung cancer, 1905, 1905t in tuberculosis, 2470 Systemic arterial pressure, normal, 1334t Systemic inflammatory response syndrome (SIRS), 2196. See also Multiple organ dysfunction syndrome (MODS); Sepsis clinical patterns of, 2562f, 2564–2565 definition of, 2563 diagnostic criteria for, 2562t epidemiology of, 2565 historical perspective on, 2561 in HIV-infected (AIDS) patients, 2246 inotrope therapy in, 2568–2569 maldistributive hypoxia in, 2617 management of, 2568–2570 source control in, 2568 metabolic management in, 2570 outcomes of, 2715 pathogenesis of, 2561–2562 pathophysiology of, 2565–2566 perfusion management in, 2568 prognosis for, 2715

underlying basis of, hypotheses of, 2566–2568 vasopressor therapy in, 2568–2569 Systemic lupus erythematosus (SLE), 1281. See also Collagen vascular disease acute lung syndromes in, 1198, 1198t alveolar hemorrhage in, 1241, 1292–1293, 1293f and bronchiectasis, 2187–2188 bronchiolitis in, 905, 1201 bronchoalveolar lavage cellular profile in, 1121t clinical features of, 1117t, 1198–1201 computed tomography of, 1117t drug-induced, 1090t, 1097 histology of, 1117t immunologic tests for, 1112t pathology of, 1285t pleural effusion in, 1497, 1498f pulmonary involvement in, 905, 1193, 1194t, 1198–1201, 1198t, 2013 pulmonary vascular disease in, 1201 respiratory abnormalities in, 1659 respiratory muscle dysfunction in, 1201, 1201f and risk of infection, 2306 sarcoidosis and, 1136t serology of, 1285t treatment of, 1117t and vasculitis, 1462–1463, 1462f Systemic sclerosis. See Scleroderma Systemic vascular resistance in exercise, 616 in pregnancy, 257t T Tabun, bronchiolitis caused by, 894t Tachypnea, in pregnancy, 254 Tacrolimus, 428 interactions with drugs for nontuberculous mycobacteria, 2503t Taenia, infestation, in immunocompromised host, 2210 Takayasu’s arteritis, 1461 Talc, bronchiolitis caused by, 893t, 894t Talcum powder, bronchiolitis caused by, 893t Tapeworms, 2413 TARC. See Thymus and activation-regulated chemokine Tartrazine, lack of airway response to, in aspirin-sensitive asthmatics, 802 Taxanes, pulmonary effects of, 1083–1084, 1083t radiation therapy and, 1181 Taylor dispersion, 176 Tazobactam, 2056 TBB. See Biopsy, transbronchial

I-113 Index T-bet, 1976 TBNA. See Transbronchoscopic needle aspiration TBX4, 84–85 T-cell antigen receptor (TCR), 323 T-cell factor 1, 86 T-cell receptor(s), 1974, 1976 T cells (T lymphocytes), 42, 1974, 1976 activation, 323 in allergic bronchopulmonary aspergillosis, 838, 2295–2296 in allergy, 792, 792f antigen-specific, migration to lung, 1976, 1977f in asthma, 776–777 CD4+, 323, 1975, 1976, 1978, 2293 in allergic bronchopulmonary aspergillosis, 2296 in chronic obstructive pulmonary disease, 715 RSV and, 2128 CD8+, 1975, 1976, 1978 in chronic obstructive pulmonary disease, 715 RSV and, 2128 chemotherapy and, 2216 cytotoxic. See Cytotoxic (cytolytic) T lymphocytes (CTL) defects of associated infections, 1983t, 2210t causes of, 1983t, 2210t helper, 324, 776 in aspergillosis, 838, 2293 and isotype switching, 324 memory, 1977 central, 1977 effector, 1977 in pulmonary fibrosis, 374–375 regulatory, 776–777, 1976 Th0, 776 Th1, 324, 776, 1976 in allergy, 792, 792f in aspergillosis, 838, 2293 in pulmonary fibrosis, 374–375 RSV and, 2128 and sarcoidosis, 1130 Th2, 324, 776, 1976 in allergic bronchopulmonary aspergillosis, 838, 2296 in allergy, 792, 792f in aspergillosis, 838, 2293–2294 in pulmonary fibrosis, 374–375 RSV and, 2128 Th17, 1976 Tcf1, 86 Tcf4, 86 Tc-99m Acutetec, 551 TE . See Expiration, duration of Tear duct(s), occlusion of, 281 Tear gas, inhalation injury caused by, 1003–1004 Technegas, 549, 551

Technetium-99m diethylenetriaminepentaacetic acid (DTPA), 550 in assessment of alveolar-capillary membrane permeability, 558–559 Technetium-99m glucoheptonate, 550 Technetium-99m-labeled aerosols, 549, 550–551 in assessment of alveolar-capillary membrane permeability, 558–559 in evaluation of mucociliary clearance, 559 Technetium-99m-labeled human albumin microspheres, 548 Technetium-99m-labeled macroaggregated albumin, 548, 548f in evaluation of mucociliary clearance, 559 scan using, in pulmonary hypertension, 556 Technetium-99m methylenediphosphonate (MDP), 550 Technetium-99m pyrophosphate, 550 Technetium-99m sulfur colloid, 550 in evaluation of mucociliary clearance, 559 Technology, advances in, 17–18 TECK, 340t TEE. See Transesophageal echocardiography Televancin, 2058 Telithromycin adverse effects and side effects of, 2056 for community-acquired pneumonia, 2110 dosage and administration of, 2056 for nontuberculous mycobacteria, 2505 penetration into lung, 2053, 2053t resistance to, 2110 Temporomandibular joint (TMJ) disease, signs and symptoms of, 2647 Tenascin-C, in lung development, 94 Teprostinol, for pulmonary arterial hypertension, 1388, 1390 Teratocarcinoma, of anterior mediastinum, 1607 Teratoma(s) malignant, primary pulmonary, 1925 mediastinal benign, 1604–1606, 1606t malignant, 1606, 1606t radiographic features of, 495–498, 498f Terbinafine for invasive fungal infections, 2311, 2312 for Pneumocystis pneumonia, 2370 Terbutaline adverse effects and side effects of, 825t for asthma, 823t, 825t

for chronic obstructive pulmonary disease, 738t dosage and administration of, 825t dosage forms, 2632t for exercise-induced asthma, 812 pulmonary effects of, 1091t receptor activity, 2632t structure-activity relationships, 2632 structure of, 2633f Terpenes exposure to, 1027t sources of, 1027t Terry, Luther, 753 Tertiary contractions, 1304 Tetrachloroethylene exposure to, 1027t sources of, 1027t Tetrachlorophthalic acid, and occupational asthma, 989 Tetracycline(s) adverse effects and side effects of, 2055 characteristics of, 2055 for cystic fibrosis patient, 875 mechanism of action of, 2055 organisms susceptible to, 2055 for pasteurellosis, 2430 penetration into lung, 2053, 2053t pharmacokinetics and pharmacodynamics of, 2054 for plague, 2432 pneumonitis caused by, 2012t pulmonary effects of, 1090t resistance to, 2055, 2099 for sarcoidosis, 1140, 1140t for tularemia, 2434 Tetralogy of Fallot, dyspnea in, 400 Tetraplegia, respiratory muscle action in, 76 Tetraspanin CD63/LAMP-3, in Weibel-Palade bodies, 31 Thalassemia, and pulmonary hypertension, 1384 Thalidomide, for sarcoidosis, 1140t, 1141 Thatched roof disease, etiology of, 1163t Theophylline adverse effects and side effects of, 828t, 2637 anti-inflammatory effects of, 2636 for asthma, 822, 823t, 828t for chronic obstructive pulmonary disease, 740 clinical use of, 2636–2637 diaphragmatic effects of, 2636 dosage and administration of, 828t for exercise-induced asthma, 811t, 812 extrapulmonary effects of, 2636 mechanism of action of, 828t pharmacology of, 2636 for pulmonary hypertension, 1377 as respiratory stimulant, 2643 structure-activity relationships, 2636 therapeutic effects of, 2636

