Fishman's Pulmonary Diseases and Disorders - PART 03 by HD Derma

PART

III Symptoms and Signs of Respiratory Disease

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SECTION SIX

Clinical Approach to the Patient

27 CHAPTER

Approach to the Patient with Respiratory Symptoms Darren B. Taichman

Alfred P. Fishman

I. HISTORY II. PHYSICAL EXAMINATION III. DYSPNEA Clinical Presentations Physiological Correlates of Dyspnea Dyspnea: Overview Dyspnea in Chronic Pulmonary Disease Dyspnea in Chronic Cardiac Disease Dyspnea in Anemia Metabolic Abnormalities and Drugs Miscellaneous Disorders IV. ABNORMAL BREATHING PATTERNS Cheyne-Stokes Respiration Kussmaul Breathing Other Abnormal Patterns V. DIAGNOSTIC TESTING IN THE EVALUATION OF DYSPNEA VI. COUGH Mechanism Circulatory Consequences Posttussive Syncope Etiology VII. HEMOPTYSIS Neoplasms Infections

Cardiovascular Disorders Trauma Miscellaneous VIII. CYANOSIS Capillary O2 Content Causes of Cyanosis IX. CLUBBING Pathogenesis X. HYPERTROPHIC OSTEOARTHROPATHY XI. THORACIC PAIN Pleuritic Pain Pulmonary Pain Chest Wall Pain Cardiac Pain Miscellaneous Pain XII. FEVER XIII. RADIOLOGIC EVALUATION XIV. COMMON CHRONIC PULMONARY DISEASES Chronic Obstructive Airway Disease Restrictive Lung Disease Syndromes of Alveolar Hypoventilation Obliterative Vascular Disease XV. CHOOSING PULMONARY FUNCTION TESTS

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The most common respiratory complaint for which a person seeks medical help is either shortness of breath or cough. Less frequent are hemoptysis, thoracic pain, cyanosis, and an abnormal breathing pattern. As in the case of any medical evaluation, the paramount diagnostic mainstays are the history and physical examination. The use of plain chest radiography for routine screening, once popular in the hope of uncovering silent disease amenable to therapy, has fallen into disuse and remains controversial because it has not been proven to decrease mortality, to be cost-effective, or to be worth either the inconvenience to the patient or the exposure to radiation. The use of computed tomography of the chest as a screening tool is also being debated and of unproven benefit. Chest radiography is now usually reserved for patients who have clinical manifestations of chest disease or are from families or populations known to be particularly vulnerable to chest disease. Serial chest radiographs often provide invaluable clues into the nature of chest lesions. More sophisticated diagnostic measures and interventions help to complete and supplement the clinical picture. Regardless of whether the analysis and diagnostic synthesis are accomplished in the clinicianâ&#x20AC;&#x2122;s mind or by computer-assisted mathematical modeling, the history, physical examination, and chest radiograph still remain the three-legged underpinning for diagnosis in chest medicine.

HISTORY Even though seasoned clinicians may be adept at spotting telltale diagnostic clues, there still is no substitute for a comprehensive, penetrating medical history. This should include a detailed inventory of substances in the air that can harm the lungs. One of the most common offenders is cigarette smoking. An attempt should be made to quantify the exposure. When did it begin? When did it stop? How many cigarettes per day (expressed in number of pack-years)? Often, the workplace is the site where toxic air is inhaled. An almost forgotten exposure to a toxic inhalant 20 years ago can explain certain types of pulmonary or pleural diseases. Symptoms that appear to improve during weekends or other periods away from work may be a clue to an occupational exposure that causes a respiratory ailment. A newly installed home humidifier or an air-conditioning system that incorporates stagnant pools of water can point the way to resolving a mysterious illness. A brief residence in an area where either cryptococcosis (southwestern United States) or histoplasmosis (southern and midwestern United States) is endemic may help to clarify the nature of an illness that mimics tuberculosis. A recent visit to a South or Central American country may bring into focus a more remote possibility (e.g., South American blastomycosis) (Fig. 27-1). The history should include a thorough evaluation of prior and current medical problems. Rheumatologic disorders such as systemic sclerosis (scleroderma) may be associated with interstitial lung disease, aspiration pneu-

Figure 27-1 Exposure in an endemic area. A. Clear lung fields. B. South American blastomycosis. (Courtesy of Dr. Nelson Porto.)

monia due to the involvement of the esophagus, or pulmonary vascular disease. Certain malignancies often metastasize to the lung (e.g., breast or colon carcinoma), or predispose to the development of venous thromboembolism (e.g., pancreatic carcinoma). Infection with the human immunodeficiency virus (HIV) should not be overlooked since pulmonary complications are often the initial presentation of acquired immunodeficiency syndrome (AIDS). Other causes of immunodeficiency, such as a hematologic malignancy or chemotherapeutic treatment of cancer, should

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Figure 27-2 Nitrofurantoin hypersensitivity pneumonitis. The ingestion of nitrofurantoin, 50 mg qid, was accompanied by the appearance of patchy interstitial and alveolar changes throughout both lungs.

heighten suspicion of infection as the cause of respiratory symptoms. Personal habits of the patient, such as intravenous drug abuse or sexual practices, may also help to uncover the cause of an unusual pulmonary disorder. Recent treatment of a disorder with immunosuppressive agents can arouse suspicion of toxicity caused by the therapeutic agent or of pulmonary infection by organisms that are usually noninvasive. Certain pharmacologic agents have a propensity for inflicting lung damage. Among these are bleomycin, nitrofurantoin, and methotrexate (Fig. 27-2). Beta blockers, administered as part of a cardiac regimen, can evoke bronchoconstriction. Even a common medication, such as aspirin may, on rare occasion, cause a severe pulmonary disorder (e.g., pulmonary edema). The family history is an essential ingredient of the medical inventory. This history can be particularly helpful in uncovering heritable diseases of the lungs (e.g., cystic fibrosis, Îą1 -antitrypsin deficiency, alveolar microlithiasis, and hereditary telangiectasia). The unraveling of a familial history of asthma, a common disease, or of familial pulmonary arterial hypertension, a rare disease, can be much more difficult.

PHYSICAL EXAMINATION Before the widespread use of chest radiography, the physical examination, along with the history, played the pivotal role in the diagnosis of pulmonary disease. The advent of chest radiography and of more sophisticated methods of imaging has tended to de-emphasize the value of the physical exami-

Figure 27-3 Chronic aspiration pneumonia. A. Chronic aspiration pneumonia in a 72-year-old man hospitalized for repair of hernia. Patchy infiltrates bilaterally. No pulmonary symptoms. Initiating cause was achalasia of esophagus. B. Eighteen months later. Persistent cough and breathlessness.

nation. Nonetheless, the physical examination remains a key diagnostic measure in the proper appraisal of chest disease. General Aspects Important clues are often available before examination of the chest. Neglected pyorrheal teeth raise the prospect of a necrotizing aspiration pneumonia. A lacerated tongue suggests that a convulsive episode may have led to aspiration (Fig. 27-3).

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Pursing of the lips during expiration (“pursed lip breathing”) is frequent in patients with chronic obstructive pulmonary disease (COPD). Subtle changes in consciousness or coordination may signal that metastasis has occurred to the brain from a primary carcinoma of the lung. In the patient with COPD, a clouded sensorium or a disturbed personality can signify acute CO2 retention. Inspection of the skin can often provide clues to diseases of the chest. Evidence to support the diagnosis of pulmonary sarcoidosis may be found in the eyes and skin. Petechiae in the skin may reflect a systemic vasculitis that also affects the vessels of the lungs. The skin lesions of neurofibromatosis type 1 (von Recklinghausen’s disease) may signify that a solitary pulmonary nodule in the paraspinal region may be a neurofibroma. A minute skin abscess can turn out to be the source of multiple lung abscesses. Distinctive scars over the antecubital veins of a drug addict can help to clarify the etiology of old lesions in the lungs as well as of fresh abscesses. Erythema nodosum and erythema multiforme occasionally complicate sarcoidosis, tuberculosis, histoplasmosis, and coccidioidomycosis; on occasion, these skin lesions may be part of a drug reaction. A variety of endocrine syndromes can accompany a carcinoma of the lung. An altered mental status may be due to hyponatremia caused by the syndrome of inappropriate antidiuretic hormone (SIADH) in a patient with a lung cancer. Clubbing of the digits may accompany various clinical disorders, including idiopathic pulmonary fibrosis, bronchiectasis, and certain carcinomas of the lung (Table 27-1). A puffy face, neck, and eyelids, coupled with dilated veins of the neck, shoulder, thorax, and upper arm (i.e., superior vena cava syndrome) may constitute the first clinical evidence of obstruction of the superior vena cava by a neoplasm of the lung. Although the causes of superior vena cava syndrome are many and diverse, at least 80 percent are attributable to a primary carcinoma of the lung (Fig. 27-4). In the patient in whom a neoplasm has evoked acute signs and symptoms of increased systemic venous pressure that progresses rapidly (e.g., to laryngeal edema), early diagnosis and prompt treatment of the neoplasm can be lifesaving. The presence of Horner’s syndrome—unilateral ptosis, miosis, and anhidrosis—in a patient with a carcinoma of the lung suggests a pulmonary sulcus tumor with involvement of the ipsilateral sympathetic pathway within the thorax (Fig. 27-5). Inspection of the Chest Observation of the chest from the foot of the bed can be informative: a visible lag of one side of the thorax localizes a pleural effusion, pulmonary infection, or a paralyzed diaphragm. The position of the trachea with respect to the midline can be a useful clue to atelectasis of one lobe or to obstruction of a major bronchus. The respiratory pattern may be informative: patients with severe airflow obstruction often take slow, deep breaths; whereas rapid and shallow breaths are often seen with restrictive processes such as interstitial lung disease or kyphoscoliosis. Inspection of the chest and abdomen in

Table 27-1 Clinical Disorders Commonly Associated with Clubbing of Digits Pulmonary and thoracic Primary lung cancer Metastatic lung cancer Bronchiectasis Cystic fibrosis Lung abscess Pulmonary fibrosis Pulmonary arteriovenous malformations Empyema Mesothelioma Neurogenic diaphragmatic tumors Cardiac Congenital Subacute bacterial endocarditis Gastrointestinal and hepatic Hepatic cirrhosis Chronic ulcerative colitis Regional enteritis (Crohn’s disease) Miscellaneous Hemiplegia

the supine position may reveal the paradoxical inward movement of the abdomen indicative of respiratory muscle weakness (e.g., as in bilateral diaphragmatic paresis or paralysis). Thoracoabdominal discoordination during sleep raises the possibility of obstructive sleep apnea. Palpation of the Chest Over the years, the role of palpation in the examination of the chest has been considerably devalued. Nonetheless, palpation can provide helpful diagnostic clues as well as confirmatory evidence for other physical signs. For example, the position of

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Figure 27-4 Local invasiveness of carcinoma of the lung. A. Sagittal section of the lung illustrating a carcinoma (blue) of the lung in the vicinity of the hilus. B. Chest radiograph showing right hilar mass. C. Angiogram showing obstruction and extensive collateral circulation. A

Figure 27-5 Courses of the recurrent laryngeal nerves. Invasion or compression of a nerve by a carcinoma of the lung causes paralysis of the vocal cord.

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the trachea determined by palpation in the suprasternal notch can be helpful in detecting a lateral displacement of the upper mediastinum. Dislocation of the apical impulse and of cardiac dullness can be useful indices in detecting shift of the lower mediastinum. Tenderness over a rib may reflect a fracture, a metastasis, or an underlying pleuritis. Enlargement of the right ventricle can be more readily detected by palpation in the subxiphoid region than by other examination of the chest. Hoover’s sign can be useful in disclosing a unilateral lag in motion of one side of the chest due to pleuritis or a pleural effusion. This sign is elicited by comparing the displacement from the midline during a patient’s deep inspiration of the examiner’s hands, each placed lightly over one hemithorax, with thumbs touching beneath the xiphoid at the start of the breath. An abnormal mass or fullness palpated in the supraclavicular space may be a clue to the presence of a neoplasm or to an involved lymph node, and suggest a convenient location to obtain a biopsy for diagnosis. Consolidation of the lung, which causes increased transmission of sound, can be detected as fremitus (i.e., as a palpable vibration) over the affected area while the patient repeats the traditional “one, two, three” as the examiner moves his/her palms systematically over the two hemithoraces. Conversely, impairment of sound transmission, as by a pleural effusion, diminishes vocal fremitus. In some instances, a pleural friction rub is palpable. Overall, the more seasoned the chest physician, the more likely is palpation to get its full due in the physical examination of the chest. Percussion of the Chest Percussion for physical examination has followed Auenbrugger’s sounding of beer barrels to determine their fluid levels. The response to percussion is impaired whenever something other than air-filled lung lies directly beneath the chest wall. Common causes of dullness to percussion are consolidation or atelectasis of the lung, fluid in the pleural space, pleural thickening, and a large mass at the surface of the lung. Widespread hyperresonance can often be elicited in emphysema and circumscribed hyperresonance over a pneumothorax or large bulla. As a rule, a decrease in breath sounds, as over a large bulla, is more characteristic than an increase in resonance. Auscultation of Lungs Ever since the time of Laennec, physicians have applied the stethoscope to the chest in search of sounds of disease. Attention is focused on the intensity and quality of the sounds, as well as the presence of abnormal (often called adventitial) lung sounds. Changes in the Intensity and Duration of Lung Sounds

The generation of lung sounds requires an ability to move air through patent airways. A global decrease in the intensity of breath sounds over the thorax or a hemithorax can be due to a variety of abnormalities: impaired movement of air due to air-

ways disease (e.g., in emphysema), paralysis of a diaphragm, or complete obstruction of a bronchus. A decrease in audible breath sounds can also occur when the transmission of sounds to the chest wall is impaired (e.g., by a pleural effusion, pleural thickening, or a pneumothorax). A bulla gives rise to a more circumscribed diminution in breath sounds. In a patient with COPD, regional variations in breath sounds correspond to the distribution of ventilation. An abnormal increase in intensity of breath sounds is accompanied by a change in their character (the sounds become either harsh or bronchial). The abnormal sounds are heard over consolidated, atelectatic, or compressed lung as long as the airway to the affected portion of the lung remains patent. Consolidated lung is presumed to act as an acoustic conducting medium that, unlike normal lung, does not attenuate transmission of tracheal sounds to the periphery. Noting the duration of the inspiratory and expiratory phases of breathing can be useful. Inspiration is normally audible for a longer period, with little if any expiratory noise. A prolongation of expiration, often longer than inspiration, is found with obstructed airways. Changes in the Transmission of Lung Sounds