I-114 Index Thermal injury(ies), upper airway obstruction caused by, 858 Thermoactinomyces, 2012 Thermoactinomyces candidus, hypersensitivity pneumonitis caused by, 1164t Thermoactinomyces faeni, hypersensitivity pneumonitis caused by, 1163t Thermoactinomyces sacchari, hypersensitivity pneumonitis caused by, 1163t Thermoactinomyces vulgaris, hypersensitivity pneumonitis caused by, 1163t, 1164t Thermodilution technique for measurement of cardiac output, 2663 transpulmonary, in acute respiratory failure, 2668 θ , definition of, 1328, 2740 Thiabendazole, for strongyloidiasis, 2418t Thiacetazone, adverse effects and side effects of, in HIV-infected (AIDS) patients, 2490 Thick filament(s), 72 Thin filament(s), 72 Thoracentesis, in children, 2132 Thoracic collections, drainage of, 535–538 Thoracic duct, embolization of, 542, 544f Thoracic electrical bioimpedance, in acute respiratory failure, 2668 Thoracic surgery, pulmonary complications of, 666, 666t Thoracoabdominal movement, abnormal, in ventilatory pump dysfunction, 2609 Thoracoplasty pulmonary function testing after, 1620t, 1623 respiratory mechanics after, 1620t, 1623 ventilatory effects of, 1623, 1623f Thoracoscopy, 650–659 complications of, 659 current techniques, 650–651 historical perspective on, 649–650, 650f incisions for, 650, 650f instrumentation for, 651 mediastinal procedures, 657–658, 657f–658f in parenchymal disease, 652–655 pericardial drainage procedure, 658 in pleural disease, 651–652, 651f in staging of NSCLC, 1854–1855 for sympathectomy, 658–659, 659f video-assisted, 2032, 2033 in children, 2132 in HIV-infected (AIDS) patients, 2247t, 2250 Thoracostomy, for solitary pulmonary nodule, 1824–1826 Thoracostomy tube(s) in children, 2132

for parapneumonic effusion or empyema, 1489, 1490t Thoracotomy and anaerobic pleuropulmonary infections, 2145t emergency room, in trauma patient, 1759 with lung resection, pulmonary complications of, 666, 666t open in children, 2132 for pneumothorax, 1530 for solitary pulmonary nodule, 1824–1826 Thorax elastic properties of, 151–152 in pregnancy, 254 Thorium dioxide, and mesothelioma, 1537 Thorotrast, and mesothelioma, 1537 Threshold limit values, 941–942 Thrombectomy, pulmonary artery, 542–543 Thrombin, 446 α-Thrombin, and airway smooth muscle proliferation, in vitro, 118 Thrombin inhibitors, for pulmonary embolism, 1439 Thrombocytopenia, 2113 and diffuse alveolar hemorrhage, 1295 sarcoidosis and, 1136t Thrombocytosis associated with lung tumors, 1930t, 1935 essential, risk of venous thromboembolism in, 1426 Thromboembolic disease. See also Chronic thromboembolic pulmonary hypertension; Venous thromboembolism associated with lung tumors, 1930t, 1935–1936 in HIV-infected (AIDS) patients, 2260 postoperative, prevention of, 673t, 674 Thromboendarterectomy, pulmonary, and respiratory failure, 2585 Thrombolytic agents and diffuse alveolar hemorrhage, 1295 for pulmonary embolism, 1439–1440 Thrombophilia, inherited, risk of venous thromboembolism in, 1426–1427 Thrombophlebitis, migratory superficial, in cancer patient, 433 Thromboxane A2 , 1341 and airway smooth muscle proliferation, in vitro, 118 mast cells and, 310t, 312 in pulmonary hypertension, 1369f Thrush, 2087, 2207 Thymectomy, VATS technique, 657, 657f Thymic carcinoid, 1601

Thymic carcinoma, 1601 Thymic hyperplasia, 1601 Thymic malignancy, 1597, 1597t. See also Thymoma staging of, 1597, 1597t Thymolipomas, 1601 Thymoma, 1597–1601, 1598f–1600f and extrathymic cancer, 1601, 1601t paraneoplastic syndromes with, 1599–1601, 1601t radiographic features of, 495, 496f, 498 resection, VATS technique, 657, 657f surgery for, and postoperative pulmonary complications, 667 Thymus, lesions of, 1597–1601 Thymus and activation-regulated chemokine, 340t Thyroid disorders, radiographic features of, 495, 496f masses, radiographic features of, 495, 496f substernal, radiographic features of, 496f Thyroid cancer radiographic features of, 485 sarcoidosis and, 1136t TI . See Inspiration, duration of TICAM-1, 355–356 Ticarcillin, 2056 Ticarcillin/clavulanate, 2056 indications for, 2157 Tidal volume, 149t, 569f, 591, 2592–2593 definition of, 568t, 1326, 2738 measurement of, 571 monitoring, in cardiopulmonary exercise testing, 611 normal, 403, 1323, 2735 in pregnancy, 254, 255f ventilator setting for, 2680–2681 Tigecycline, 2058 for nontuberculous mycobacteria, 2505 Tight junctions of airway epithelial cells, 137–138 of type I alveolar epithelial cells, 34, 35f Time zero, in diagnostic spirometry, minimal recommendations for, 570t Tinidazole, indications for, 2400–2401 Tiotropium adverse effects and side effects of, 829t, 2636 for asthma, 822, 823t, 829t, 2635–2636 for chronic obstructive pulmonary disease, 738t, 739, 2635 dosage and administration of, 829t mechanism of action of, 829t pharmacology of, 2635 Tissue culture, sample preparation for, 2033 Tissue diagnosis, in HIV-infected (AIDS) patients, 2250

I-115 Index Tissue factor pathway inhibitor, for community-acquired pneumonia, 2110 Tissue gram stain, 2034 Tissue inhibitors of matrix metalloproteinase (TIMP), 338, 339 in ECM remodeling, 380–381 in lung parenchyma, 721–722, 721t TIMP3 and hypersensitivity pneumonitis, 1171 and pigeon breeder’s disease, 1162 Tissue oxygenation, 2614–2617 Tissue plasminogen activator recombinant, for pulmonary embolism, 1439–1440 in Weibel-Palade bodies, 31 Tissue sampling, 2031–2032 TLC. See Total lung capacity TLRs. See Toll-like receptors Tobacco control, 753, 760 Tobacco smoke, environmental, and risk of asthma, 795 Tobacco use. See also Smoking cultural aspects of, 749 economic aspects of, 749 historical perspective on, 747 and Master Settlement Agreement, 749 social aspects of, 749 Tobacco worker’s disease, etiology of, 1163t Tobramycin, 2058 for cystic fibrosis patient, 875, 2179 for hospital-acquired pneumonia, 2061 nebulized, 2058–2059 for nontuberculous mycobacteria, 2505 plus ceftazidime, for cystic fibrosis patient, 875 Tocainide, pneumonitis caused by, 2012t Tocolytic agents, pulmonary effects of, 1091t, 1093 Tocolytic pulmonary edema, 259t, 1091t, 1093 Tolerance to beta-adrenergic agonists, 2634 definition of, 2634 Toll-like receptors, 1970–1971, 1973, 1976 in aspergillosis, 2293–2294 and mast cell activation, 309 in viral infection, 355–356, 355f Tolmetin, and aspirin-induced asthma, 802t Toluene exposure to, 1027t sources of, 1027t Toluene diisocyanate hypersensitivity pneumonitis, etiology of, 1164t Toluene diisocyanate inhalational challenge test, 585t Tomography, standard, of solitary pulmonary nodule, 1818