Changes in voice sounds are often easier to appreciate than changes in breath sounds. Large pleural effusions, pneumothorax, and bronchial occlusion produce distant or inaudible breath sounds. Transmission of voice sounds is enhanced by consolidation, infarction, atelectasis, or compressions of lung tissue. Accompanying the increased transmission is a change in the character of the voice sounds that causes them to be higher pitched and less muffled than normal (bronchophony). When bronchophony is extreme, spoken words assume a nasal or bleating quality (egophony) and the sound “ee” is heard through the stethoscope as “ay.” Egophony is most common when consolidated lung and pleural fluid coexist; sometimes it is heard over an uncomplicated lobar pneumonia or pulmonary infarction. Transmission of whispered voice sounds with abnormal clarity (whispered pectoriloquy) has the same significance as bronchophony. Changes in the Quality of Lung Sounds

Normal breath sounds have a smooth, soft quality and are referred to as vesicular. Adventitious Lung Sounds Abnormal lung sounds have traditionally been resistant to meaningful clinical classification. The American Thoracic Society attempted to develop a rational and clinically useful classification based on acoustic analysis of tape recordings and the nomenclature introduced by Forgacs (Table 27-2). With this approach, lung sounds are categorized as continuous (wheezes, rhonchi, or stridor) or discontinuous (crackles). Wheezes, rhonchi, and stridor are musical adventitious sounds. Wheezes originate in airways narrowed by spasm, thickening of the mucosa, or luminal obstruction. Although

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Table 27-2 Classification of Common Lung Sounds

Acoustic Characteristics

American Thoracic Society Common Nomenclature Synonyms

Discontinuous, Coarse crackle interrupted explosive sounds; loud, low in pitch

Coarse rale

Discontinuous, Fine crackle interrupted explosive sounds; less loud than above and of shorter duration; higher in pitch than coarse crackles or rales

Fine rale, crepitation

Continuous sounds longer than 250 ms, high-pitched; dominant frequency of 400 Hz or more, hissing sound

Sibilant rhonchus

Wheeze

Continuous sounds Rhonchus longer than 250 ms, low-pitched; dominant frequency about 200 Hz or less, snoring sound

Approach to the Patient with Respiratory Symptoms

during the previous expiration. Crackles have been subdivided according to their timing during inspiration (early or late) and by differences in their quality (“wet” or “dry”); at times they have been termed “rales”. Noting differences in timing has been advocated as a way of distinguishing between possible causes (e.g., “dry” crackles in the fibrosis of interstitial lung disease vs. “wet” crackles in pulmonary edema). Unfortunately, wide variation in the interpretation of these sounds generally renders such attempts at classification of little value and often a cause of confusion. Crackles may accompany alterations in the elastic recoil of airways (emphysema), the presence of secretions (bronchitis or pneumonia), inflammation or fibrosis (interstitial lung disease) or fluid (pulmonary edema). Crackles can also be due to atelectasis, as in bedridden patients, and may clear with sequential deep breaths. Pleural Rub A pleural friction rub is a coarse, grating, or leathery sound that is usually heard late in inspiration and early in expiration; most often a pleural friction rub is audible low in the axilla or over the lung base posteriorly. The rub sounds close to the ear and usually is not altered by coughing.

DYSPNEA

Sonorous rhonchus

Source: From Loudon R, Murphy RLH: Lung sounds. Am Rev Respir Dis 130:663–673, 1984.

wheezes are more apt to occur during forced expiration, which further narrows airways, they may occur during both inspiration and expiration in asthma. Wheezes presumably originate through a combination of limitation to airflow and vibrations in the walls of the airways. Rhonchi are due to the presence of liquid or mucus in the airways; the quality and location may be readily changed by asking the patient to cough, thus moving the secretions. Stridor is predominantly inspiratory and best heard over the neck. Common causes of stridor are a foreign body in the upper intrathoracic airway or esophagus, an acquired lesion of the airway (e.g., carcinoma in adults), or a congenital lesion in children. Crackles Crackles are generally attributed to a rapid succession of explosive openings of small airways that closed prematurely

Dyspnea is the medical term for breathlessness or shortness of breath. For the patient, dyspnea involves an experience of discomfort in breathing. It is alarming to most patients and can arouse great concern about a potential dire cause, making it one of the most frequent complaints that prompts patients to seek medical evaluation. In the extensive medical, physiological, and psychological literature, dyspnea is used variously to designate a range of sensations from awareness of breathing on the one hand, to respiratory distress on the other. The wide range of meanings is understandable on several counts: (1) dyspnea is a subjective complaint without consistency in objective signs such as tachypnea; (2) few physicians have experienced the respiratory discomfort associated with chest disease, so that most interpretations of the complaint represent extrapolations from normal breathlessness (e.g., after strenuous exercise); (3) most experimental observations relating to dyspnea are based on the study of normal subjects or animals under artificial circumstances; and (4) most physicians apply the term loosely, based on their experience with the predominant patient population that they serve (e.g., patients with COPD or asthma). Despite this variability, in clinical medicine, the complaint of dyspnea almost invariably implies respiratory discomfort. Because of its subjective nature, the sensation of dyspnea is an amalgam of two components. The first is the sensory input to the cerebral cortex, which consists of information from specialized receptors, predominantly mechanoreceptors, at various sites in the respiratory

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Symptoms and Signs of Respiratory Disease Efferent signals

Afferent signals Motor cortex

Effort

Sensory cortex

Chemoreceptors

Effort ?

Air hunger Brain stem

Upper airway

Chest tightness

Vantilatory muscles

Chest wall

Figure 27-6 Pathways to the sensation of breathlessness. Respiratory effort is believed to originate as a signal transmitted from the motor cortex simultaneously to the sensory cortex and to the motor command to ventilatory muscles. The brain stem may also contribute to the sense of effort. The perception of air hunger is believed to arise, in part, from increased respiratory activity within the brain stem, whereas the sensation of chest tightness probably results from stimulation of vagal irritant receptors. Although afferent information from airway, lung, and chest-wall receptors most likely passes through the brain stem before reaching the sensory cortex, the dashed lines indicate uncertainty about whether some afferents bypass the brain stem and project directly to the sensory cortex. (From Manning HL, Schwartzstein RM: Pathophysiology of dyspnea. N Engl J Med 333:1547–1553, 1995, with permission.)

apparatus (predominantly the upper airways) and face (Fig. 27-6). The different sites of stimulation may contribute to the disparities in the sensation. Furthermore, no specific area in the central nervous system has been identified as the sensory locus for dyspnea. The input—from airways, lungs (via the vagus nerves), respiratory muscles, chest wall, and chemoreceptors—is processed at consecutive levels of the nervous system (i.e., spinal cord and supraspinal regions en route to the sensorimotor cortex). Additional sensory input, triggered by inadequate oxygen delivery or utilization, is poorly understood. The second component is the perception of the sensation, which rests heavily on the interpretation of information arriving at the sensorimotor cortex. The interpretation depends greatly on the psychological makeup of the person. A variety of influences can modify the psychological component of dyspnea. During “Kussmaul breathing” (see below), “air hunger” may seem obvious to the observer, even though the patient does not feel short of breath. In contrast, patients with congestive heart failure or COPD frequently volunteer the complaint of “air hunger.” Blunting of the sensorium, as by narcotics or by acute hypercapnia, can eliminate the sensation of breathlessness, even though the abnormal breathing pattern remains. Anxiety can heighten the sense of breathlessness. Indeed, anxiety can be responsible for the clinical syndrome of psychogenic dyspnea, in which the patient experiences “breathing discomfort” that eludes explanation on the basis of a somatic cause. Ill-defined sensations may

accompany a full-blown hyperventilation syndrome consisting of light-headedness, tingling of the hands and feet, tachycardia, inversion of T waves on the electrocardiogram, and even syncope. Breathing discomfort at rest that decreases with activity is often seen when anxiety or other psychological issues are the cause, and is a distinctly unusual pattern for dyspnea due to a cardiopulmonary abnormality. The quality of dyspnea can vary greatly. In normal persons, as well as in those with chest disease, dyspnea may simply signify the transition from an effortless process that is ordinarily conducted at a subconscious level to the awareness that muscular effort is being expended in breathing. The healthy athlete completing a dash experiences breathlessness that can be exhilarating rather than uncomfortable. The asthmatic often interprets breathlessness in terms of “tightness in the chest.” The patient with COPD often complains of lesssevere breathlessness than would be expected from the degree of airway obstruction, possibly reflecting adaptation either to the chronic obstructive airway disease or to CO2 retention. Patients may use different terms to describe breathing discomfort due to various causes. In some instances these descriptors may be useful in establishing a differential diagnosis and in assessing the response to therapy. Patients with asthma or myocardial ischemia often refer to “chest tightness.” Patients with pulmonary edema may suffer a sensation of “air hunger” or “suffocation.” Patients with COPD and hyperinflation of the chest often note an inability to take a deep, satisfying breath. Individuals who are physically out of

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shape may complain of “heavy breathing.” Unfortunately, no descriptor has sufficient sensitivity or specificity to be used alone in establishing the cause of a patient’s dyspnea.

Clinical Presentations Dyspnea may be acute, chronic, or paroxysmal (Table 27-3).

Table 27-3 Causes of Acute and Chronic Dyspnea∗ Acute Pulmonary edema Asthma Injury to chest wall and intrathoracic structures Spontaneous pneumothorax Pulmonary embolism Pneumonia Adult respiratory distress syndrome Pleural effusion Pulmonary hemorrhage Chronic, progressive

Approach to the Patient with Respiratory Symptoms

Acute The usual causes of acute dyspnea in children differ from those in adults. In children, upper-airway infection (e.g., epiglottis, laryngitis, or acute laryngotracheobronchitis) is a common cause. In adults, the causes of acute dyspnea are much more varied (Table 27-3). Among the most common are an episode of acute left ventricular failure, a thromboembolic event, pneumonia, and spontaneous pneumothorax. Less common, but not unusual, is massive collapse of one lung due to inability to clear the airways of thick tenacious secretions (e.g., in chronic bronchitis or asthma) or the first attack of asthma. Chronic (and Progressive) Dyspnea Chronic dyspnea is almost invariably progressive. As a rule, this type of dyspnea begins with breathlessness on exertion— which, in time, progresses to dyspnea at rest. Pulmonologists encounter dyspnea in patients who have COPD; cardiologists more often deal with dyspnea in patients who are in chronic congestive heart failure. Especially in older patients, distinction between the heart and lungs in the etiology of dyspnea, or the relative contributions of each, can be difficult to establish. Asthma is a common cause of recurrent bouts of dyspnea which are usually accompanied by cough and wheezing. Cardiac dysfunction is another cause of acute bouts of bronchospasm, especially in middle-aged or elderly persons. Another, much less frequent cause of paroxysmal wheezing and breathlessness is bronchopulmonary aspergillosis. Etiologies of asthma vary in different parts of the world; where schistosomiasis is endemic, an attack of asthma may accompany the migratory stage of schistosomiasis (i.e., larvae traversing the lungs).

Chronic obstructive pulmonary disease Left ventricular failure Diffuse interstitial fibrosis Asthma Pleural effusions Pulmonary thromboembolic disease Pulmonary vascular disease Psychogenic dyspnea Anemia, severe Postintubation tracheal stenosis Hypersensitivity disorders ∗ Many

chronic processes (eg, left ventricular failure, asthma, and COPD) may have acute exacerbations.

Physiological Correlates of Dyspnea Historically, attempts to understand the physiological bases of dyspnea have evolved along four separate lines: ventilatory performance, the mechanics of breathing, chemoreception, and exercise testing. Ventilatory Performance The earliest investigations related dyspnea to minute ventilation. Dyspnea was found to correlate with an excessive minute ventilation for the level of oxygen uptake. Most of the increase in ventilation was accounted for by an increase in respiratory rate, especially in patients with stiff lungs. In patients who continued to ventilate excessively for the level of oxygen uptake (e.g., those with chronic left ventricular failure), the sensation of breathlessness gradually diminished, suggesting adaptation to the continued stimulus. A second ventilatory measurement that proved to correlate well with dyspnea is the maximum voluntary ventilation (MVV). MVV is decreased by diseases of the lungs, airways, or chest cage. The smaller the maximum breathing capacity, the more likely is dyspnea to occur.

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A third time-honored approach to measurement is the “breathing reserve.” This value is determined as the difference between the MVV and the actual minute ventilation. In principle, the sensation of breathlessness during the performance of any ventilatory task may be related to the fraction of the maximum breathing capacity that is used for force generation by the respiratory apparatus. Thus, the closer the minute ventilation is to the maximum breathing capacity, the more likely is the subject to complain of breathlessness. Indeed, when the actual level of ventilation reaches 30 to 40 percent of the maximum breathing capacity, dyspnea is inevitable. Unfortunately, the breathing reserve correlates better with the dyspnea of normal subjects during exertion than with the dyspnea of chronic bronchitis and COPD or of left ventricular failure. Thus, in COPD the minute ventilation may be a very large fraction of the MVV (greater than 50 percent) without eliciting dyspnea. In contrast, in acute left ventricular failure, a mild increase in ventilation and a nearly normal MVV may be associated with considerable breathlessness. Mechanics of Breathing One teleological way to regard dyspnea is as a sensation that prompts an unconscious effort to minimize the work, energy cost, or force of breathing. In this light, dyspnea protects the respiratory apparatus from overwork and inefficient operation. This approach has led to exploration of the relationships between dyspnea and the work or oxygen cost of breathing.

Work, Oxygen Cost, and Efficiency of Breathing It has not been possible to identify a critical level for the work of breathing at which dyspnea will occur. However, a breakdown of the work of breathing into its elastic, resistive, and inertial components has helped to relate physiological disturbances to particular diseases. For example, in chronic mitral stenosis with pulmonary congestion, the elastic work is greatly increased (Fig. 27-7), whereas in obstructive airway disease, resistive work predominates. Moreover, such observations have reinforced the concept that patterns of breathing are automatically adjusted to minimize the work done by the respiratory muscles in breathing. The relationship between ventilation and O2 consumed by the respiratory muscles is curvilinear (Fig. 27-8). This O2 cost of breathing can increase extraordinarily in patients with COPD or with abnormalities of the chest wall. Indeed, in patients with COPD, the quantity of O2 delivered to the respiratory muscles during the large ventilatory effort may fail to satisfy their aerobic needs, leading to anaerobic metabolism and lactic acidosis. Although the greater the O2 cost of breathing the greater the likelihood of dyspnea, the determination of O2 cost provides no more useful insight into the mechanism of dyspnea than does the work of breathing. Calculation of the efficiency of breathing (i.e., the work of breathing related to energy cost) provides no further clarification.

Figure 27-7 Partition of the work of breathing in pulmonary congestion and edema at rest and during exercise. A. Normal. The minimal work of breathing at rest was at a respiratory frequency of 12 breaths per min; during exercise, the minimal work was done at a higher frequency (25 breaths per min). B. Mitral stenosis. At rest, the frequency for least respiratory work was abnormally high (22 breaths per min); during exercise it increased further (to 28 breaths per min). The dashed vertical line (capped by arrowheads) in each frame indicates the respiratory frequency at which respiratory work was minimal. (From Christie RV: Dyspnea in relation to the visco-elastic properties of the lung. Proc R Soc Med 46:381–386, 1953, with permission.)

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Table 27-4 Modified Borg Category Scale Rating

Intensity of Sensation

Nothing at all

0.5

Very, very slight (just noticeable)

Very slight

Slight

Moderate

Figure 27-8 Oxygen cost of breathing in restrictive lung disease. Relationship between ventilation and O2 consumption in pulmonary fibrosis. At each level of ventilation, the patient with pulmonary fibrosis does more work and expends more energy in breathing than does the normal subject.

Somewhat severe

Severe

Length-Tension Inappropriateness The concept of “length-tension inappropriateness” explains dyspnea as a mismatch between the central motor command to the respiratory muscles (i.e., the motor signal emitted from the brain) and the suboptimal (“inappropriate”) shortening of the respiratory muscles elicited by this command (e.g., suboptimal thoracic expansion for any level of central motor command). In essence, this concept pictures a decrease, instead of an increase, in the pressure-generating capacity of the respiratory muscles in the face of the increased need arising from the heightened respiratory drive.

Chemoreception Chemoreceptors in the medulla respond to changes in pH and PaCO2 . Peripheral receptors in the aortic arch and carotid body also respond to alterations in PaO2 . Acute hypoxia, hypercapnia, and acidosis are the traditional stimuli for ventilation. For example, upon ascent to altitude, acute hypoxia can stimulate ventilation to the level of awareness that may progress to discomfort during exertion. The effects of these stimuli on breathing decrease if they continue unabated. In addition, side effects, such as blunting of the sensorium during chronic CO2 retention, diminish the likelihood of dyspnea, even if the level of ventilation is increased. In patients with abnormal pulmonary mechanics, the onset of abnormalities in blood gas composition, as during exercise, can aggravate or contribute to dyspnea. In general, acute hypercapnia is a stronger stimulus for dyspnea than is acute hypoxia. Scaling A variety of scaling methods have been devised in the attempt to quantify dyspnea during exercise and various experimental conditions. Some, such as the Borg Category Scale (Table 27-4), use numbers and descriptive terms to depict a change in the intensity of the stimulus (“threshold stimu-

6 Very severe

8 9 10

Very, very severe (almost maximal) Maximal

lus detection methods”). Others rely on visual analog scales, which are straight lines, usually 10 cm long, that extend from “not breathless” at one end to “extremely breathless” at the other. The patient marks on this line the intensity of respiratory discomfort elicited by external stimuli, such as resistive loads or exercise testing. The score is measured as the length of the line between “not breathless” and the mark made by the patient. The Shortness of Breath Scale issued by the American Thoracic Society (Table 27-5) has also been used in one form or another, particularly in epidemiological studies. No single scale is applicable to all subjects or patients.

Dyspnea: Overview In general, the sensation of dyspnea seems to be related to the intensity of afferent input from thoracic structures (especially the respiratory muscles) and from the chemoreceptors (central, peripheral, local). In patients with respiratory disease, dyspnea occurs most often when breathing is impeded, mechanics of breathing are abnormal, the lungs are stiffened, ventilatory musculature is weakened, and/or chemoreceptor input is increased.

Dyspnea in Chronic Pulmonary Disease Two common types of pulmonary disease in which dyspnea features prominently are chronic obstructive airway disease and restrictive lung disease.

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Table 27-5 American Thoracic Society Scale Descriptions

Grade

Degree

Not troubled by shortness of breath when hurrying on the level or walking up a slight hill

None

Troubled by shortness of breath when hurrying on the level or walking up a slight hill

Mild

Walks more slowly than people of the same age on the level because of breathlessness or has to stop for breath when walking at own pace on the level

Moderate

Stops for breath after walking about 100 yards or after a few minutes on the level

Severe

Too breathless to leave the house; breathless on dressing or undressing

Very severe

Chronic Obstructive Pulmonary Disease (COPD) COPD refers to a spectrum of airway diseases in which obstruction to airflow is the common denominator. Cigarette smoking is the leading cause of COPD. The outer limits of the spectrum are marked by chronic bronchitis at one end and emphysema at the other. Most patients with COPD fall into categories between those limits (i.e., they manifest mixtures of chronic bronchitis and emphysema which vary in degrees) (Fig. 27-9). Asthma constitutes a different entity, not only in its clinical expressions but also because it is usually episodic and is often related to allergic manifestations, and generally affects younger individuals. Cystic fibrosis is another distinct entity because of its genetic basis, clinical and radiographic presentations, and nature of the airway obstruction (i.e., by inspissated mucus) and proclivity to superinfection. Dyspnea is a regular feature of each of these causes of chronic airways obstruction. Patients with COPD suffer from disturbances in the mechanics of breathing, abnormal lung volumes, and derangements in gas exchange. The minute ventilation, which may be only slightly increased at rest, constitutes an abnormally large fraction of the maximum breathing capacity (i.e., the “breathing reserve” is low). Abnormalities in the mechanics of breathing dominate the scene: resistance to airflow is high; the thorax assumes a hyperinflated position, placing the inspiratory muscles at

mechanical disadvantage; the work of breathing is greatly increased. The O2 cost of breathing is correspondingly high. Derangements in dead space ventilation and in alveolar-capillary gas exchange add to the afferent stimuli. As a result of the disturbances in mechanics and gas exchange, swings in pleural pressure (a measure of force applied to the lungs) are large, and a considerable muscular effort is expended in breathing; instead of the normal increase of about 1 ml of O2 uptake per liter of ventilation per minute, the O2 uptake increases enormously (up to 25 ml/min). Should O2 delivery to the overworked respiratory muscles be insufficient, fatigue and exhaustion may send nervous and chemical signals of their own to the brain. Finally, if the patient accumulates excess water in the lungs, the juxtacapillary (“J”) receptors provide additional sensory input to the central integrating mechanism. As noted above (see “Length-Tension Inappropriateness”), the convergence of these diverse stimuli upon the sensorimotor cortex may generate an inordinate motor command to the respiratory muscles, which cannot mobilize the thorax sufficiently to generate the pleural pressures needed for adequate ventilation. One enigma is why some patients with COPD settle for a lower ventilation than others. For example, despite equal abnormalities in conventional pulmonary function tests, the “CO2 retainer,” with respiratory acidosis and arterial hypoxemia, often breathes less than does the non–CO2 retainer in whom blood gas levels are near normal. One teleological explanation is that the lower ventilation in the CO2 retainer causes less dyspnea. However, this explanation affords no insight into the physiological mechanism. Treatment of the patient with COPD is directed at diminishing airways resistance and restoring arterial blood gases toward normal. Unfortunately, bronchodilators and corticosteroids generally exert little effect, and the basic abnormalities in the mechanics of the lungs and airways remain. Consequently, the load on the respiratory muscles is not readily alleviated by medical management. Accordingly, therapeutic interest in these disorders has turned to ways by which the performance of the respiratory muscles can be improved. These have generally taken the form of training exercises to facilitate adaptive changes and to increase both muscle strength and endurance. Exercise reconditioning in patients with COPD has been shown to diminish breathlessness, possibly owing to three interactive mechanisms: (1) increased mechanical efficiency of the exercising muscles, which decrease ventilatory requirements; (2) improved function of the respiratory muscles; and (3) increased tolerance of the “dyspneagenic” sensory input to the brain. Attempts to rest the respiratory muscles have no lasting effect on dyspnea. Asthma The mechanisms described above for COPD apply as well to asthma. However, these mechanisms do not account for the sensation of “tightness in the chest” or the inordinate sense of labored breathing that accompanies the breathlessness in asthma.

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Figure 27-9 Chronic obstructive pulmonary disease (COPD). Sagittal sections showing patterns of emphysema. A. Normal lung from a patient who died of unrelated causes. B. Predominantly centrilobular emphysema. C. Predominantly centrilobular and panlobular emphysema. D. Predominantly panlobular emphysema. Centrilobular emphysema is less marked. The three patients with emphysema (B, C, D) also had clinical manifestations of chronic bronchitis confirmed by histological sections.

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Dyspnea in Chronic Cardiac Disease

Table 27-6 Common Causes of Restrictive Lung Disease Cause

Example

Interstitium Interstitial fibrosis and/or infiltration

Asbestosis

Pulmonary edema

Left ventricular failure

Pleura Pleural disease

Fibrothorax

Thoracic cage and abdomen Neuromuscular disease

Poliomyelitis

Skeletal abnormalities

Severe kyphoscoliosis

Marked obesity

Grossly overweight

Restrictive Lung Disease Restrictive lung diseases can be due to different causes, but usually they have in common a reduction in lung volumes and diffusing capacity (Table 27-6). Diffuse interstitial disease, has many different causes and may be either acute or chronic (Table 27-7). Characteristically, in widespread interstitial disease, the diffusing capacity is low and accompanied by a considerable decrease in total lung capacity and in vital capacity accompanied by lesser decrements in functional residual capacity and residual volume. Similar findings occur in severe kyphoscoliosis or encasement of the lung by pleural thickening (Fig. 27-10). In contrast, in pulmonary vascular disease, such as idiopathic pulmonary arterial hypertension, a low diffusing capacity may be accompanied by normal lung volumes. Neuromuscular disease that affects the inspiratory muscles sufficiently to diminish maximum inspiratory pressures may only decrease the vital and total lung capacities, leaving the functional residual capacity and residual volume unaffected. Patients with widespread pulmonary fibrosis breathe faster and maintain a higher minute ventilation than do normal subjects, both at rest and during exercise. The work and oxygen cost of ventilating the stiff lungs are increased. The maximum breathing capacity is well preserved. In these patients, dyspnea is attributable to the considerable effort by the respiratory muscles in ventilating the stiff lungs and in sustaining the high ventilatory rate. During exercise, dyspnea may become intolerable.

The mechanisms responsible for dyspnea in cardiac disease vary with the extent to which the lungs are stiffened. Without Stiff Lungs Dyspnea occurs in many forms of heart disease that are not associated with congestion of the lungs. Uncomplicated pulmonic stenosis is an excellent example. The symptom is probably related to an inadequate cardiac output during exercise. In tetralogy of Fallot, dyspnea is sometimes severe and often relieved by assuming a squatting position. In this and other forms of cyanotic heart disease, both dyspnea and fatigue appear during exertion when the arterial oxyhemoglobin saturation decreases appreciably below the resting level. With Stiff Lungs Cardiac dyspnea is associated with an increase in blood and water content of the lungs. It is a common occurrence in left ventricular failure and mitral stenosis, both of which are accompanied by increases in pulmonary venous and capillary pressures. The engorged pulmonary circulatory bed, coupled with interstitial and alveolar edema, stiffens the lungs (i.e., decreases their compliance) and stimulates the ventilation via â&#x20AC;&#x153;Jâ&#x20AC;? receptors. In chronic left ventricular failure, pulmonary fibrosis, consequent to long-standing interstitial edema, contributes to the stiff lungs. Edema of the tracheobronchial mucosa increases airway resistance. As a result of the stiff lungs and increased airway resistance, the swings in pleural pressure during the respiratory cycle are large and the work and energy cost of breathing are increased. Arterial hypoxemia, generally mild, may add to the ventilatory drive. Exercise exaggerates the pulmonary congestion and edema, promotes arterial and mixed venous hypoxemia, and increases the dyspnea. In patients with pulmonary congestion and edema, tachypnea is a regular feature at rest and increases during exercise. Although tachypnea is consistent, its degree is generally modest and probably not entirely responsible for the dyspnea. Fatigue is a common concomitant of low cardiac output and may stem from diminished O2 delivery to the respiratory muscles, contributing to respiratory discomfort. Orthopnea and Other Positional Forms of Breathlessness Orthopnea signifies dyspnea in the recumbent, but not in the upright or semivertical position; it is usually relieved by two or three pillows under the head and back. Oppositely, platypnea signifies dyspnea induced by assuming the upright position and relieved by assuming the recumbent position. Platypnea can be seen when, due to gravity, increased blood flow worsens right to left shunting of blood through arteriovenous malformations at the lung bases. Orthopnea is a hallmark of pulmonary congestion that stiffens the lungs (i.e., decreases

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Table 27-7 Some Types of Diffuse Interstitial Disease Etiology

Example

Common Features Acute

Infections

Miliary tuberculosis, histoplasmosis

Opportunity for exposure to organism

Pneumocystis, cytomegalic inclusion virus, fungi

Immunosuppression

Pulmonary edema

Narcotic overdosage, nitrogen dioxide (silo-fillerâ&#x20AC;&#x2122;s disease), uremia

Distinctive history

Inhalation

Byssinosis

Monday morning asthma and fever

Aspiration

After loss of consciousness

History of alcoholism or epilepsy

Immunologic

Goodpastureâ&#x20AC;&#x2122;s syndrome

Renal and pulmonary involvement

Carcinoma of lung

Alveolar cell carcinoma Chronic

Inhalation

Pneumoconioses

History of exposure to inorganic dust

Radiation therapy

After mastectomy

Gradual evolution after treatment

Lymphangitic spread

Carcinoma of breast, lung, stomach, pancreas

Evidence of primary carcinoma

Medications

Hexamethonium hydralazine, bleomycin, busulfan, nitrofurantoin

History, suggestive chest radiograph

Systemic disorders

Sarcoidosis, collagen, disorders, histiocytosis X, amyloidosis, tuberous sclerosis

Multi-organ involvement; biopsy

Idiopathic

Idiopathic pulmonary fibrosis

Exclusion of known causes

their compliance). The decrease in compliance on lying flat is attributable to the fact that more of the lung is located at or below the level of the heart. During recumbency, the swings in pleural pressure, the work of breathing, and the respiratory frequency increase. The increase in respiratory frequency appears to be automatically adjusted to minimize the work of ventilating the more rigid lungs. Some patients with chronic lung disease or asthma are also intolerant of recumbency. In these people, the discomfort is attributed to the greater difficulty of performing vigorous movements of the chest bellows in the recumbent position. Paroxysmal Nocturnal Dyspnea In an episode of paroxysmal nocturnal dyspnea, the patient is aroused from sleep gasping for air and must sit up or stand to

catch his or her breath; sweating may be profuse. Sometimes the patient throws a window open wide in an attempt to relieve the oppressive sensation of suffocation. The chest tends to become fixed in the position of forced inspiration. Both inspiratory and expiratory wheezes, often simulating typical asthma, are heard. In some instances, overt pulmonary edema occurs, accompanied by many inspiratory crackles. The acute pulmonary edema is rarely fatal, however, the attacks occasionally recur several times a night, forcing the patient to sleep upright in a chair. An episode of paroxysmal nocturnal dyspnea represents precipitous failure of the left ventricle caused by the factors that produce orthopnea (see above), abetted by pulmonary hypervolemia caused by a surge in systemic venous return. Mobilization of peripheral edema from the periphery as the extremities are elevated from the

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dependent position may contribute to the increase in systemic venous return. The acute increase in pulmonary blood volume increases pulmonary capillary pressures, thereby promoting pulmonary edema, while the surge in venous return imposes an additional burden on the left ventricle. A variety of factors can trigger an episode of paroxysmal nocturnal dyspnea: coughing, abdominal distention, the hypercapnic phase of Cheyne-Stokes respiration, a startling noise, or anything that causes a rise in heart rate and further increases the pulmonary capillary and venous pressures. Usually the attack is terminated by assumption of the erect position and a few deep breaths. Cough, an important manifestation of pulmonary congestion, frequently occurs during the attack.