Tongue, assessment of, 2647 Tonsillectomy, and anaerobic pleuropulmonary infections, 2145t Tonsillitis, and anaerobic pleuropulmonary infections, 2145t Toothpaste shadows, 1222 in allergic bronchopulmonary aspergillosis, 841 Topoisomerase inhibitors, for Pneumocystis pneumonia, 2370 Topoisomerase IV, 2056–2057 Torulopsis, infection (incl. pneumonia), immune defect associated with, 1983t, 2210t Total Exposure Assessment Methodology, 1026, 1027t Total lung capacity, 23, 148, 149t, 568–569, 569f, 582, 582f absolute, 577, 578f age-related changes in, 270–271, 271f definition of, 568t, 1326, 2738 in health and disease, 577, 578f normal, 1323, 2735 percent predicted, 577, 578f postoperative changes in, 664 in pregnancy, 254 Total lymphocyte count, in nutritional assessment, 2694 Total pulmonary resistance, definition of, 1327, 2739 Toxic epidermal necrolysis, 436, 436f Toxic gas(es), inhalation of, 2013 Toxic oil syndrome, and pulmonary hypertension, 1383–1384 Toxic pneumonitis, occupational, 934t Toxic shock syndrome, 2112, 2133 Toxin(s), inhaled. See also Inhalation injury(ies), toxic and diffuse alveolar damage, 2042 systemic illness from, 1004–1006 Toxocara, infection, 1092 Toxocara canis, 2013, 2414t, 2418t, 2419–2421, 2421f and eosinophilic pneumonia, 1215–1216 Toxocara catis, 2414t, 2418t, 2419 Toxocara spiralis, 2421 Toxocariasis, 2419–2421 Toxoplasma gondii, life cycle of, 2401 Toxoplasmosis, 1995, 2401–2402 in bone marrow and stem cell transplant recipients, 2223, 2229 in cancer patients, 2219 in cell-mediated immunodeficiency, 2236 clinical features of, 2401–2402 congenital, 2402 cytopathology of, 524 diagnosis of, 2002, 2402 epidemiology of, 2401

in HIV-infected (AIDS) patients, 2212, 2212t, 2215, 2248, 2258, 2402 radiographic findings in, 2214, 2214t, 2249t immune defect associated with, 1983t, 2210t in immunocompromised host, 2209, 2401–2402 prophylaxis for, and prevention of Pneumocystis pneumonia, 2367 pulmonary-thoracic involvement in, 2402, 2403f reactivation, 2401, 2402 treatment of, 2402 TPE. See Tropical pulmonary eosinophilia Trachea, 44 adenoid cystic carcinoma of, 854 development of, 94, 94f embryology of, 81, 82f extrinsic compression of, 856–857 focal compression of, 852f idiopathic giant, 856 malignancy of, 854 metastases to, 854 squamous cell carcinoma of, 854 upper-airway obstruction caused by, 849f stenosis of, 854–855 tumors, radiographic features of, 498–499 Tracheal gas insufflation, in ALI/ARDS, 2556 Tracheal pressure, 2670 Tracheitis bacterial, 2088, 2379 adult, upper airway obstruction in, 853 pain in, 418 viral, 2376t, 2380, 2381 Tracheobronchial compression, 1564, 1566f Tracheobronchial injury(ies), in trauma patient, 1759–1760, 1760f Tracheobronchial perforation, and mediastinitis, 1561–1562 Tracheobronchial tree duplication cyst, radiographic features of, 498 topographic anatomy of, 477, 479f–481f Tracheobronchiomalacia, therapeutic bronchoscopy in, 642 Tracheobronchiopathia osteoplastica, differential diagnosis of, 701t, 702 Tracheobronchitis acute, 742t in acute oxygen toxicity, 2627–2628 Aspergillus, 2304 pseudomembranous, 2292t, 2304 ulcerative, 2292t, 2304 clinical features of, 2379, 2380–2381 differential diagnosis of, 2381

I-116 Index Tracheobronchitis (Cont.) infectious, treatment of, 2058 pain in, 418 pathogenesis of, 2381 prevention of, 2381 treatment of, 2381 viral causes of, 2376t, 2380–2381 Tracheobronchomegaly, 2138 differential diagnosis of, 701t, 702 Tracheoesophageal fistula, 857, 1564 Tracheomalacia, 2138 diagnosis of, 856 management of, 856 upper airway obstruction in, 855–856 Tracheomegaly, 856 differential diagnosis of, 701t, 702 Tracheopathia osteoplastica, 851f upper airway obstruction in, 855 Tracheostomy, 861 and aspiration, 1311 laryngotracheal stenosis after, 854–855 percutaneous, kit for, 2654 Trachipleistophora, 2410 Tractor lung, etiology of, 1165t TRALI. See Transfusion-related acute lung injury Tramline shadows, 1222, 1224f in allergic bronchopulmonary aspergillosis, 841 Tranquilizers, pneumonitis caused by, 2010 Transbronchial aspiration, 513 Transbronchoscopic needle aspiration, 631, 634–635 image-guided, 634 ultrasound-guided, 634 Transbronchoscopic needle biopsy, 634–635 Transcutaneous oxygen monitoring, in acute respiratory failure, 2669 Transdiaphragmatic pressure measurement, 1644 Transepithelial electrical resistance, 138 Transepithelial voltage, 138, 138f Transesophageal echocardiography, in acute respiratory failure, 2667 Transferrin, 1970 serum, in nutritional assessment, 2694 Transforming growth factor (TGF) α, eosinophils and, 310t, 315 Transforming growth factor (TGF) β, 1971, 1976 effects/functions of, 338, 781t eosinophils and, 310t, 315 isoforms of, 338 and isotype switching, 324 in lung development, 92–94 in lung inflammation and injury, 338–339 mast cells and, 310t, 312 sources of, 338, 781t

and surfactant production, 132 targets of, 781t Transfusion reaction(s), 2207 Transfusion-related acute lung injury and respiratory failure, 2584–2585 treatment of, 2586 Transitional flow, 154, 154f Transpulmonary indicator dilution techniques, in acute respiratory failure, 2668 Transpulmonary lithium dilution, in acute respiratory failure, 2668 Transpulmonary pressure, 149–150, 149f, 150f, 157, 575, 575f, 576f at end-expiration, 148 at end-inspiration, 148 Transpulmonary thermodilution, in acute respiratory failure, 2668 Transthoracic esophageal echocardiography, in acute respiratory failure, 2667 Transthoracic needle aspiration and biopsy, 513, 629–630, 2105–2106 complications of, 647 contraindications to, 645–646 image guidance for, 646 indications for, 645 needle for insertion of, 646 selection of, 646 results, 646–647 technique for, 646 Transthoracic pressure, 575f, 576 Transthyretin, 1233–1234 Transtracheal aspiration, 1987, 2143 Transversus abdominis muscle, 72f, 77 actions of, 77 Trapezius muscle, 72f Traube, Moritz, 15 Trauma abdominal, pulmonary complications of, 1446 and abnormal breathing pattern, 403 chest, and anaerobic pleuropulmonary infections, 2145t head, pulmonary complications of, 1446 hemoptysis caused by, 413t, 414 oxygen therapy in, 2619 thoracic, 1757–1766 airway management in, 1757–1758 ARDS after, 1765–1766 blunt, 1757, 1759–1764 breathing management in, 1757–1758 emergency department interventions for, 1758–1759 initial management of, 1757–1759 penetrating, 1757, 1764–1765, 1764f upper airway obstruction caused by, 858