Cardiac Asthma Asthmatic wheezes, often audible in patients with pulmonary congestion, have given rise to the term cardiac asthma. The wheezes are a manifestation of tracheobronchial edema and often are accompanied by overt signs of pulmonary edema. In addition to the reduction in the lumen of the airways and thickening of bronchial walls by edema, the high intrathoracic pressures which are required to overcome the obstruction during expiration tend to narrow the airways even further. The resistance to airflow is increased during both inspiration and expiration, and the compliance of the lungs is greatly reduced, reaching values as low as one-tenth of normal. Upon recovery from the acute episode of pulmonary edema, airway resistance and pulmonary compliance return toward normal unless previous episodes have left a residue of pulmonary fibrosis.

Dyspnea in Anemia Shortness of breath during exercise or excitement is a common complaint in severe anemia (e.g., hemoglobin concentration under 6 to 7 g/dl). It is more common in acute than in chronic anemia. Often the dyspnea is associated with dizziness or faintness, and invariably the patient manifests signs of a high cardiac output and low peripheral resistance (i.e., bounding pulse, warm skin, and systolic cardiac murmurs). Although the pathogenesis of the dyspnea is not entirely clear, inadequate O2 delivery to the respiratory muscles has been proposed.

â&#x2020;? Figure 27-10 Restrictive lung disease. A. Asbestosis with markedly thickened pleura that encases and compresses the lungs. In addition, the lungs were afflicted with diffuse interstitial fibrosis. B. Compressed, distorted lung in patient with kyphoscoliosis. The lungs were otherwise normal, so that in this instance restriction was imposed by the chest wall rather than by intrapulmonary or pleural disease. B

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Metabolic Abnormalities and Drugs Increases in CO2 production demand a concomitant rise in ventilation to dispose of the metabolic load, and can thus result in dyspnea. To prevent acidemia, patients with diabetic ketoacidosis may require an enormous increase in minute ventilation in order to reduce PaCO2 to even single digits. Thyrotoxicosis, fever, infection, and pregnancy can also cause an increase minute ventilation; so can drugs, such as aspirin and progesterone.

Miscellaneous Disorders Breathlessness is not uncommon in patients with musculoskeletal disorders. The usual explanation is the heightened motor drive that is needed to activate the weakened respiratory muscles. In the intensive-care unit, inadequate ventilator settings for flow and tidal volume may fail to satisfy the intrinsic ventilatory drive of the patient, generating the sensation of breathlessness.

ABNORMAL BREATHING PATTERNS An important clue to the nature of a clinical problem in pulmonary disease is sometimes provided by bedside observation of a patient’s breathing pattern. The pertinent features are the rate, regularity, depth, and apparent effort being expended in breathing. A normal person at rest breathes about 12 to 15 times per minute, with a tidal volume of 400 to 800 ml. As a result, minute ventilation is normally greater than 5 L/minute. The pattern is quite regular except for an occasional slow, deep breath, and the respiratory movements appear effortless. In the patient with lobar pneumonia, both the rate and depth of breathing accompany the increase in body temperature. Severe skeletal deformity, as well as massive obesity, can limit chest excursions to cause alveolar hypoventilation. Neuromuscular weakness, as in myasthenia gravis or GuillainBarr´e disease, can do the same, not only by diminishing ventilatory excursions as a result of generalized weakness of the respiratory muscles but also by causing overload of respiratory muscles (e.g., residual effects of poliomyelitis). Unilateral involvement of one pleural space by pneumothorax, effusion, or fibrothorax limits excursions on the affected side. Massive chest trauma can cause flail chest. In COPD, a slow respiratory rate and large tidal volumes are characteristic. This pattern presumably serves to minimize the work of breathing. Pursed-lip breathing, a selfinduced type of positive-pressure breathing, is often part of the picture. In contrast, persons with restrictive lung disease adopt a breathing pattern that is characterized by small tidal volumes and a rapid respiratory rate, often with little apparent effort. This pattern is seen in patients with a decrease in the distensibility of the lung or chest wall or with reduction of the vital capacity from any other cause. During exercise,

Approach to the Patient with Respiratory Symptoms

minute ventilation increases inordinately with respect to the level of O2 uptake and frequency increases more than tidal volume. Fatigue of the diaphragm and intercostal muscles, sufficient to disturb their coordinated contractions, can give rise to paradoxical breathing which heralds the onset of respiratory failure.

Cheyne-Stokes Respiration In the fourth century b.c., in a preterminally ill person with fever, sweats, and black urine, Hippocrates described a pattern of breathing in which “the respiration throughout [was] like that of a man correcting himself, and rare and large.” Presumably he had observed Cheyne-Stokes breathing, which was described more graphically by William Stokes two millennia later (in 1854) as follows: The symptom in question (previously described by Dr. Cheyne) consists in the occurrence of a series of inspirating, increasing to a maximum, and then declining in force and length, until a state of apparent apnea is established. In this condition the patient may remain for such a length of time as to make his attendants believe that he is dead, when a low inspiration, followed by one more decided, marks the commencement of a new ascending and descending series of inspirations.

Cheyne-Stokes breathing is characterized by alternating periods of hypoventilation and hyperventilation (Fig. 2711). In its typical form, an apneic phase, which lasts for 15 to 60 s, is followed by a phase during which tidal volume increases with each successive breath to a peak level and then decreases in a progressive fashion to the apneic phase. At the onset of apnea, CO2 tension in brachial or femoral arterial blood is at its lowest. As apnea persists, CO2 tension gradually increases, and respiration is stimulated. CO2 tension continues to increase until maximum hyperventilation is attained, after which ventilation decreases until apnea again occurs. The arterial oxyhemoglobin saturation varies in an inverse manner, being highest at the onset of apnea and lower during mid-hyperpnea. During the cycle, CO2 tension varies by as much as 14 mmHg and oxyhemoglobin saturation by as much as 18 percent. In patients with congestive heart failure, the respiratory oscillations are attributable to slowing of the circulation so that the blood gases reaching the respiratory centers in the brain are 180 degrees out of phase with those in pulmonary capillary blood. This mechanism has been verified experimentally by eliciting Cheyne-Stokes breathing in dogs by prolonging the circulation time from heart to brain by way of an extracorporeal circuit. Fluctuations in mental state and electroencephalographic patterns, and evidence of nervous system dysfunctioning, may occur during Cheyne-Stokes breathing because of swings in cerebral blood flow. In neurological disorders, Cheyne-Stokes breathing can be due to supramedullary

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doses (e.g., alcoholic ketoacidosis). The usual sequence leading to this type of breathing is renal failure with a progressive decrease in plasma bicarbonate and resultant acidosis. The “compensatory” increase in ventilation that Kussmaul described mitigates the fall in systemic pH caused by the fall in plasma bicarbonate.

Other Abnormal Patterns Gasping respirations are characteristic of severe cerebral hypoxia. The pattern consists of irregular, quick inspirations associated with extensions of the neck and followed by a long expiratory pause. It is commonly seen in shock or in other conditions associated with severe reduction in cardiac output. Hyperventilation is commonly seen in anxious patients without structural disease of the lungs. In some of these patients, striking deep sighs dominate the ventilatory pattern.

DIAGNOSTIC TESTING IN THE EVALUATION OF DYSPNEA

Figure 27-11 Cheyne-Stokes breathing, illustrating the relationship between the ventilation and the blood and alveolar gas tensions during the periods of apnea and hyperpnea. (From Cherniack NS, Fishman AP: Abnormal breathing patterns. Dis Mon 3–45, 1975, with permission.)

dysfunctions, particularly in patients who have destructive lesions in the tegmentum of the pons. Less common than in heart failure or neurological disorders is the occurrence of Cheyne-Stokes respiration in normal infants, in healthy elderly persons, and in normal persons at high altitude. It is also seen occasionally after the administration of respiratory depressants (e.g., morphine) often accompanied by an increase in intracranial pressure, uremia, or coma. At one time, the respiratory center was believed to be depressed in Cheyne-Stokes respiration. This hypothesis has been proved to be in error, since it has been shown that the respiratory response to inhalation of CO2 is greater than normal in individuals with Cheyne-Stokes respiration. Respiratory alkalosis is common and the arterial PCO2 remains subnormal in both the apneic and hyperpneic phases.

Kussmaul Breathing In 1874, Kussmaul described three patients with diabetic ketosis who manifested “air hunger”: they were breathing with large tidal volumes and so rapidly that there was virtually no pause between breaths. In essence, they were breathing at rest as though they were exercising; breathing was accomplished with little apparent effort. Since then, this pattern of breathing has been observed in other types of severe metabolic aci-

Attention to important history and physical examination findings as described in the preceding sections will help to focus the initial approach to diagnosis. In most cases, the initial diagnostic impression can be confirmed or excluded with only a few tests, and appropriate therapy instituted or the hunt for a cause continued (Table 27-8). In some instances, the response to a therapy instituted empirically on the basis of the history and physical examination findings is itself diagnostic. For example, the relief of dyspnea following the administration of diuretics given to a patient with progressive orthopnea, bilateral basilar inspiratory crackles, and a prominent third heart sound (S3 ) is strong evidence of heart failure as the cause. A plain chest radiograph is frequently useful in demonstrating changes suggestive of COPD (chest hyperinflation, bullous changes). Vascular engorgement, an enlarged cardiac silhouette, interstitial markings and pleural effusions may indicate left heart failure. Interstitial markings may also have a pattern consistent with an inflammatory or fibrotic process. Spirometry is useful in identifying airways obstruction, at times noting a change in values following the administration of a bronchodilator. The measurement of lung volumes or the diffusing capacity may be reserved for when there is suspicion of an interstitial process or other cause of restriction (e.g., muscle weakness). Measurement of arterial oxyhemoglobin saturation both at rest and with exertion is important. While oxyhemoglobin desaturation may not itself indicate the etiology of the problem, its presence is always an important indicator of the severity of the disease and may itself warrant treatment with oxygen while the evaluation of its cause continues. An echocardiogram can be used to assess ventricular or valvular cardiac function or to estimate pulmonary arterial pressures.

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Table 27-8 Common Tests in the Evaluation of Dyspnea Test

Some Possible Abnormalities

Some Possible Diagnoses

Plain chest radiograph

Cardiac enlargement Vascular enlargement Abnormal interstitial markings Pleural effusions Hyperinflation Nodules/masses

Congestive heart failure COPD Malignant pleural effusion Neoplastic disease Infection

Diffusing capacity

Obstructive ventilation defect (Decreased FEV1 /FVC ratio) Restrictive ventilatory defect Decreased

Inspiratory and expiratory maneuvers

Increased Decreased values

Asthma COPD Interstitial lung disease Interstitial lung disease Pulmonary vascular disease Alveolar hemorrhage Respiratory muscle weakness

Computed tomography

Abnormal interstitial markings Cystic changes Lymphadenopathy Vascular filling defects Ground-glass opacities

Interstitial lung disease Congestive heart failure Atelectasis Pulmonary embolism Neoplastic disease

Blood tests

Elevated white blood cell count Anemia BNP Cr HCO3 ABG

Infection Anemia Heart failure Acidoses (respiratory or metabolic)

Pulmonary function tests Spirometry

Alkaloses (respiratory)

COPD, Chronic obstructive pulmonary disease; FEV1 /FVC, forced expiratory volume in 1s/forced vital capacity; BNP, brain natriuretic peptide; Cr, creatine; HCO3 , bicarbonate; ABG, arterial blood gas.

A complete blood count may reveal anemia or suggest an infection. Electrolytes may indicate the presence of an acidosis or renal dysfunction. Measurement of brain natriuretic peptide (BNP) has been useful in helping to exclude heart failure as an acute cause of dyspnea. Fewer than 5 percent of patients with BNP values below 50 pg/ml have heart failure as the acute cause of dyspnea. Additional testing is usually not required unless the cause of dyspnea remains unclear following these more basic studies. Further tests often include computed tomography (CT) of the chest which may rarely reveal changes of emphysema or an interstitial process not suggested by plain radiographs or lung function testing. The CT may additionally help to better characterize an interstitial process identified on plain radiographs. Cardiopulmonary exercise testing may be helpful in differentiating between cardiac and respiratory causes of dyspnea, or in excluding a significant abnormality of either system and suggesting deconditioning as the culprit.

Arterial blood gas measurements may be necessary to characterize the level of blood oxygenation or to identify hyperventilation or hypercapnia. More invasive testing, including cardiac catheterization or lung biopsy (by either bronchoscopy or surgery), is reserved for when the diagnosis remains unsettled and the results will be helpful in guiding therapy or discussions of prognosis.

COUGH Cough is one of the most frequent causes of visits to the doctorâ&#x20AC;&#x2122;s office. Patients are frequently anxious about the possibility of a serious malady as the cause. They may also be troubled by the complications of cough, including chest pain from intercostal muscle strain or even a fractured rib in patients with bone disease. They may be embarrassed by

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ReceptorMechanical/Chemical

Voluntary Control

Noses and Sinuses

CN-V

Posterior Pharynx

CN-IX

Pericardium Diaphragm

Ear Canals/Drums Trachea Bronchi Esophagus Stomach Pleura

Medullary Cough Center

Effectors

Spinal Motor

Expiratory Muscles

Phrenic

Diaphragm

CN-X

Larynx Trachea Bronchi

CN-X

Phrenic

Figure 27-12 Signaling pathways in the development of cough. CN, cranial nerve. (After Silvestri RC, Weinberger SE: Evaluation of chronic cough in adults. In Rose B (ed), UpToDate. Wellesley, MA, 2006.)

cough-induced incontinence of the bladder or stool. Embarrassment, and even social isolation may also arise from the frequent fear of others that the patient’s cough is infectious and communicable. A cough is an explosive expiration that protects the lungs against aspiration and promotes the movement of secretions and other airway constituents upward toward the mouth. It is a critical element in the self-cleansing and protective mechanisms of the lungs—a reflex act that usually, but not invariably, arises from stimulation of the bronchial mucosa somewhere between the larynx and the second-order bronchi. On rare occasions the cause is remote: impacted cerumen in an external ear or an inflammatory process of the pleura (see “Mechanism” below) (Fig. 27-12). The stimuli that can elicit a cough are diverse: inhaled particles, mucus that has been elaborated by the lining of the airways, inflammatory exudate in airways or parenchyma, a new growth or foreign body in an airway, pressure on the external wall of the bronchus. A cough may be voluntary, involuntary, or a combination of the two if the subject attempts to control an involuntary cough. Three categories of stimuli are commonly at work in producing an involuntary cough: mechanical, inflammatory, and psychogenic. Mechanical and chemical causes range from inhalation of irritants, such as smoke or dust, to distortions of the airways produced by pulmonary fibrosis or atelectasis. Most often, coughs are due to tracheobronchial inflammation. The cigarette smoker is particularly vulnerable to exacerbation of cough by inhaled particles and fumes because of underlying chronic pharyngitis, laryngitis, and tracheobronchitis. As a rule, cough represents organic disease. But on occasion, psychogenic influences are responsible for a dry cough that is related to anxiety. Psychogenic stress can aggravate cough due to organic causes.