Trauma patient(s), pneumonia in, 2193–2200. See also Pneumonia, nosocomial Treacher-Collins syndrome, 2647 Treadmill exercise Bruce protocol for, 614 invasive, 615–616 modified Naughton protocol for, 614, 614t noninvasive, 614–615, 614t Treatment right to forgo, 2724–2725 withdrawal of, 2724–2725, 2731 withholding of, 2724–2725, 2731 Tree-in-bud opacity(ies), 2021, 2021f, 2022f, 2023f in allergic bronchopulmonary aspergillosis, 840f, 841 Trematodes, 2413, 2423–2425 Trench mouth, 2087 Triage, 2726–2727 Triamcinolone acetonide adverse effects and side effects of, 826t for asthma, 823t, 826t dosage and administration of, 826t Triangularis sterni muscle actions of, 76, 77 anatomy of, 76, 77f Trichinella spiralis and eosinophilic pneumonia, 1214t immune response to, 314 1,1,1-Trichloroethane exposure to, 1027t sources of, 1027t Trichloroethylene, bronchiolitis caused by, 893t Trichomonas, infestation, cytopathology of, 524 Trichomonas tenax, 2410 Trichosporon cutaneum contamination of bronchoscope, 2279 hypersensitivity pneumonitis caused by, 1165t Trichosporon terrestris, and eosinophilic pneumonia, 1214t Trimellitic anhydride and occupational asthma, 989 pulmonary effects of, 1294–1295 Trimellitic anhydride hypersensitivity pneumonitis, etiology of, 1164t Trimethoprim-sulfamethoxazole, penetration into lung, 2053, 2053t Trimethoprim-sulfamethoxazole (TMP-SMX) adverse effects and side effects of, 2056, 2207, 2367 for brucellosis, 2429t, 2439 for cryptosporidiosis, 2404 for cystic fibrosis patient, 875 dosage and administration of, 2056 mechanism of action of, 2056

I-117 Index for melioidosis, 2429t, 2440 for Moraxella catarrhalis infection, 2445 for nontuberculous mycobacteria, 2505 organisms susceptible to, 2056 for Pneumocystis jiroveci infection, 2254 for Pneumocystis pneumonia, 2367–2369, 2368t prophylactic in HIV-infected (AIDS) patients, 2245, 2246, 2252 for Pneumocystis pneumonia, 2366 resistance to, 2056, 2099 toxicity of, 2366 for yersiniosis, 2441 Trimethylbenzenes exposure to, 1027t sources of, 1027t Trimetrexate, for Pneumocystis pneumonia, 2368t, 2370 Tripe palms, 432, 432f Troleandomycin, 2639 Tropheryma whippelii, staining characteristics of, 2037 Tropical pulmonary eosinophilia, 818, 2013, 2418–2419 clinical course of, 1219–1220 clinical features of, 1218, 1230t diagnosis of, 1219 differential diagnosis of, 1230t etiology of, 1219 histopathology of, 1219 historical perspective on, 1218 laboratory findings in, 1218 prognosis for, 1219–1220 pulmonary function testing in, 1218–1219 treatment of, 1219 Trovafloxacin, 2057 for pasteurellosis, 2430 Trypanosoma brucei gambiense, 2409 Trypanosoma brucei rhodesiense, 2409 Trypanosoma cruzi, 2407, 2408f infestation in cancer patients, 2219 in immunocompromised host, 2209 Trypanosomiasis, 2407–2409 African, 2409 American, 2407–2409. See also Chagas’ disease Tryptase and airway smooth muscle proliferation, in vitro, 118 and aspirin-induced asthma, 804 in asthma, 782 mast cell, 308, 310t, 311, 316 L-Tryptophan, pulmonary effects of, 1090t, 1091t, 1093, 1110t T Spot-TB, 2462, 2471 TST. See Tuberculin skin test TTE. See Transthoracic esophageal echocardiography

TTF1, gene for, and lung development, 82 TTI. See Diaphragm tension–time index TTNA. See Transthoracic needle aspiration and biopsy TTNB. See Transthoracic needle aspiration and biopsy Tuberculids, 431 Tuberculin skin test, 2002, 2452–2454, 2453t, 2470, 2471t in HIV-infected (AIDS) patients, 2490 Tuberculoma, 2023f Tuberculosis, 2022, 2024, 2101, 2146 age and, 2449 anatomic sites involved in, 2450 bone/joint involvement in, 2473 and bronchiectasis, 2186 bronchoalveolar lavage cellular profile in, 1121t bronchogenic, 2025 imaging of, 2021, 2022f in cancer patients, 2216–2217 case classification of, 2448, 2448t cavitary, 1990, 1991f CDC case definition of, 2448, 2448t central nervous system involvement in, 2474 in children, 2134–2135, 2134f, 2450 age distribution of, 2475 clinical features of, 2475 drug dosages for, 2482t immune defects and, 2139 mortality rate for, 2475 in chronic granulomatous disease, 2237 clinical case definition of, 2448, 2448t computed tomography of, 1115t congenital, 2475 control of, 2452 cutaneous lesions in, 390, 431 in cystic fibrosis patient, 880 diagnosis of, 1999, 2452–2454, 2461–2462, 2470–2472 by direct microscopic examination, 2462 indirect methods, 2461–2462 rapid, 2462 differential diagnosis of, 2266 disseminated, 2468 drug-resistant, 2451 testing for, 2463 treatment of, 2484 theoretical basis for, 2476 drug treatment of, pulmonary effects of, 1090t in elderly clinical presentation of, 2475 radiographic findings in, 2475–2476 empyema in, 2469, 2473 endobronchial, 854 epidemiology of, 1999, 2447–2451 ethnic distribution of, 2449 extensively (extremely) resistant, 2484 extrapulmonary, 2468

anatomic sites involved in, 2450, 2472 frequency of, 2472 gastrointestinal/peritoneal involvement in, 2473–2474 genitourinary, 2474 hemoptysis in, 410, 412f, 413–414 high-risk groups for, 2448–2449 positive tuberculin skin test in, criteria for, 2453t historical perspective on, 14–15, 2467 history and physical findings in, 2100t–2101t in HIV-infected (AIDS) patients, 1999, 2212, 2212t, 2213, 2246, 2252–2253, 2253f, 2447, 2450–2451, 2487–2491 clinical features of, 2475, 2489–2490 diagnosis of, 2475, 2489–2490 epidemiology of, 2248, 2487–2488, 2488f extrapulmonary involvement in, 2489 incidence of, 2475 infection control considerations in, 2247 miliary, 2475 pathogenesis of, 2488–2489 and pneumothorax, 1524 prevention of, 2490–2491 pulmonary involvement in, 2468 radiographic findings in, 2213f, 2214t, 2215, 2249t, 2475, 2489, 2489f treatment of, 2455–2456, 2484, 2490–2491 adverse effects and side effects of, 2490 drug regimens for, 2481t in homeless persons, 2451 hospitalization rate for, 2105t host determinants of, 2460–2461 imaging findings in, 2019 immune response in, 2460–2461, 2468 in immunocompromised host, 1997, 2204 in incarcerated persons, 2451 incidence of, 2448–2449 trends in, 2448–2449, 2449f Koch’s work on, 16, 2470 laboratory diagnosis of, diagnostic criteria for, 2448, 2448t laryngeal involvement in, 854, 2087 latent, 2450, 2452 diagnosis of, 2462, 2470–2471 in HIV-infected (AIDS) patients, 2491 treatment of, 2455–2456, 2455t in HIV-infected (AIDS) patients, 2491 lung cancer and, 2215–2216 lymphadenitis in, 2472

I-118 Index Tuberculosis (Cont.) lymphadenopathy in, 2028 meningeal, 2474 epidemiology of, 2450 miliary, 1985, 1987f, 1991, 1997, 2025, 2048, 2474–2475, 2474f in children, 2134–2135, 2134f, 2475 complications of, 2474–2475 cutaneous manifestations of, 431 in elderly, 2475 epidemiology of, 2450 fever with, 420 high-risk groups, 2475 in HIV-infected (AIDS) patients, 2475 mortality rates for, 2475 radiographic features of, 483, 485 multidrug-resistant, 2447–2448, 2451, 2484 exposure to, management of, 2456 neonatal, 2475 in neutropenic host, 2217 nosocomial, 2280t occupational, 934t pathogenesis of, 2079, 2080, 2467–2468 pathology of, 1990, 1991f, 2048, 2050f pleural effusion in, 1493–1494 pleural involvement in, 2472–2473 post-primary, 2021–2022, 2023f, 2449 prevention of, 2452, 2463 in HIV-infected (AIDS) patients, 2490–2491 primary, radiographic findings in, 2468–2469, 2468f progressive primary, 2021, 2468 pulmonary clinical presentation of, 2468–2470 complications of, 2469–2470, 2470f computed tomography of, 2469 epidemiology of, 2468 in HIV-infected (AIDS) patients, 2468 laboratory findings in, 2468 radiographic findings in, 2468–2469, 2468f, 2469f signs and symptoms of, 2468 pulmonary alveolar proteinosis complicated by, 2014 racial distribution of, 2449 radiographic features of, 498 radiography of, historical perspective on, 18 reactivation, 2449, 2468 radiographic findings in, 2469, 2469f relapse, treatment of, 2484 scintigraphy in, 557 and silicosis, 976 solitary pulmonary nodule in, 1817 spinal, 2473 radiographic features of, 503f in substance abusers, 2451 surveillance, 2448

transmission of, 2451–2452 in indoor air, 1032 treatment of, 2464. See also specific drug adherence to, 2484 adjunctive corticosteroids in, 2484 advances in (future directions for), 2464 adverse effects and side effects of, 2483t in HIV-infected (AIDS) patients, 2490 monitoring for, 2480–2481 and antiretroviral therapy, 2482t, 2490 common errors in, 2480, 2480t directly observed therapy in, 2476, 2484 drug interactions with, 2456 drug regimens for, 2480, 2481t, 2482t duration of, 2481–2484 first-line drugs for, 2476–2478 dosage and administration of, 2482t historical perspective on, 2476 in HIV-infected (AIDS) patients, 2484, 2490–2491 adverse effects and side effects of, 2490 initiation of, 2480 in patients with negative sputum, 2483 in patients with positive pretreatment sputum, 2481–2483 in relapse, 2484 response to, evaluation of, 2481–2484 second-line drugs for, 2479–2480 dosage and administration of, 2482t in older adults, 2482t surgical, 2484 theoretical basis for, 2476 in United States age distribution of, 2449 ethnic distribution of, 2449 in foreign-born persons, 2449–2550, 2550f high-risk groups, 2448–2449 racial distribution of, 2449 trends in, 2448–2449, 2449f upper airway obstruction in, 854 Tuberous sclerosis, 1255 computed tomography of, 1115t epidemiology of, 1261, 1261t with pulmonary involvement, 1261–1262, 1261t skin lesions in, 438–439 without pulmonary involvement, 1261–1262, 1261t Tularemia, 1985, 2006, 2020, 2428t, 2432–2434. See also Francisella tularensis clinical features of, 2433

diagnosis of, 2002, 2429t, 2433–2434 differential diagnosis of, 2433–2434 epidemiology of, 2004, 2428t, 2432–2433 lymphadenopathy in, 2028 pathogenesis of, 2433 pathophysiology of, 2433 prevention of, 2434 radiologic features of, 2433, 2433f treatment of, 2429t, 2434 Tumor(s). See also Malignancy; Neoplasm(s); specific tumor acinic cell, 1925–1926 benign, 1917–1920, 1918t esophageal, and aspiration, 1310, 1312f Fechner, 1925–1926 immune defects caused by, 2215–2216 malignant non-bronchogenic, 1917, 1919t, 1920–1926 types of, 1831–1832, 1832t WHO classification of, 1831–1832, 1832t pharyngeal, and aspiration, 1310 pleural, thoracoscopic management of, 651, 651f salivary gland, 1845–1846, 1925–1926 Tumor embolism, 1445 Tumorlets, 444 Tumor necrosis factor (TNF) α, 1970, 1971, 1973, 1976, 1978 in acute lung injury, 2528–2529 in aspergillosis, 2293, 2501 in asthma, 118 in coccidioidomycosis, 2501 in disease, 336 effects/functions of, 336, 781t in fibrosis, 337 in histoplasmosis, 2334, 2501 and hypersensitivity pneumonitis, 1171 inhibitors, 2501 pulmonary toxicity of, 440 for sarcoidosis, 1140t, 1141 and leukocyte adherence and migration, 347–348 in listeriosis, 2501 mast cells and, 310t, 312, 316 in nontuberculosis mycobacterial infection, 2501 and pigeon breeder’s disease, 1161–1162 in septic shock syndrome, 449 and SIRS/MODS, 2566–2567 sources of, 781t and surfactant production, 132 targets of, 781t therapy with, pulmonary effects of, 1093 in tuberculosis, 2461, 2501 Tumor suppressor gene(s), 1802–1804 and cell cycle, 1809–1811, 1810f in lung cancer, 1805–1806

I-119 Index Tungsten carbide, and occupational asthma, 990 Turbulent flow, 154, 154f, 176 Turkey handler’s disease, etiology of, 1164t Turkey proteins, hypersensitivity pneumonitis caused by, 1164t TV. See Tidal volume TWAR agent. See Chlamydia pneumoniae Two-hit hypothesis, for SIRS/MODS, 2567 Type I alveolar epithelial cells, 33–35, 33t, 34f, 40, 40f, 47f, 87, 282 formation of, 99, 101 functions of, 35 molecular markers for, 33, 34t repair of, 35 tight junctions, 34, 35f Type II alveolar epithelial cells, 33, 33t, 34f, 35f, 36–39, 36f, 87, 282 formation of, 99, 101 functions of, 36 lamellar bodies, 36–38, 36f, 37f microvilli of, 36, 36f molecular markers for, 33, 34t organelles of, 36, 36f, 37f programmed cell death in, 104 and surfactant catabolism, 126, 126f, 132 surfactant synthesis and secretion by, 37–39, 37f, 38f Typhlitis, in neutropenic host and cancer patient, 2217 U UARS. See Upper airway resistance syndrome UIP. See Usual interstitial pneumonia Ulcerative colitis, and bronchiectasis, 2185t, 2188 Ulcerative colitis (UC) erythema nodosum in, 434 sarcoidosis and, 1135, 1136t Ultrasound, 2018 of diaphragm, in acute lung injury, 2673 endobronchial, 631–632, 632f of mediastinal masses, 1589 Undernutrition, in chronic obstructive pulmonary disease, 2605 Unexplained dyspnea and shrinking lungs syndrome, 1201 Univent tube, 2657 UPET. See Urokinase Pulmonary Embolism Trial Upper airway airflow in, 2647 anatomy of, 845, 2646–2648 in adult, 2646f in infant, 2646f bronchoscopic assessment of, 632 definition of, 845 disorders, signs and symptoms of, 2647 extrinsic compression of, 856–857

function, bronchoscopic assessment of, 632 malignancy of, 854 Mallampati Scale for, 2648, 2648t management of, 2648–2649 airways for, 2650, 2650f equipment for, 2649–2650 extraglottic devices for, 2651, 2652f historical perspective on, 2657–2658, 2657f masks for, 2650–2651, 2650f resuscitation bags for, 2650, 2651f techniques for, 2649–2650 muscles of coordinated activity of, 166 innervation of, 166 physical examination of, 2647 Upper airway cough syndrome, 410 Upper airway obstruction causes of, 845, 846, 852–860 clinical features of, 846–852 diagnosis of, delayed, 846 differential diagnosis of, 819t fixed, 605, 606f, 848, 848f historical perspective on, 846 and lower airway obstruction, 846 management of, 845, 846, 860–862 physiological assessment of, 846–850, 847f–850f pulmonary function testing in, 604t, 605–606, 606f, 606t radiographic assessment of, 850–852, 850f–852f signs and symptoms of, 846 in tuberculosis, 854 variable, 605, 848–849 extrathoracic, 605, 606f intrathoracic, 605–606, 606f Upper airway resistance syndrome, 1724–1725, 1724f definition of, 1698 Upper esophageal sphincter (UES), 1302, 1304 contraction, in dysphagia, 1306, 1307f incompetence, 1308–1309 Upper extremity(ies), exercise training, in pulmonary rehabilitation, 768 Upper motor neuron disease, ventilatory impairment in, 1648–1651 Upper respiratory tract infections of, 2085–2091. See also specific infection irritation, occupational exposure and, 934t Ureaplasma urealyticum, infection (incl. pneumonia), in early infancy, 2130 Uremic pleuritis, 1502 Urine, bacterial antigen detection in, 2001 Urine anion gap, 216–217 Urokinase, 535 for pulmonary embolism, 1439–1440