The site and significance of a cough can sometimes be localized from telltale signs and symptoms (Table 27-9). For example, the cough of acute tracheitis is often associated with retrosternal “burning.” Acute laryngitis is usually associated with hoarseness and sore throat as well as cough. Tuberculosis of the larynx is associated not only with painful swallowing but also with unequivocal evidence of pulmonary tuberculosis. In asthma, cough is part of a constellation of airway obstruction. Body position can influence the persistence of a cough. When the pathological process is changing, as in pneumonia or a neoplasm, the cough undergoes concomitant change, reflecting the evolution of the disorder. Interpretation of the significance of a cough depends on the clinical company that it keeps. It has to be viewed in context: Is it acute or chronic? productive or nonproductive? How long has it lasted? What is the general condition of the patient, and what co-morbidities are present? For example, the acute onset of a hacking, nonproductive cough accompanied by coryza, sore throat, malaise, sweating, and fever generally heralds a viral upper respiratory infection. An episode of asthma may begin with cough and wheezing. In contrast, a persistent cough, even if virtually ignored by the patient, may be a harbinger of serious disease (e.g., carcinoma of the lung). In a cigarette smoker, in whom bronchi are chronically irritated, a change in the nature of the cough from nonproductive to productive may signify the onset of a serious tracheobronchial infection or pneumonia. Alternatively, a lung neoplasm may present with a dry cough that not only persists and intensifies but also gradually becomes associated with systemic manifestations (e.g., loss of weight). The implications of dry cough are different from those of productive cough. Before a cough can be regarded as

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Table 27-9 Some Causes and Characteristics of Cough Cause

Characteristics

Sinusitis or nasopharygnitis

Cough following an upper respiratory syndrome or sinus symptoms; sensation of a need to clear the throat; postnasal drip

Acute infections of lungs Tracheobronchitis

Cough associated with sore throat, running nose and eyes

Lobar pneumonia

Cough often preceded by symptoms of upper respiratory infection; cough dry, painful at first; later becomes productive

Bronchopneumonia

Cough dry or productive, usually begins as acute bronchitis

Mycoplasma and viral pneumonia

Paroxysmal cough, productive of mucoid or blood-stained sputum associated with flulike syndrome

Exacerbation of chronic bronchitis

Cough productive of mucoid sputum becomes purulent

Chronic infections of lungs Bronchitis

Cough productive of sputum on most days for more than 3 consecutive months and for more than 2 years Sputum mucoid until acute exacerbation, when it becomes mucopurulent

Bronchiectasis

Cough copious, foul, purulent, often since childhood; forms layers upon standing

Tuberculosis or fungus

Persistent cough for weeks to months, often with blood-tinged sputum

Parenchymal inflammatory processes Interstitial fibrosis and infiltrations

Cough nonproductive, persistent, depends on origin

Smoking

Cough usually associated with injected pharynx; persistent, most marked in morning, usually only slightly productive unless succeeded by chronic bronchitis

Tumors Bronchogenic carcinoma

Cough nonproductive to productive for weeks to months; recurrent small hemoptysis common

Alveolar cell carcinoma

Cough similar to that with bronchogenic carcinoma except in occasional instances, when large quantities of watery, mucoid sputum are produced

Benign tumors in airways

Cough nonproductive; occasionally hemoptysis

Mediastinal tumors

Cough, often with breathlessness, caused by compression of trachea and bronchi

Aortic aneurysm

Brassy cough (Continued)

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Table 27-9 (Continued) Cause

Characteristics

Gastrointestinal Gastrioesophageal reflux (GERD)

Nonproductive cough often following meals or with recumbancy; may (or may not) be accompanied by other symptoms of GERD (e.g., heartburn, a bitter oral taste, belching)

Foreign body Immediate, while still in upper airway

Cough associated with progressive evidence of asphyxiation

Later, when lodged in lower airway

Nonproductive cough, persistent, associated with localizing wheeze

Cardiovascular Left ventricular failure

Cough intensifies while supine, along with aggravation of dyspnea

Pulmonary infarction

Cough associated with hemoptysis, usually with pleural effusion

Medication-induced Angiotensin-converting enzyme (ACE) inhibitors

Nonproductive cough, more common in women, may occur at any time (following soon after drug initiation or with years of use)

nonproductive, the possibility should be weighed carefully that sputum has been produced but swallowed. Failure to probe deeply into this possibility once led to the notion that British and American patients suffered from different types of chronic bronchitis. Improved history taking and interviews discounted this idea. A cough that is productive of purulent sputum is generally a reliable indication of infection in the tracheobronchial tree or lungs. When this symptom is associated with an acute illness, the characteristics of the sputum can be of considerable diagnostic help. Rust-colored sputum, which contains its distinctive coloration from the even dispersion of blood in yellow, purulent sputum was previously seen often in pneumococcal pneumonia but less so today due to the widespread use of antibiotics. The classic description of sputum in Friedlanderâ&#x20AC;&#x2122;s pneumonia is a resemblance to currant jelly; it also contains blood, but it is bright red and more translucent and viscid than the sputum of pneumococcal pneumonia. Purulent sputum with a foul odor usually indicates an anaerobic infection, commonly due to streptococci or Bacteroides in a lung abscess. A persistent cough that is productive of purulent sputum occurs in chronic bronchitis, bronchiectasis, and a variety of other suppurative disorders. Sputum that is mucoid can be a consequence of any long-standing bronchial irritant. Copious sputum production (bronchorrhea) may be a sign of bronchoalveolar carcinoma.

Mechanism The cough begins with a rapid inspiration, followed, in rapid sequence, by closure of the glottis, contraction of the abdominal and thoracic expiratory muscles, abrupt increase in pleural and intrapulmonary pressures, sudden opening of the glottis, and expulsion of a burst of air from the mouth (Fig. 27-13). The high intrathoracic pressures, which often exceed 100 to 200 mmHg, increase the velocity of airflow through the airways, hastening the propulsion of the offending particles and producing the sound of a cough by setting into vibration airway secretions, the tracheobronchial walls, and the adjacent parenchyma (Fig. 27-14). Afferent stimuli for a cough originate in irritant receptors and are conveyed centrally by the vagus, glossopharyngeal, trigeminal, and phrenic nerves (Fig. 27-12). In subjects with an idiopathic, persistent, nonproductive cough, increased sensitivity of the afferent nerves of the airways due to neuropeptides stored in them has been proposed. The vagus nerve carries impulses not only from the larynx, trachea, and bronchi but also from the pleura and stomach. Receptors in the airways are most concentrated in the larynx, diminish in density in the conducting airways, and are absent from the distal airways, enabling the pooling of secretions in the periphery. The glossopharyngeal nerve carries stimuli from the pharynx; the trigeminal nerve, from the nose and paranasal sinuses; the phrenic nerve, from the pericardium and diaphragm. The motor pathways are even more extensive,

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Figure 27-13 Sequence of events during a cough. Simultaneous recordings obtained during a single explosive cough by a normal subject. The three phases of a cough are identified by the boxes at the bottom of the figure. They correspond to (1) a deep initial inspiration, (2) compression of air in the lungs and airways by forceful contraction of the expiratory muscles coupled with tight closure of the glottis and opening of the larynx, and (3) sudden explosive expiration followed by narrowing of the glottis and return of the larynx to its normal inspiratory position. (From Yanagihara, von Leiden, Werner-Kukuk: Acta Otolaryngol 61:495–510, 1965.)

comprising not only the cranial and phrenic nerves but also the nerves to the muscles of the rib cage and the accessory muscles. Additional impulses from chemoreceptors are located in the esophagus and carried by the phrenic nerve. The effectiveness of a cough is strongly influenced by the lung volume at which it occurs. As indicated elsewhere in

Approach to the Patient with Respiratory Symptoms

this volume, cough only removes particles toward the mouth (“downstream” from the “equal pressure points”). In healthy persons at high lung volumes, the equal pressure points are located in the larger airways; they move toward the alveoli (“upstream”) as lung volume decreases. A series of coughs without any intervening inspiration moves the equal pressure points even closer to the small airways, helping to clear the depths of the lungs. The cough reflex may be impaired by interrupting or blunting any step in the sequence. Irritant receptors can be damaged by a local destructive process (e.g., bronchiectasis), or their sensitivity can be diminished by narcotics or anesthetics. The reflex pathways can be damaged as part of a neurological disease. Tracheostomy, which eliminates glottic closure, decreases peak intrapulmonary pressures. Contraction of the respiratory muscles can be impaired by weakness due to illness, age, or neuromuscular disease. In general, as long as the patient can achieve maximum expiratory pressures greater than about 60 cm H2 O, the peak flow will suffice to produce effective coughs.

Circulatory Consequences The increase in intrathoracic pressure that is part of the cough mechanism exerts considerable circulatory effects. However, because the increase in intrathoracic pressure is accompanied by an equal rise in vascular (and cerebrospinal fluid) pressures, distending pressures on the vessels of the heart, lungs, and other vital organs are unaltered, so they are normally spared the ill consequences of marked swings in transmural pressures. The increase in intrathoracic pressure is accompanied by reflex vasodilation of systemic arteries and veins. Both of these effects contribute to a decrease in cardiac output. In patients with cor pulmonale and right heart failure, cough impedes systemic venous return and may result in syncope.

Posttussive Syncope

Figure 27-14 Effects of tracheal narrowing during a cough. The forced expiratory effort during coughing causes invagination of the noncartilaginous part of the intrathoracic trachea by the high intrathoracic pressure. Air rushing with a high linear velocity through the exceedingly narrow trachea dislodges the material to be dispelled and propels it into the throat. (From Comroe: Physiology of Respiration. St. Louis, Mosby-Year Book, 1965, p 122.)

Charcot recognized the syndrome of posttussive syncope in individuals without underlying cardiopulmonary disease 100 years ago. Originally conceived of as a form of epilepsy or a consequence of a laryngeal reflex, it is now attributed to the same circulatory consequences of raised intrathoracic pressures that coughing evokes in a normal person. However, the patient with cough syncope probably coughs more forcefully and longer than do normal persons. The syncope usually develops within a few seconds after the onset of a paroxysm of coughing and ends quickly once the coughing has stopped. Return to consciousness is without sequelae unless the subject falls and is injured during the faint. Posttussive syncope nearly always occurs in men, probably because they generate a higher intrathoracic pressure and much more profound decrease in cardiac output than do women. It is not clear why this type of fainting occurs in the supine as well as the upright position; this occurrence suggests that the reduction in cerebral blood flow during posttussive

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syncope reflects more than interference with cardiac output. The extent to which intense reflex vasodilation contributes to posttussive syncope is unclear.

Etiology The most common causes of chronic cough (defined as lasting longer than 8 weeks) are postnasal drip (recently termed upper airway cough syndrome), gastroesophageal reflux disease (GERD), and asthma. In patients treated with angiotensinconverting enzyme (ACE) inhibitors, the drug is very often the cause of a chronic cough (even one developing after years of uncomplicated use). A deliberate evaluation can identify the cause in the vast majority of patients. Usually, the diagnosis is established only by the resolution of the cough following a specific intervention (Fig 27-15). For example, cough that disappears after antihistamines and inhaled nasal steroid treatment for allergic rhinitis can logically be attributed to postnasal drip. Similarly, cough may disappear after interventions for GERD (e.g., the use of H2 -blockers) or asthma (use of inhaled bronchodilators and steroids). A cough that resolves after discontinuation of an ACE inhibitor was presumably caused by the drug. Although the more common causes of chronic cough are usually benign, a chest radiograph is nonetheless warranted at the beginning of the evaluation of a chronic cough to assess for possible worrisome causes.

HEMOPTYSIS The coughing up of blood is termed hemoptysis. The material and amount produced varies from mere blood streaking of expectorated sputum to massive volumes of pure blood. Massive hemoptysis has been variably defined according to the volume, but implies a life-threatening process requiring immediate evaluation and treatment. An initial decision faced by the physician who is told that blood has been coughed up is whether to conclude that the blood is coming from the respiratory tract. Any portion of the respiratory tract can be the source of bleeding including a main bronchus, the lungs, or the nose or throat. On occasion, blood from the nose and throat is inhaled and then expectorated. As long as this possibility is kept in mind, bleeding that originates in the nose, throat, or larynx is not apt to be overlooked. An additional consideration is distinguishing hemoptysis from hematemesis (vomited blood). Even if the blood is aspirated and then coughed up, the patient can usually tell if the blood originated in the respiratory or alimentary tract. The appearance of the bloody material also helps to distinguish between hemoptysis and hematemesis: blood that originates in the airways is usually bright red, is mixed with frothy sputum, has an alkaline pH, and contains alveolar macrophages that are laden with hemosiderin; in contrast, blood from the stomach usually is dark, has an acid pH, contains food particles, and often occurs in patients with a long history of gastric complaints.

Blood arising from the bronchial arteries is more often the source of massive hemoptysis, owing to its higher perfusion pressure than blood from the pulmonary circulation. The bronchial circulation may be the source of lifethreatening bleeding, for example, in patients with bronchiectasis in whom the vessels frequently become distorted and easily ruptured. The differential diagnosis of hemoptysis includes disorders arising within the airways and the pulmonary parenchyma. Inflammatory processes (e.g., bronchitis and bronchiectasis) and neoplasms are the most common causes of blood arising within the airways. Within the pulmonary parenchyma common causes are infections, such as tuberculosis, pneumonia, Aspergillus, or lung abscess. Inflammatory processes that involve the lung, such as Wegnerâ&#x20AC;&#x2122;s granulomatosis or Goodpastureâ&#x20AC;&#x2122;s syndrome are also important causes of hemoptysis (Fig. 27-16). Bleeding may be iatrogenic, as for example, after a lung biopsy or when chemotherapy for bone marrow transplantation evokes diffuse alveolar hemorrhage. Vascular disorders, including pulmonary embolism, arteriovenous malfunctions, and mitral stenosis are also to be considered in the differential diagnosis. The list of causes of hemoptysis is long and diverse (Table 27-10). The clinical setting is usually helpful in identifying the cause. Hemoptysis before middle age usually brings to mind infections; after 40 to 45 years of age or if there is a history of smoking, bronchogenic carcinoma heads the list. In patients left with a pulmonary cavity after pulmonary disease that has healed (e.g., tuberculosis), and in regions of the country where pulmonary fungal diseases are prevalent, a bout of hemoptysis is occasionally the first sign of the disease. In patients who have a predisposing cause, such as oral contraceptives or chronic heart failure, pulmonary embolism must be considered. The evaluation of hemoptysis involves a careful history, physical examination, and a chest radiograph. Initial studies also include a complete blood count. The degree of anemia may influence the rapidity of further testing, and thrombocytopenia may be a contributing factor to hemoptysis. Rapid correction of anemia, thrombocytopenia, or coagulopathy with the transfusion of appropriate blood products may be required promptly depending upon the clinical status and degree of abnormality. Similarly, measurement of coagulation times are important. Studies of renal function and a urinalysis may be indicated when a systemic process which causes a pulmonary-renal syndrome is a possibility. Sputum should be zealously collected and, depending on the circumstance, microbiologic cultures and stains or cytologic examination should be performed. Depending on whether a cause is identified, and the risk factors for a serious cause of bleeding, the evaluation next involves additional studies to search for a source. Because hunting for the cause and the source of bleeding is generally uncomfortable for the patient and often expensive, the intensity of the search depends on the circumstances. For example, rarely is a search for the bleeding site needed in a patient with acute bronchitis, pneumonia, or

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Chronic Cough

Investigate and Treat

History, examination, chest X-ray

A cause of cough is suggested

Smoking ACE-I

Discontinue

Upper Airway Cough Syndrome (UACS) (i.e., postnasal drip) Inadequate response to optimal Rx

Empiric treatment

No response

Asthma Ideally evaluate (Spirometry, bronchodilator, reversibility, bronchial provocation challenge) or empiric treatment Non-asthmatic eosinophilic bronchitis (NAEB) Ideally evaluate for sputum eosinophilia or empiric treatment Gastroesophageal Reflux Disease (GERD) Empiric treatment For initial treatments see box below

Inadequate response to optimal Rx

Further investigations to consider: • 24 h esophageal pH monitoring • Endoscopic or Videofluoroscopic Swallow Evaluation • Barium esophagram • Sinus imaging • HRCT • Bronchoscopy • Echocardiogram • Environmental assessment • Consider other rare causes

Important General Considerations Optimize therapy for each diagnosis

Initial Treatments

Check compliance

Asthma — ICS, BD, LTRA

Due to the possibility of multiple causes maintain all partially effective treatment

UACS - A/D

NAEB- ICS GERD — PPI, diet/lifestyle

Diagnosis is often made only with clinical assessment of response to empiric treatment

Figure 27-15 Algorithm for the evaluation of chronic cough lasting 8 weeks in adults. ACE-I = ACE inhibitor; BD = bronchodilator; LTRA = leukotrienes receptor antagonist; PPI = proton pump inhibitor; ICS = inhaled corticosteroid; A/D = antihistamine/decongestant; HRCT = high-resolution computed tomography. (After Irwin RS, et al: Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 129(1 Suppl):1S–23S, 2006, with permission.)

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Figure 27-16 Causes of hemoptysis. A. Old tuberculosis cavities in right apex. They were removed surgically to control hemoptysis. B. Goodpastureâ&#x20AC;&#x2122;s syndrome. C. Fungus ball in coal minerâ&#x20AC;&#x2122;s pneumoconiosis. Sagittal section of lung. (Courtesy of J. Gough.) D. Fungus ball due to aspergillosis in old tuberculosis cavity. Recurrent hemoptysis was arrested by surgical removal of right upper lobe.

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Table 27-10 Some Common Causes of Hemoptysis Infections Bronchitis Tuberculosis Fungal infections Pneumonia Lung abscess Bronchiectasis Neoplasms Bronchogenic carcinoma Bronchial adenoma Cardiovascular disorders Pulmonary infarction from thromboembolism Mitral stenosis Trauma Foreign body Hematologic/immunologic Blood dyscrasia Goodpasture’s syndrome

bronchopulmonary suppuration. But as a rule, unless the cause is evident, a full-scale investigation is mandatory, particularly if this is not the first episode. Patients with hemoptysis and a history of tobacco smoking, individuals who are more than 40 years of age, or those who experience hemoptysis that lasts for more than 1 week are at greater risk for a worrisome cause and warrant additional studies. A high-resolution computed tomography (HRCT) of the chest is usually the next step if the patient has no history of tobacco use or if the plain chest radiograph suggests a parenchymal abnormality, such as bronchiectasis or arteriovenous malformation. Patients with a history of tobacco use or other risk factors for a malignancy warrant fiberoptic bronchoscopy. In practice, HRCT and bronchoscopy are often complementary for visualizing abnormalities that are not apparent on plain chest radiographs. Patients with chronic bronchitis and at low risk for malignancy, or in whom the chest radiograph is normal or identifies the cause of hemoptysis (e.g., epistaxis or pneumonia) can usually be treated initially for bronchitis with follow-up appraisals to show prompt resolution of hemoptysis. However, should hemoptysis recur, further evaluation is required.

Neoplasms Nonmassive hemoptysis is common in bronchogenic carcinoma; less frequently it is the cause of massive hemoptysis. The likelihood of a neoplastic cause of hemoptysis is greatly

Approach to the Patient with Respiratory Symptoms

increased in a cigarette smoker. Usually a troublesome cough and vague chest pain precede and accompany the hemoptysis. For hemoptysis to occur, the lesion must communicate with the airways. Most often the bleeding is a consequence of ulceration caused by an expanding tumor; sometimes it is due to a pneumonic process or to an abscess in the lung behind the obstructive lesion. Hemoptysis rarely complicates metastatic tumors of the lungs, since few (primarily renal and colon carcinomas) intrude on the airways until preterminal. Not only malignant but also benign tumors of the lung cause bleeding. The classic example is bronchial carcinoid, which often causes bleeding that is generally difficult to arrest.

Infections Hemoptysis can accompany a severe infection anywhere from the top to the bottom of the respiratory tract. It is uncommon in the usual viral or bacterial pneumonia. Conversely, it is not uncommon in the pneumonia that complicates bronchogenic carcinoma or in the pneumonia that is caused by staphylococci, influenza virus, or Klebsiella. The infecting organism determines the appearance and composition of the material that is expectorated with the blood. As indicated above, in pneumococcal lobar pneumonia, the sputum at the onset is characteristically rusty-looking, but sometimes it is faintly or grossly bloody. In staphylococcal pneumonia, the blood is mixed with pus. In Klebsiella pneumonia, the bloody sputum often resembles currant jelly. Brisk bleeding is common in lung abscess; the blood is mixed with copious amounts of foul-smelling pus. In lung gangrene, blood is associated with necrotic lung tissue. Bleeding is common in bronchiectasis. Because it usually originates in a bronchial artery, bleeding is often brisk. While most episodes stop spontaneously, it tends to recur and can be life-threatening. Fungal infections of the lungs can cause hemoptysis (Fig. 27-16). As in tuberculosis, hemoptysis is generally a consequence of a continuing necrotizing and ulcerating inflammatory process or of bronchiectasis. The most common fungal disorder associated with hemoptysis is a “fungus ball” that resides either in a healed tuberculous or bronchiectatic area or in a cystic residue of sarcoidosis. Aspergillus is the usual fungal agent; less often another fungus (e.g., Mucor) is the cause. The most common source of hemoptysis used to be an active tuberculosis cavity. But currently tuberculous pneumonia is a more common cause of hemoptysis than is active cavitation. Despite the increasing frequency of tuberculosis, hemoptysis is uncommon because of effective antituberculous therapy. If tuberculosis is allowed to progress to the point of extensive fibrosis and causation, or becomes complicated by bronchiectasis, hemoptysis can be troublesome and persistent. Hemoptysis from a Rasmussen’s aneurysm involves the erosion of a small or medium-sized pulmonary artery into an adjacent tuberculosis cavity. The “right middle lobe syndrome” is frequently associated with hemoptysis. It is due to a partial or complete

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obstruction of the right middle lobe bronchus, resulting in atelectasis and/or pneumonitis in the right middle lobe. The obstruction is more often caused by scarring and/or inflammation than by physical compression of the lumen by an enlarged lymph node. The cause is usually infectious; the infection can be tuberculosis. In parts of the world where amebiasis is endemic, hemoptysis follows perforation into the airways of an amebic lung abscess. The sputum resembles anchovy sauce.

Cardiovascular Disorders Pulmonary congestion and alveolar edema sometimes produce blood-tinged sputum. In chronic pulmonary congestion, secondary to left ventricular failure or to mitral valve disease, alveolar macrophages in the sputum are often laden with hemosiderin (“heart failure cells”). In severe congestion and edema, the sputum is often pink and frothy. Usually there is no difficulty in recognizing that inadequate performance of the left ventricle is the cause of the bloody sputum. Pulmonary thromboembolism can produce hemoptysis when associated with infarction (Fig. 27-17). The hemoptysis of pulmonary infarction is usually associated with pleuritic pain and often with a small pleural effusion because of the peripheral location of the infarct. Tight mitral stenosis is sometimes first manifested by a bout of brisk, bright-red hemoptysis that is difficult to con-

trol. The source of the bleeding is the submucosal bronchial veins, which proliferate considerably in this disorder. Massive hemoptysis due to mitral stenosis is a medical emergency and is an indication for surgical intervention to relieve the obstruction at the mitral valve. Hemoptysis from other circulatory disorders is much less common. Occasionally, an aortic aneurysm penetrates into the tracheobronchial tree, causing death by exsanguination and asphyxiation. An extraordinary event is the communication of an arteriovenous fistula with a small airway, causing bleeding that is exceedingly difficult to arrest.

Trauma Hemoptysis follows a variety of chest injuries: puncture of a lung by a fractured rib, contusions of a lung by severe blunt trauma to the chest, and necrosis of the lining of the tracheobronchial tree by inhaled fumes or smoke. Blunt trauma from the steering wheel during an automobile collision sometimes lacerates or fractures the tracheobronchial tree. Stab or gunshot wounds often tear the lungs or airways. On occasion, mucosal lacerations in the course of severe coughing evoke hemoptysis. After pneumonectomy or lobectomy, a large hemothorax occasionally empties into the airways. This is an alarming and ominous event. Its imminent occurrence is often heralded by the expectoration of blood-stained sputum after a paroxysm of coughing. The hemothorax must be promptly evacuated and the bronchus surgically repaired. Hemoptysis within a few weeks to months after pneumonectomy has different implications: recurrence of tumor, granulation tissue, or bronchial sutures. Prompt bronchoscopy is necessary for accurate appraisal of the situation.

Miscellaneous

Figure 27-17 Hemorrhagic pulmonary infarcts. Several subpleural areas of infarction are clearly demarcated.

Other causes of hemoptysis are listed in Table 27-10. They vary greatly in severity, urgency, and prognosis. Sometimes the cause is obscure, as in the occasional instance of hemoptysis that accompanies menstruation (“catamenial hemoptysis”). An aspirated foreign body produces bleeding by damaging the mucosa on impact; if allowed to remain in place, it sometimes causes bronchiectasis, which in turn may cause bleeding. Pulmonary calcific foci, either in the pulmonary parenchyma or in lymph nodes, sometimes cause hemoptysis by ulcerating into a bronchus. Blood dyscrasias, notably thrombocytopenic purpura and hemophilia, and the therapeutic use of anticoagulants are occasional causes of hemoptysis. In areas where scurvy is endemic, vitamin C deficiency is a major cause. Hemoptysis in Goodpasture’s syndrome (Fig. 27-16) or in idiopathic hemosiderosis is life-threatening. This grim prospect has led to an aggressive therapeutic approach, including use of plasmapheresis and immunosuppressive agents.

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Management of Massive Hemoptysis The first priority in the care of a patient with life-threatening hemoptysis is to protect the airway and prevent asphyxiation. Intubation should be performed promptly, and consideration given to selective intubation of one lung in order to protect it from spillage of blood from the other. When the site of bleeding is known, one simple, initial bedside maneuver is to place the involved side in a dependent position in order to protect the uninvolved lung. Bronchoscopy should be performed promptly in order to identify the source. This may also allow bronchoscopic interventions such as the placement of a balloon catheter to isolate the involved segment, lavage with iced saline, or the application of topical epinephrine (1:20,000). Bronchoscopic localization may help to guide attempts at arresting the bleeding by angiographic embolization. If these modalities fail to stop the bleeding, surgical exploration may be required. Not surprisingly, emergency procedures are accompanied by a high mortality. None of the approaches has been rigorously studied and the choice is frequently dictated by the urgency, local experience, and availability of bronchoscopy.

CYANOSIS Cyanosis refers to a bluish discoloration of the skin that is caused by increased amounts of reduced hemoglobin in the subcapillary venous plexus. The discoloration is most apparent in the lobes of the ears, the cutaneous surfaces of the lips, and the nail beds. In patients with dark skin, the mucous membranes and the retina are important sites to examine for cyanosis. Unless flow through the skin is slowed, as in heart failure, cyanosis implies arterial hypoxemia. Cyanosis does not appear in carbon monoxide poisoning or in severe anemia even though arterial O2 content is extremely low. This is because there is an insufficient amount of reduced hemoglobin present for the cyanotic discoloration to be visible. The presence of abnormal pigments in blood, such as methemoglobin or bilirubin, complicates the detection of cyanosis.

Capillary O2 Content An increase in the amount of reduced hemoglobin in the capillaries of the skin, as elsewhere, results from inadequate oxygenation of arterial blood, excessive removal of O2 from capillary blood (as when the circulation through a region is slowed by vasoconstriction or a very low cardiac output), or from a combination of the two. The concentration of reduced hemoglobin in the skin capillaries must reach about 5 g/dl before cyanosis becomes discernible. Thus, in severe pernicious anemia, in which hemoglobin concentrations are exceedingly low (on the order of 3 to 4 g/dl), although virtually all the hemoglobin can be reduced in traversing the skin capillaries, an insufficient amount of reduced hemoglobin remains to produce a visible discoloration. Oppositely, the polycythemic patient develops cyanosis at a higher arterial O2 saturation than does the normal individual.

Approach to the Patient with Respiratory Symptoms

The combination of intense vasoconstriction and excess reduced hemoglobin is responsible for the distinctive gray or heliotrope color that is frequently seen in patients with circulatory collapse and severe pulmonary edema.