Urokinase Pulmonary Embolism Trial, 551 Urticaria, 435 Urticarial vasculitis, 435–436 U.S. Anti-Doping Agency, 812 Usual interstitial pneumonia, 491f, 1144, 1145, 2013 in collagen vascular disease, 1194t histopathology of, 1195–1196, 1196f computed tomography of, 1112, 1114f, 1115t and idiopathic pulmonary fibrosis, 1156 in mixed connective tissue disease, 1210 occupational exposures and, 935t pathology of, 1150–1151, 1150f, 1151f, 1154 in polymyositis-dermatomyositis, 1208 in rheumatoid arthritis, 1204–1206, 1205f in Sj¨ogren’s syndrome, 1211 Uterine cancer, pulmonary metastases, 1943 Utilitarianism, 2718, 2723 V Vaccine(s) advances in (future directions for), 2073–2074, 2080 adverse effects and side effects of, in severe combined immunodeficiency, 2236 for asthmatic patient, 821–822 against bacterial pathogens, 2066–2070, 2066t in chronic obstructive pulmonary disease, 734 cost-effectiveness of, 2065–2066 for HIV-infected (AIDS) patients, 2212 for immunocompromised host, 2209 mycoplasmal, and IgA antibody, 281 nicotine, 756 against pulmonary infection, 2065–2074, 2080. See also specific vaccine safety of, 2065 viral, 2375t and IgA antibody, 281 against viral pathogens, 2070–2073, 2070t. See also specific vaccine Vacuum-assisted closure, 2169 Valganciclovir, indications for, 2395 Valvular heart disease cardiopulmonary exercise testing in, 621–622, 621f, 622f pregnancy and, 258 Vanadium, and occupational asthma, 990 Vancomycin adverse effects and side effects of, 2169 for cystic fibrosis patient, 875 for hospital-acquired pneumonia, 2061, 2061t, 2062 penetration into lung, 2053

I-120 Index Vancomycin (Cont.) pharmacokinetics and pharmacodynamics of, 2054 for staphylococcal pneumonia, in children, 2132 Vanishing lung, 913, 915t VAP. See Pneumonia, ventilator-associated Vapor, definition of, 994t Varenicline, in smoking cessation, 756 Varicella-zoster virus (VZV) assays for, 1989t characteristics of, 2375t and diffuse alveolar damage, 2042 in herpes zoster oticus, 2092 infection (incl. pneumonia) in adults, 2389 in bone marrow and stem cell transplant recipients, 2223, 2229 in cancer patients, 2218 in children, 2135 in common variable immunodeficiency, 2235 in HIV-infected (AIDS) patients, 2212t immune defect associated with, 1983t, 2210t in immunocompromised host, 2204, 2209, 2392 in neutropenic host and cancer patient, 2217 seasonal variation in, 2374 in severe combined immunodeficiency, 2236 treatment of, 2394 pneumonia, 1994, 2025, 2026f in immunocompromised host, 1997 transmission of, 2374 vaccine against, 2070t, 2072–2073 Vasa vasorum, 32 Vascular cell adhesion molecule (VCAM), VCAM-1, 347 in inflammation, 783 in inflammatory/fibrotic lung disease, 374 and leukocyte adherence and migration, 347–348 Vascular disorders, hemoptysis in, 410 Vascular endothelial growth factor (VEGF), 717 and lung development, 87, 89, 89f in lung development, 92–94 VEGF-120, 87 VEGF-164, 87 VEGF-188, 87 VEGF-C, 87 VEGF-D, 87 Vascular endothelial growth factor (VEGF) receptor(s) and lung development, 87 VEGFR1, 87 VEGFR2, 87 VEGFR3, 87

Vascular ring(s), respiratory symptoms caused by, 857 Vascular tree, design of, 49–50 Vasculitis, 1449–1465 ANCA-associated, 1241, 1283, 1449–1450, 1450f, 1450t, 1451–1461, 1451f and diffuse alveolar hemorrhage, 1288–1290 organ systems affected by, 1452t pathophysiology of, 1458–1459 treatment of, 1459–1461 Churg-Strauss, 2013 classification of, 1449–1450, 1450t in collagen vascular disease, 1194t, 1196–1197 computed tomography of, 1115t cutaneous manifestations of, 435–436 drug-induced, 1091t, 1092–1093, 1241–1242, 1463–1464 epidemiology of, 1450–1451 interstitial lung disease associated with, 2013 large vessel, 1450t medium-sized vessel, 1450t in mixed connective tissue disease, 1209 nomenclature for, 1449–1450, 1450t primary systemic, 1449, 1450t in rheumatoid arthritis, 1202 sarcoidosis and, 1136t secondary, 1449 small vessel, 1450t systemic, and diffuse alveolar hemorrhage, 1288 in systemic lupus erythematosus, 1201 urticarial, 435–436 Vasoactive intestinal peptide (VIP), in pulmonary hypertension, 1369 Vasoactive substances processing of, by lungs, 445–446, 446t production of, by lungs, 445–446, 446t Vasoconstriction, hypoxic, 179–180 Vasoconstrictor(s), and pulmonary circulation, 1347 Vasodilator(s) and pulmonary circulation, 1347 pulmonary effects of, 1093 for pulmonary hypertension, 1377–1378 Vasopressin, hypersensitivity pneumonitis caused by, 1164t Vasovagal events, in pulmonary hypertension, 1392, 1392f VC. See Vital capacity Vc. See Pulmonary capillary blood volume V D /VT . See Physiological dead space, ratio of, to tidal volume Veillonella, 2086 in acute mediastinitis, 2166t

Vein(s) percutaneous transluminal angioplasty and stenting of, 540 pulmonary, development of, 97, 100, 108–110 Vena cava filter, for pulmonary embolism, 1441 Vena cava interruption, for pulmonary embolism, 1441 Venography, 467–469 Venous oxygen content, calculation of, 612t Venous thromboembolism, 1423 associated with lung tumors, 1930t, 1935–1936 chronic, management of, 1441–1442 and gas-exchange abnormalities, 1428, 1429f hemodynamic effects of, 1427–1428, 1427f pathophysiology of, 1427–1428 in pregnancy, 259–260, 259t prophylaxis, 1442–1443, 1442t risk factors for acquired, 1425–1426 genetic, 1426–1427 Ventilation assessment of, in acute respiratory failure, 2669 central neural mechanisms involved in, 165 changes in, in respiratory failure, 2515, 2516t control of, 161–171 disorders of, pathophysiology of, 168–171 distribution of, in lungs, radiographic evaluation of, 473–476 of each lung separately, for acute respiratory distress syndrome, in trauma patient, 1766 in exercise, 235, 235f determinants of, 236, 236t expired volume of, 591 inspired volume of, 591 maldistribution of, in chronic obstructive pulmonary disease, 711, 712–713 measurements related to, terminology for, 1327, 2739 nocturnal, in chronic obstructive pulmonary disease, 743 regional, mechanical determinants of, 157–159 regulation of, 2592–2593 and swallowing, integration of, 1304 total, changes, in response to ventilation-perfusion inequality, 181f, 185–186, 185f Ventilation-perfusion inequality, 178–187 age and, 273 anatomically based, 179