Causes of Cyanosis Several types of cyanosis are usually identified according to the underlying mechanism. They include peripheral cyanosis, cyanosis arising from pulmonary disease, cyanosis from venous admixture, and cyanosis due to abnormal pigments in the blood. Peripheral Cyanosis This type is secondary to abnormally large extraction of O2 from blood flowing through peripheral capillaries. The most common cause is a diminished cardiac output associated with peripheral vasoconstriction. Not only the hands and feet but also the tip of the nose becomes blue in severe heart failure. Indeed, in patients with intractable heart failure, necrosis occasionally develops at the tip of the nose. Peripheral vasoconstriction per se, as in Raynaudâ&#x20AC;&#x2122;s disease, also produces cyanosis of the nail beds. Cyanosis in Pulmonary Disease Patients with chronic bronchitis and emphysema characteristically manifest derangements in ventilation-perfusion relationships. In some, arterial hypoxemia results. In patients with diffuse interstitial fibrosis, normal arterial oxygenation at rest is succeeded by arterial hypoxemia, and sometimes by cyanosis, during exercise. Another cause of arterial hypoxemia is the syndrome of alveolar hypoventilation in patients with normal lungs. In any of these situations, cyanosis is intensified if heart failure supervenes and slows blood flow through the skin (i.e., decreases O2 delivery). Cyanosis Due to Venous Admixture In patients with intracardiac right-to-left shunts, cyanosis arises from a mixture of venous and arterial blood. The effect of venous admixture is particularly striking if the O2 content of mixed venous blood is inordinately low, as in some types of congenital heart disease and in severe heart failure. Often secondary polycythemia contributes to the cyanosis. On occasion, regional cyanosis is diagnostic. For example, in patent ductus arteriosus with reversal of blood flow, the lower extremities are deeply cyanotic, whereas the upper extremities are virtually normal in color. Cyanosis Due to Abnormal Pigments in Blood Methemoglobinemia is an occasional cause of cyanosis. Methemoglobinemic blood is chocolate brown, and spectrophotometric examination of blood reveals the characteristic pigment. Arterial blood examination discloses a normal PO2 . The cause of methemoglobinemia may be hereditary (i.e., due to the presence of hemoglobin M or a deficiency in methemoglobin reductase) or, more often, acquired (e.g.,

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by exposure to chemical agents such as aniline dyes, chlorates, nitrates, and nitrites); or methemoglobinemia may result from drugs such as dapsone acetanilide, nitroglycerin, phenacetin, and primaquine. Nitrates are a common cause of methemoglobinemia. Nitrates are reduced to nitrites by bacteria in the intestinal tract. Excessive use of nitroglycerin, an organic nitrate, leads to methemoglobinemia. In methemoglobinemia, the ferrous iron is oxidized to ferric iron, rendering the hemoglobin molecule incapable of binding O2 or CO2 . Methemoglobin is formed continuously in the normal erythrocyte, but its level within the cell is kept low (less than 2 percent) by intracellular reductive mechanisms. High levels of methemoglobin result from hereditary abnormalities (e.g., a deficiency in methemoglobin reductase) or from exposure to drugs or chemicals that increase the rate of oxidation beyond the reductive capacity of the erythrocytes. Clinical manifestations of methemoglobinemia vary with the blood levels. Concentrations of methemoglobin between 10 and 25 percent usually cause asymptomatic cyanosis. When these levels are exceeded, dizziness, fatigue, and headache appear. Because of the normal methemoglobin reductase and Nicotinamide adenine dinucleotide (NADH) generated during anaerobic glycolysis, treatment beyond discontinuation of an offending drug is often unnecessary unless serious manifestations occur (angina, stupor, or coma). Then methylene blue is given intravenously (1 to 2 mg/kg as a 1 percent solution) over 5 to 10 min. Cyanosis should disappear within 1 h; if not, the dose should be repeated. Larger doses of methylene blue engender the risk of aggravating the methemoglobinemia. Methylene blue should not be used in patients with glucose-6-phosphate dehydrogenase deficiency (common in certain African-American and Mediterranean populations) as it cannot be metabolized and may result in accidental toxicity.

CLUBBING Clubbing of the digits is a classic finding in medicine that dates back to Hippocratesâ&#x20AC;&#x2122; awareness of the association between characteristic changes in the fingertips and empyema. Occasionally it constitutes a valuable clue to clinically unapparent disease of the lungs and pleura. Clubbing of the fingers designates the selective bulbous enlargement of the distal segments of the digits due to an increase in soft tissue (Fig. 27-18). Although most often it is painless, clubbing remains an important finding as its presence should signal an evaluation for potential serious causes. When full-blown, clubbing is easy to recognize: (1) the nails, particularly the index finger, become abnormally curved in the longitudinal and coronal planes; (2) the hyponychial angle, viewed in profile, becomes blunted, often in conjunction with softening and sponginess of the base of the nail; and (3) the undersurface of the terminal digit becomes large and bulbous. Early stages of clubbing are subtle and generally diffi-

cult to diagnose. Clubbing often has to be distinguished from simple curvature of the nails and occasionally from chronic paronychia and Heberdenâ&#x20AC;&#x2122;s nodes. A variety of methods have been proposed for quantifying clubbing (e.g., measuring casts of the fingertips), but none has become popular. Clubbing is generally acquired, but it may be hereditary. Acquired clubbing is seen in a wide variety of disorders, both extrathoracic and thoracic (Table 27-1). It is important to recognize that clubbing is not caused by all forms of chronic lung disease. COPD, for example, does not cause clubbing. The presence of clubbing in a patient with COPD should alert the clinician to the possibility of a second process, commonly lung cancer. As a rule, clubbing is bilaterally symmetrical, affecting hands and feet; on occasion, local factors, such as injury of a finger or of the median nerve, may cause clubbing that is confined to a single finger. Rarely, clubbing may be confined to the digits of one hand (e.g., in an ipsilateral pulmonary sulcus tumor that has invaded the brachial plexus or following hemiplegia). In certain types of congenital heart disease, a telltale distribution of clubbing is of considerable diagnostic value. For example, in patent ductus arteriosus associated with reversal of shunt through the ductus, clubbing affects only the toes.

Pathogenesis The pathogenesis of clubbing is unknown, and no suitable animal model of clubbed fingers has yet been developed, largely because so few species other than primates have fingers. A common denominator in the pathogenesis of clubbing appears to be vasodilation of vessels in the fingertip, including formation of the arteriovenous connections. As a result, hydrostatic pressures increase in the capillaries and venules, promoting the transduction of fluid into the interstitium. The reason for this preferential vasodilation is unclear. A popular notion is that a humoral substance escapes normal deactivation by pulmonary capillaries. This theory could account for clubbing in cyanotic congenital heart disease, in various pulmonary diseases in which proliferation of the bronchial circulation occurs, and in hepatic cirrhosis in which pulmonary arteriovenous anastomoses and right-to-left shunts are common. However, it is difficult to relate this theory to the high incidence of clubbing in subacute bacterial endocarditis. At present, a single hypothesis that would account for the clubbing that occurs in such diverse disorders as subacute bacterial endocarditis, carcinoma of the lung, hemiplegia, chronic mountain sickness, and purgative abuse is not possible. Indeed, it seems likely that clubbing of the digits is a stereotyped consequence of diverse influences that have in common the capacity to induce marked digital vasodilation and interstitial edema of the soft tissue.

HYPERTROPHIC OSTEOARTHROPATHY Occasionally, clubbing of the digits is accompanied by hypertrophic osteoarthropathy (HOA), a separate entity both

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Figure 27-18 Clubbing of the digits and hypertrophic osteoarthropathy. A 40-year-old woman developed swelling and tingling of the fingertips in association with painful swelling of both knees. She was a heavy smoker (36 packyears) and had an 8-month history of a dry cough. A. Clubbing of all fingers. B. Index finger. C. Left hilar mass that proved to be a primary adenocarcinoma of the lung. D. Subperiosteal formation of new bone on the medial aspect of the diaphysis of the femur. E. Bone scan, using 99m Tc methylene diphosphonate. An abnormal accumulation of isotope is seen in the area of new bone (arrow).

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clinically and radiographically. Clinically, HOA is manifested by pain and swelling of the soft tissues over the distal ends of the long and tubular bones. Radiographically, the distinctive feature of HOA is the formation of new bone beneath the periosteum of the distal diaphyses of the long bones of the extremities (Fig. 27-18). The most common disorder associated with HOA is carcinoma of the lung. The incidence is about 5 percent and is unrelated to the cell type of the cancer, except that smallcell carcinoma is rarely implicated; a peripheral carcinoma of the lung is slightly more common than a central one. Joint symptoms precede the local signs of tumor in about onethird of the cases; the interval is sometimes as long as 2 years. Pulmonary metastases rarely cause HOA. Pulmonary tuberculosis is seldom, if ever, associated with HOA. Cystic fibrosis and idiopathic pulmonary fibrosis can be accompanied by HOA. Pregnancy can rarely be a cause of HOA, with symptoms resolving promptly with delivery. As in the case of clubbing of the digits, theories about pathogenesis tend to focus on humoral factors generated elsewhere. However, a neurogenic theory has also been advanced on the basis of two types of observations: (1) in a few patients, vagotomy has relieved the symptoms of inoperable carcinoma of the lung and led to regression of the bony lesions; and (2) in keeping with the observations on the few patients, vagotomy in dogs is usually followed by a decrease in blood flow to the limbs. At present, neither theory has much convincing support, but both suggest future directions for exploration. In contrast to clubbing of the digits, which is rarely painful, HOA associated with carcinoma of the lung often causes severe rheumatic symptoms. These symptoms vanish after resection of the carcinoma, even though clubbing usually remains. In patients who are treated with radiotherapy for unresectable carcinoma, pain in the vicinity of the joints usually decreases greatly and usually does not recur even if metastases develop to the lungs or elsewhere.

THORACIC PAIN First thoughts about chest pain almost invariably turn to the pain of myocardial ischemia. However, cardiac pain is often distinguishable from other types of chest pain because of its viselike nature; its characteristic radiation to the left arm, shoulder, or neck; and its lack of relation to breathing. Extracardiac painful sensations can arise from various sites within the thorax, most often from the pleura, the lungs, and the chest wall. Pain may also be referred to the thorax as a result of GERD.

Pleuritic Pain The most characteristic pain associated with the respiratory apparatus is pleural pain. It originates in the parietal pleura and endothoracic fascia; the visceral pleura is insensitive to pain. In contrast to the deep, oppressive substernal pain of

myocardial infarction, pleuritic pain is identified by the patient as being close to the thoracic cage. It is predominantly an inspiratory pain reflecting the stretching of inflamed parietal pleura during movement of the thorax; coughing or laughing is exceedingly distressing; the patient often clutches the chest to minimize its excursion. The pain is usually local, but sometimes it spreads along the course of the intercostal nerves that supply the affected area. Irritation of the diaphragmatic pleura by an inflammatory process either below or above the diaphragm often causes ipsilateral shoulder pain when the central portion of the diaphragm is involved; sometimes the pain is referred to the abdomen when the outer diaphragmatic pleura is irritated. As a rule, pleural pain is part of a syndrome of pleural inflammation that includes malaise and fever; an important exception to this generalization is the pleural pain of pulmonary infarction, which is often unassociated with any premonitory signs. In addition to inflammation and malignant etiologies, pleuritic pain occurs with pneumothorax.

Pulmonary Pain A second distinctive type of respiratory chest pain accompanies a tracheitis or tracheobronchitis. The pain is searing and is most pronounced after cough. Invariably this central chest pain is associated with evidence of upper respiratory infection. An uncommon type of chest pain is associated with pulmonary hypertension. It is usually absent at rest and appears during exertion. The pain is substernal and is invariably associated with dyspnea; it subsides promptly when exercise stops. It is often mistaken for left heart angina until the presence of pulmonary hypertension is uncovered. It may be due to right ventricular strain and ischemia.

Chest Wall Pain Pain in the chest is a common clinical problem. It may arise from within the thorax (the heart, pericardium, lungs, pleura, chest wall) or be referred from elsewhere (e.g., from below the diaphragm). Characteristic patterns and associations may help to clarify the source of the pain. Pleural pain is generally associated with fever or dyspnea. Most often it is abrupt in onset, unilateral, and incapacitating. As a rule, it affects the lower part of the chest, but occasionally it is referred to the shoulder or abdomen. Almost invariably, pleural pain is aggravated by deep breathing or coughing. The patient tends to splint the chest on the affected side. Tachypnea and shallow tidal volumes are a consistent pattern. Musculoskeletal pain arising in the chest that is also aggravated by breathing may be confused with pleuritic pain. It is rarely severe and incapacitating, is often bilateral, and generally is intensified by changes in body position or flexing the thorax. The affected muscles are often tender to gentle pressure. A fractured rib is often identified as the source of pain by a history of a fall, injury, or trauma. Additional clues

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Figure 27-19 Pulmonary sulcus tumor. A. Chest radiograph. B. Relationships of apex of the lung to adjacent bony structures. C. Lateral view of area occupied by apex of lung, showing proximity not only to nerves of brachial plexus but also to sympathetic chain and to blood vessels. A mass that grows posteriorly and laterally can encounter sympathetic chain and bony structures; superiorly, the axillary vessels, brachial plexus, and bony structures; anteriorly, the subclavian vein and its tributaries. (From Pernkopf: Atlas of Topographical and Applied Human Anatomy. Philadelphia, WB Saunders, 1964, p 22.)

are point tenderness and crepitus of the affected area, reproduction of the pain upon manual compression of the chest, or radiographic evidence of the broken rib. Pain arising from the large airways is usually burning in nature and retrosternal in location and is disturbing rather than incapacitating. It is aggravated by cough and is commonly accompanied by evidence of a bronchitis. Cold air may be intolerable. The pain of a pulmonary sulcus tumor (Fig. 27-19) is quite distinctive. This unusual location of a carcinoma of the lung was originally described by Pancoast in 1932 as characterized by pain along the distribution of the eighth cervical and the first and second thoracic nerves, Hornerâ&#x20AC;&#x2122;s syndrome,

local destruction of bone by the tumor, and atrophy of hand muscles. The chest radiograph is distinctive in showing a small, sharply defined shadow at one apex. Destruction of one or more of the upper three ribs posteriorly and of their adjacent transverse processes may also be observed.

Cardiac Pain Attention was called above to the pain of myocardial ischemia. Another type of cardiac pain is that of pericarditis. Pericardial pain is often aggravated by deep breathing and, almost invariably, is accompanied by a telltale rub that is synchronous

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with the heartbeat. The discomfort may be relieved by leaning forward. The postcommissurotomy (postpericardiotomy) syndrome is characterized by chest pain that develops within a few days to weeks after cardiac surgery or pericardiotomy. The pain is usually sudden in onset and substernal, with radiation to the left side of the neck; often it is aggravated by deep breathing. Low-grade fever and a high sedimentation rate are regular concomitants. Chest pain can also be troublesome in patients who have undergone cardiac transplantation. The diagnosis is usually self-evident when account is taken of the antecedent history of cardiac surgery. Indeed, confusion is more apt to arise with the pain of myocardial infarction than with respiratory causes of chest pain.