I-121 Index and arterial hypoxemia, 2616–2617, 2616t oxygen therapy for, 2618–2619 assessment of, 187–188 alveolar-arterial oxygen difference in, 187 arterial PO2 :FIO2 ratio in, 187 multiple inert gas elimination technique, 187 venous admixture in, 187 collateral blood flow and, 179 collateral ventilation and, 179 compensatory mechanisms for, 184–187 fractally based, 178–179 and gas exchange, 180–187 principal effects of, 184 gravity-based, 178, 178f, 473 longitudinally based, 179 reactive vasoconstriction and, 179–180 Ventilation-perfusion lung scanning in bullous disease, 921, 923f, 924f in diagnosis of acute pulmonary embolism, 551–554, 555–556, 556f matched defects on, 549 mismatched defects on, 549, 549f preoperative, for lung resection, 671 of pulmonary embolism, 549, 549f, 1432–1433, 1434f, 1435f in pulmonary hypertension, 556 quantitative, 556–557, 557f radiopharmaceuticals in, 548–551 reverse mismatch on, 549, 549f techniques, 548–551 views used in, 548, 548f Ventilation-perfusion ratio and gas exchange, 180–187 in small homogeneous unit of lung, and gas exchange, 180–184, 180f–182f Ventilation-perfusion relationships, 61, 61f knowledge of, historical perspective on, 13 mismatch, 549, 549f in chronic obstructive pulmonary disease, 711, 712–713, 713f, 731 parallel ventilation/parallel perfusion and, 61f, 65 reverse mismatch, 549, 549f serial ventilation/parallel perfusion and, 61f, 65 two-compartment models of, 182–184, 182f, 183t Ventilator(s). See also Mechanical ventilation fractional inspired oxygen concentration with, 2682–2683 inspiratory flow rate with, 2681–2682, 2682f

positive end-expiratory pressure with, 2683–2684, 2683t respiratory rate with, 2681, 2681f settings, 2679–2684 tidal volume setting, 2680–2681 triggering, 2679–2680, 2679f, 2680f Ventilator-associated lung injury, 2529–2530 Ventilator-induced lung injury, 2529–2530 Ventilator lung, etiology of, 1164t Ventilator waveforms, in acute respiratory failure, 2672–2673 Ventilatory control age-related changes in, 264t, 268–270 in exercise, 241–247 arterial chemoreflex control and, 245–246, 247f cardiocirculatory reflex control and, 246–247 central chemoreflex control and, 244–245 central neural control, 241–242 long-term potentiation and, 242–243 muscle reflex control and, 243–244, 244f, 245f short-term potentiation and, 239f, 242 Ventilatory demand factors increasing, 2512–2513, 2514t vs. supply, 2512–2513, 2512f Ventilatory drive, nonventilatory measures of, 599 Ventilatory pump, 2511, 2511f abnormalities assessment of, 2609 physical findings with, 2609 signs and symptoms of, 2609 treatment of, 2609–2611 failure, 2591–2611 compensatory/adaptive mechanisms and, 2592–2598 decompensating/maladaptive responses and, 2598–2605 rapid, shallow breathing in, 2602–2605, 2605f treatment of, 2609–2611 Ventilatory supply factors reducing, 2512–2513, 2513t vs. demand, 2512–2513, 2512f Ventilatory support, noninvasive, in neuromuscular disorders, 1670, 1670f, 1671–1672, 1671f criteria for successful use of, 1674, 1674t Venturi mask, 2622–2623, 2622t, 2623f Verrucosa cutis, tuberculosis, 431 Very late antigen, VLA-4, in inflammatory/fibrotic lung disease, 374 Vesalius, Andreas, 4, 5t, 11, 2645, 2675 Video-assisted thoracoscopy, 650–659 in plication of bullae, 928 for pneumothorax, 1530

for solitary pulmonary nodule, 1824–1826 Videobronchoscopy, 630 Vilanova’s disease, 434 Villemin, 15 Vinblastine and interstitial lung disease, 1111t pulmonary effects of, 1083t, 1084 Vinca alkaloids, pulmonary effects of, 1083t, 1084 Vincent’s angina, 2087 Vincristine, pulmonary effects of, radiation therapy and, 1181 Vindesine, pulmonary effects of, 1083t, 1084 Vinorelbine, pulmonary effects of, 1083t, 1084 Viomycin, adverse effects and side effects of, 2483t Viral infection(s), 1996, 2005, 2005t, 2020, 2025, 2027f, 2373–2395. See also specific virus and acute bronchitis, 2097 and acute exacerbations of chronic obstructive pulmonary disease, 742t, 2116, 2116t, 2121t and acute otitis media, 2092 antecedent to surgery, and postoperative pulmonary complications, 669 and asthma, 774–775, 816 and bacterial colonization, 2375 in bone marrow and stem cell transplant recipients, 2222–2223, 2224, 2228 and bronchiolitis, 896, 897 bronchoalveolar lavage cellular profile in, 1121t in cancer patients, 2215, 2216, 2218, 2221, 2221t in cell-mediated immunodeficiency, 2236 chemokines in, 355–356, 355f in children, 2374 and common cold, 2085–2086 in common variable immunodeficiency, 332 croup caused by, 2087–2088, 2379 cytopathic, 2043t cytopathology of, 522–523, 522f–523f diagnosis of, 2000–2001, 2002, 2393–2394 assays for, 1986–1987, 1989t and diffuse alveolar damage, 2042 in DiGeorge’s syndrome, 2236 epidemiology of, 2004, 2373–2374 histopathology of, 2034 in HIV-infected (AIDS) patients, 2212t, 2213, 2242t, 2257–2258 radiographic findings in, 2215 and idiopathic pulmonary fibrosis, 1156 imaging findings in, 2019, 2022

I-122 Index Viral infection(s) (Cont.) immune response to, 314, 1971, 1973, 1976–1977 in immunocompromised host, 2204, 2207, 2207t immunomodulating in immunocompromised host, 2207, 2207t and net state of immunosuppression, 2205 laryngitis caused by, 2087 lower respiratory tract and asthma, 796 and exacerbations of asthma, 796 wheezing syndromes associated with, 796 of lower respiratory tract, 1993–1994 in lung transplant recipient, 1790 lymphadenopathy in, 2028 mortality rate for, 2374 nosocomial, 2008, 2280, 2280t, 2281t occupational, 934t in organ transplant recipient, 2230 pathogenesis of, 1991–1994, 2080, 2374–2376, 2393 pathology of, 1991–1994, 2043, 2043t and pharyngitis, 2086 pleural effusion in, 1494 pneumonia caused by. See also Pneumonia; specific virus in children, 2130–2134, 2135 in early infancy, 2128–2130 neonatal, 2127 in purine nucleoside phosphatase deficiency, 2236–2237 rapid diagnosis of, by antigen detection, 2001 and sarcoidosis, 1127 seasonal variation in, 2374 serum procalcitonin in, 2107–2108 in severe combined immunodeficiency, 2236 staining characteristics of, 2035t supraglottitis caused by, 853 systemic effects of, 451–453, 451t transmission of, 2374 vaccines against, 2070–2073, 2070t.

See also specific vaccine virology of, 2374–2376 in X-linked agammaglobulinemia, 2234 Virchow, Rudolph, 1425 Virchow’s triad, 1425, 1425t Virulence, microbial definition of, 2207 host-pathogen interactions and, 2207 and infection, 2207 Virulence determinant(s), 2077 Virulence factor(s), 2080–2081 Virus(es) DNA, assays for, 1989t emerging, 2389–2391

in indoor air, sources of, 1022t respiratory antigenic types of, 2374 characteristics of, 2374, 2375t classification of, 2374 transmission of, 2374 RNA assays for, 1989t infection (incl. pneumonia) in immunocompromised host, 2392–2393 treatment of, 2394 Visceral larva migrans, 2414t Vital capacity, 149t, 569f, 571, 602–603 definition of, 568t, 1326, 2738 in diagnostic spirometry, minimal recommendations for, 570t measurement of, 571 closed-circuit method, 571 open-circuit method, 571 normal, 1323, 2735 postoperative changes in, 664 in pregnancy, 254 relaxed (slow), 580–581 subdivisions of, 569f, 571 Vitamin A, as antioxidant, 2626 Vitamin C as antioxidant, 2626 deficiency of, hemoptysis associated with, 414 Vitamin E, as antioxidant, 2626 Vitiligo, sarcoidosis and, 1136t Vitreous fibers, man-made, health risks with, 1030 Vocal cord(s) anatomy of in adult, 2647 in infant, 2647 dysfunction of, 859–860, 859f after toxic inhalation injury, 996 paralysis of, 391f, 848, 858, 859 Voice, changes in, in upper airway obstruction, 846 Volatile chemicals exposure to, 1027t sources of, 1027t Volatile flavoring agents, and bronchiolitis, 896 Volatile organic compounds, in indoor air, sources of, 1023t Volume of isoflow, 591 Volume-pressure relationships, terminology for, 1328, 2740 Volutrauma, 2530, 2546 Vomiting, 1304–1305, 1304t von Euler, U. S., 16 von Helmholtz, Herman, 8 von Mayer, Julius Robert, 5t, 8 von Pettenkofer, Max, 8 von Voit, Carl, 5t, 8

von Willebrand factor in acute lung injury, 2528 in Weibel-Palade bodies, 31 Voriconazole, 2299 for allergic bronchopulmonary aspergillosis, 842 for blastomycosis, 2348 for candidiasis, 2316 for coccidioidomycosis, 2345 for cryptococcosis, 2334 for histoplasmosis, 2340 for invasive fungal infections, 2310t, 2311t, 2312 prophylaxis, 2313 Vt. See Transepithelial voltage VT . See Tidal volume VTE. See Venous thromboembolism VX, bronchiolitis caused by, 894t VZV. See Varicella-zoster virus W Wakefulness drive, 161, 162f Walk test 6-minute, 225, 599–600 timed, 600 Wangiella, infection (incl. pneumonia), in cancer patients, 2217 Warfarin drug interactions with, 1392 for pulmonary arterial hypertension, 1391 for pulmonary embolism, 1440–1441 Warthin-Starry stain, 2037 Wasting in chronic obstructive pulmonary disease, 2605 in pulmonary disease, 452–453 Water lily sign, 2422, 2423f Wave speed limitation theory, 157 Wegener’s granulomatosis, 1281–1282, 1288–1289, 1289f, 1997 alveolar hemorrhage in, 1241 cavitary disease in, 1991, 1992f clinical features of, 1118t, 1451–1456, 1453f computed tomography of, 1115t, 1118t cutaneous manifestations of, 435 diagnosis of, 1451–1456, 1453f–1457f differential diagnosis of, 1464 hemoptysis in, 410 histology of, 1118t immunologic tests for, 1112t organ systems affected by, 1451, 1452t pathology of, 1283f, 1285t, 2048 pulmonary involvement in, 2013 serology of, 1285t solitary pulmonary nodule in, 1817 treatment of, 1118t, 1459–1461 upper airway obstruction in, 855 Weibel-Palade bodies, 31 Weigert, Carl, 15

I-123 Index Weight gain, smoking cessation and, 757–758 Weight loss for obesity, 1629 for obstructive sleep apnea, 1714 in pulmonary disease, 452–453 West African trypanosomiasis, 2409 Westermark’s sign, 468f, 472, 475f, 1431 Western red cedar wood dust, and occupational asthma, 990 Wheezes, 392–393, 393t Wheezing in bronchiolitis, 2381–2383 evaluation of, in evaluation of impairment/disability, 679 laryngeal, 859 Whipple’s disease. See also Tropheryma whippelii pathology of, 2043t Whispered pectoriloquy, 392 Wine grower’s lung, etiology of, 1163t Winterstein, Hans, 5t, 12–13 Wirz, K., 11, 12 Wiskott-Aldrich syndrome (WAS), pulmonary infection in, 2237 Withdrawal of treatment, 2724–2725, 2731 Withholding treatment, 2724–2725, 2731 Wnt growth factor(s), and lung development, 86–88, 89f Wood dust and occupational asthma, 985t, 986, 990 occupational lung disease caused by, 934t Wood dust hypersensitivity pneumonitis, etiology of, 1163t Woodman’s disease, etiology of, 1164t Wood pulp worker’s disease, etiology of, 1163t Wood smoke, health effects of, 1026 Wood trimmer’s disease, 2319 etiology of, 1163t Wood worker’s lung, 935t Wool-sorter’s disease, 2428t Workers’ compensation programs federal, 688–690 for occupational lung disease, 941 state, 687–688 World Anti-Doping Agency, 812 World Health Organization (WHO) classification of lung tumors, 1831–1832, 1832t classification of non-small cell lung cancer, 1831–1832, 1832t functional classification of pulmonary hypertension, 1379, 1379t

World Trade Center collapse, emergency responders at asthma in, 984–986, 990 reactive upper airway dysfunction syndrome in, 996 Worms, parenchymal and vascular diseases caused by, 2413, 2414t Wuchereria bancrofti, 2414t, 2418–2419, 2418t and eosinophilic pneumonia, 1214t, 1219 X Xanthine dehydrogenase, 360 Xanthine oxidase, 360, 360f Xanthomonas, drug-resistant, 2282 Xanthomonas maltophilia. See Stenotrophomonas maltophilia Xenon-127, ventilation scan using, 549, 550 Xenon-133, ventilation scan using, 549–550, 550f X-linked agammaglobulinemia, 331, 2139 and bronchiectasis, 331, 2188 pulmonary infection in, 331, 2233–2234 X-rays discovery of, 1173 physics of, 1174–1175 X-ray therapy, definition of, 1895 Xylenes exposure to, 1027t sources of, 1027t Y Yellow nail syndrome, 436, 436f, 1502 Yersinia, infection (incl. pneumonia). See also Plague in immunocompromised host, 2207 Yersinia enterocolitica, 2428t, 2440–2441 bacteriology of, 2428t culture of, 2429t pharyngitis caused by, 2086 staining characteristics of, 2429t Yersinia pestis, 2005t, 2006, 2428t, 2430–2432. See also Plague bacteriology of, 2428t, 2431 as bioweapon, 2430–2431 culture of, 2429t ecology of, 2431 epidemiology of, 1984t infection (incl. pneumonia), 2289 staining characteristics of, 2429t Yersiniosis, 2428t, 2440–2441 diagnosis of, 2429t epidemiology of, 2428t treatment of, 2429t

Young syndrome, and bronchiectasis, 2185t, 2187 Z Zafirlukast adverse effects and side effects of, 828t for asthma, 823t, 828t clinical use of, 2640 dosage and administration of, 828t safety of, 2640 Zanamivir indications for, 2375t for influenza, 2387–2388, 2387t Zenker’s diverticulum, 1309, 1310, 1311f Ziehl-Neelsen stain, 2035t, 2038–2039, 2041f Zileuton, 312 for asthma, 823t, 828t contraindications to, 2640–2641 dosage and administration of, 828t Zinc chloride, inhalation injury caused by, 1000t, 1003, 1004f Zinc oxide, inhalation injury caused by, 1000t, 1003, 1004f Zinc powder, stearate, bronchiolitis caused by, 893t Zomepirac, and aspirin-induced asthma, 802t Zoonotic bacteria, as bioweapons, 2428 Zoonotic infection(s), 2427–2435, 2428t Zorpin, and aspirin-induced asthma, 802t Zuntz, Nathan, 5t, 8 Zygomycetes. See also Zygomycosis classification of, 2316t fungus ball, 2049 in hospital environment, 2274–2275 identification of, in tissue, 2035, 2038t staining characteristics of, 2034, 2035t, 2036f Zygomycosis. See also Zygomycetes angioinvasion in, 2318, 2318f clinical features of, 2318–2319 diagnosis of, 2319–2320 differential diagnosis of, 2319, 2323t epidemiology of, 2317 histopathology of, 2319, 2319f mycology of, 2316t, 2317 pathogenesis of, 2317–2318 pathophysiology of, 2317 pulmonary, 2316–2321 radiographic findings in, 2318–2319 risk factors for, 2317 surgery for, 2320–2321 treatment of, 2320–2321 Zymosan, 1970