Miscellaneous Pain Other structures in the mediastinum can be the source of chest pain. Noteworthy are the types of pain arising from the esophagus (peptic esophagitis) and dissection of the aorta. Their patterns and intensity help to distinguish them from respiratory pain. Esophageal disease is typically accompanied by a burning pain, frequently after eating. Acid reflux may worsen with recumbency. Aortic dissection is often described with a sharp, tearing sensation of acute onset with radiation to the shoulder; these are often signs of impending cardiovascular collapse. Arthritis of the cervical spine is a common cause of thoracic pain. Usually the cause is quite clear because of the characteristic distribution of the pain. Cervical spondylosis occasionally causes severe pain in the chest and arms, but it is more apt to mimic myocardial infarction than is respiratory pain. A metastatic tumor to the thoracic spine often causes bilateral symmetric pain; there is often discomfort to palpation over the affected area. Unilateral pain, along the distribution of an intercostal nerve, is characteristic of herpes zoster before the appearance of the skin eruption and is often described as an intense burning sensation. Anxiety can produce or intensify chest pain. Usually, pain related to anxiety is accompanied by dyspnea and hyperventilation. Manifestations of vasomotor instability, such as excessive palmar sweating, flushing, and tachycardia, may accompany the complaint of chest pain due to anxiety. Rarely does the pain conform to a characteristic or consistent pattern. Anxiety also interferes with the quantification of pain originating in a somatic lesion and with its management.

FEVER In the patient with lung disease, fever usually, but not invariably, signifies infection. When the lung disease is chronic, as in bronchitis and emphysema, a bout of acute bronchitis usually elicits only a modest fever, even though the sputum turns purulent. In contrast, an acute pneumonia of lung abscess may be associated with high fever.

The possibility that fever is due to infection lends urgency to the situation. Elsewhere in this book, the patterns of acute pulmonary infection are considered with particular attention to systemic effects, chest radiography, white blood cell count, sedimentation rate, and sputum examination. Often overlooked at the outset is miliary tuberculosis, which occasionally escapes detection on the initial chest radiograph. Favoring this diagnosis is a history of recent contact with a patient experiencing active tuberculosis, general malaise, easy fatigability, and anorexia during the previous few weeks. This insidious onset differs strikingly from the more sudden onset of acute pneumonia. Neoplasms are also associated with fever. In certain neoplasms, such as carcinoma within a bronchus, the fever is generally a secondary effect attributable to infection distal to obstruction; necrosis within the tumor is a less common cause. In others, such as hypernephroma, fever and chills are striking, even though evidence of infection is absent. A mesothelioma of the pleura is often associated with fever. Presumably, in patients with neoplasms who have no evidence of infection, necrosis within the tumor leads to the elaboration of pyogenic substances within and around the tumor. Hypersensitivity pneumonitis (extrinsic allergic alveolitis) is sometimes followed by fever as well as by pulmonary disability after exposure to the offending antigen. In contrast to the pulmonary disorders in which fever is a characteristic feature, pulmonary sarcoidosis is uncommonly associated with fever unless there is extrapulmonary involvement, such as lymphadenopathy or erythema nodosum. Nor is pneumoconiosis associated with fever unless complicated by necrosis in the midst of conglomerate fibrosis or by superimposed tuberculosis. Among the other extensive disorders of the lungs that cause no fever (and few systemic complaints) are idiopathic pulmonary fibrosis, lymphangitic carcinomatosis, multiple pulmonary metastases, alveolar proteinosis, idiopathic pulmonary hemosiderosis, and alveolar microlithiasis.

RADIOLOGIC EVALUATION The radiologic evaluation of the patient presenting with respiratory symptoms is dealt with in considerable detail elsewhere in this book (see Chapter 30). Over the years, the chest radiograph has become an invaluable tool, not only for diagnosis but also for following the result of treatment (Fig. 27-20) and for directing interventions. The value of routine screening films in asymptomatic subjects (e.g., as part of annual physicals or in chronic cigarette smokers to detect cancer) is still a matter of debate. The diagnostic yield of such studies has not been impressive. In contrast, the chest radiograph is an integral component of the initial evaluation of the patient with new respiratory symptoms. In recent years, the conventional chest radiograph has been supplemented by a succession of imaging techniques, such as computed tomography, magnetic resonance imaging,

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and positron emission tomography. Although these powerful tools are generally used as complementary techniques, they often assume primary roles (e.g., examination of the mediastinum for lymphadenopathy or invasion of the chest wall in a patient with carcinoma of the lung). As successive improvements in these techniques continue to be made, the future seems to hold even brighter prospects for these noninvasive methods.

COMMON CHRONIC PULMONARY DISEASES The great majority of chronic pulmonary diseases that affect both lungs fall into four categories: chronic obstructive airway diseases, restrictive lung diseases, global alveolar hypoventilation, and obliterative pulmonary vascular diseases.

Chronic Obstructive Airway Disease A

Figure 27-20 Occasional response of interstitial lung disease to corticosteroids. A. Interstitial lung disease in a 67-year-old man before administration of corticosteroids. Widespread interstitial lung disease, more marked on the right. The lung function tests were characteristic of severe restrictive lung disease. B . After corticosteroids. Pulmonary function tests improved dramatically along with clearing of the pulmonary lesions on the chest radiograph.

Obstruction of the airways generally occurs during expiration. Based on expiratory maneuvers, airway obstruction has been categorized by a wide variety of tests (see Chapter 50). But it is remarkable how much information about the obstruction can be obtained from the forced expiratory volume in 1 s (FEV1 ; determined serially, before and after administration of a bronchodilator), inspection of the flow-volume loop, and arterial blood gas analyses. Preoccupation with expiration may obscure disorders characterized primarily by inspiratory obstruction. These are commonly overlooked because of failure to elicit stridor on the physical examination. In asthma, generalized wheezing occurs during both inspiration and expiration. Except for attacks precipitated by specific antigens, two common mechanisms often precipitate an episode: a respiratory infection, usually viral rather than bacterial, and an emotional event. Between episodes, most asthmatics, even those who are symptom-free, can be shown to have heightened bronchomotor tone (Fig. 27-21). In a latent asthmatic, a brief period of hyperventilation generally suffices to induce a bout of asthma. In patients with left ventricular failure, a paroxysm of wheezing (â&#x20AC;&#x153;cardiac asthmaâ&#x20AC;?) occasionally heralds the onset of acute pulmonary congestion and edema. The new onset of asthma in an elderly person should be carefully assessed with respect to the state of the left ventricle before vigorous bronchodilator therapy is initiated.

Restrictive Lung Disease The diagnosis of restrictive lung disease usually begins with a complaint of dyspnea, reinforced by a telltale chest radiograph. Indeed, without abnormalities on the chest radiograph, detection of interstitial disease by pulmonary function testing is uncommon. The combination of tachypnea, the typical chest radiograph, concentric reduction in lung volumes, and the appearance of arterial hypoxemia during exercise almost invariably clinches the diagnosis; a low value for the

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Figure 27-21 Simultaneous flow-volume curves in asthma. Top: Normal subject. Beginning at the end of a quiet expiration (a), the curves were recorded during a normal tidal breath (small, shaded loops) and during a forced expiration from peak lung inflation (b) to full expiration (e). Peak flow rates were reached at c. Expiration then continued along segment cde. In the record of the tidal breath, inspiration is hatched and expiration is solid black. The interval between each dot is 0.05 s. Center: Asthmatic subject. The vital capacity (be) is abnormally small, and flow rates along cde are diminished. Bottom: Same asthmatic subject 2 weeks after clinical recovery. Although flow rates are considerably higher than during the acute attack, the slope of segment de is still abnormally low, indicating that the resistance to airflow as lung volume decreases is still inordinately high. (From Mellins R, Lord GP, Fishman AP: Dynamic behavior of the lung in acute asthma. Med Thorac 24:81â&#x20AC;&#x201C;98, 1967, with permission.)

diffusing capacity of the lungs is final proof and is useful in following the course of the disease. Much more troublesome is the identification of the cause (Table 27-6). An important distinction at the outset is whether the disease is acute or chronic (Table 27-3). Some types of interstitial disease, such as asbestosis, take years to become symptomatic. Others, such as hypersensitivity pneumonitis can have a more fulminant onset.

Figure 27-22 Interstitial edema and infection. Pneumocystis infection in an immunosuppressed patient in uremia. A. Bilateral interstitial and alveolar pattern and enlarged cardiac silhouette suggestive of pulmonary edema. Pneumocystis carinii (Pneumocystis jiroveci) was obtained by bronchial lavage. B . Three weeks later. Reduction in size of cardiac silhouette and clearing of infiltrates after marked diuresis and treatment with antibiotics.

Another way to assist in categorization is the presence of systemic complaints. Sometimes, particularly in immunosuppressed patients, distinction between interstitial infection and interstitial edema may be difficult to make (Fig. 27-22). Persistent fever suggests infection. Lung impairment by a

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Figure 27-23 Scleroderma. A. Raynaudâ&#x20AC;&#x2122;s phenomenon of the toes. B .Diffuse bilateral basilar interstitial infiltrates on chest radiograph.

systemic disease, such as scleroderma, is often suggested by telltale stigmas in extrapulmonary sites (Fig. 27-23). In some instances, the cause is self-evident. This relationship is striking in some occupational disorders (e.g., silo-fillerâ&#x20AC;&#x2122;s disease that occurs after exposure to moldy hay). Also, the chest radiograph in sarcoidosis or silicosis is sometimes so characteristic as to be virtually diagnostic (Fig. 27-24). But sometimes the cause remains enigmatic or idiopathic despite elaborate laboratory investigations, including lung biopsy. In essence, uncovering the cause of diffuse interstitial fibrosis is often a matter of painstaking and discriminating medical detection. The flash of brilliant insight, in the tradition of Sherlock Holmes or Lord Peter Wimsey, is apt to

Approach to the Patient with Respiratory Symptoms

Figure 27-24 Sarcoidosis. Unilateral hilar adenopathy due to sarcoidosis in a 27-year-old asymptomatic man with left hilar adenopathy and interstitial lung disease of upper lobes. Bronchoscopic biopsy disclosed widespread noncaseating granulomas.

be less revealing about cause than is a meticulous, systematic account of lifestyle, habits, occupation, and background. The distribution and pattern of disease on the chest radiograph often provide clues to the next step in diagnosis. Sometimes the identification of abnormal constituents in sputum is diagnostically helpful (e.g., blood or blood products in the macrophages of the patient with Goodpastureâ&#x20AC;&#x2122;s syndrome or eosinophils in the patient with a hypersensitivity disorder). In many instances, diagnosis rests on lung biopsy. Unfortunately, except in diseases such as sarcoidosis, biopsy is often deferred indefinitely, owing to a perceived lack of likely change in treatment. As a result, biopsy is usually performed at the stage of nonspecific interstitial fibrosis when scarring is so indiscriminate that neither etiology nor pathogenic mechanisms are decipherable. As pointed out above, the physiological hallmarks of diffuse interstitial disease are those of restrictive lung disease (i.e., stiffening of the lung [low compliance] and concentric reduction in lung volumes [decrease in vital capacity, residual volume, and total lung capacity]). Accompanying the decrease in compliance is an increase in the work of breathing and a breathing pattern of rapid, shallow tidal volumes. The chest radiograph demonstrates the inability of the patient to expand fully the stiffened lungs. Dyspnea is evoked at first by mild exercise and later persists at rest. The once-popular picture of widespread disease confined to the alveolar-capillary interstitium has been modified by the recognition that alveoli are generally implicated in the underlying process. In interstitial pulmonary edema, groups of alveoli are often flooded. In inflammatory processes, such as sarcoidosis or desquamative interstitial pneumonia, alveoli,

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as well as the interstitial space, are commonly caught up in the process. In pneumonia caused by Pneumocystis carinii (Pneumocystis jiroveci), the organisms are found in alveoli as well as in the interstitial spaces. Therefore, the designation of diffuse interstitial disease should not be misconstrued as being confined solely to the interstitium of the lungs, even though the term generally does identify the predominant seat of disease.

Syndromes of Alveolar Hypoventilation The common denominator in disorders characterized by alveolar hypoventilation is an abnormally high value for arterial (and alveolar) Pco2 . The most common cause is chronic bronchitis and emphysema (COPD), which produces hypercapnia by deranging ventilation-perfusion relationships. This “net” alveolar hypoventilation is conceptually different from the “generalized” alveolar hypoventilation that results from a disorder of respiratory control or of the chest bellows as occurs in kyphoscoliosis, respiratory muscle weakness, or obesityhypoventilation. The usual manifestation of generalized alveolar hypoventilation is the combination of normal lung volumes and FEV1 , normal chest radiograph in conjunction with arterial hypoxemia, hypercapnia, and respiratory acidosis.

Obliterative Vascular Disease Pulmonary thromboemboli usually affect large as well as small vessels. Occlusive vascular diseases, such as idiopathic pulmonary arterial hypertension, which are more confined to small (“resistance”) pulmonary vessels, are much less common. More often, the pulmonary resistance vessels are caught up in the adjacent and surrounding diffuse interstitial disease. In pulmonary vascular disease that compromises the area available for gas exchange, the diffusing capacity becomes subnormal. Occlusive vascular diseases of the lung are usually recognized when the extent of the disease is sufficient to cause considerable pulmonary hypertension. The diagnosis is most often first suggested by the estimated pulmonary artery pressure in the echocardiogram. Additional testing is required to establish the cause (e.g., pulmonary function testing to rule out airways obstruction, a polysomnogram to assess possible sleep apnea); confirmation of pulmonary arterial hypertension requires right heart catheterization.

CHOOSING PULMONARY FUNCTION TESTS In Chapter 34, pulmonary function testing is discussed in some detail. Often a combination of pulmonary function tests is needed to characterize a patient’s abnormalities. Pulmonary function tests can be particularly helpful in obstructive diseases of the airways, in which chest radiographs are often normal. Some of the tests are simple; others require special facilities and personnel. For example, closing volume and closing capacity, previously popular as “sensitive” tests

for obstruction of small airways, have proved to be of little clinical value. There is certainly no value to these tests once the FEV1 is abnormal. Nonetheless, the possibility exists that such sensitive tests may be useful in special conditions (e.g., in assessing obstruction of small airways in occupational disease). The battery of tests that is used experimentally to portray the full length and breadth of the patient’s pulmonary disorder is rarely needed for clinical purposes. However, only a few physiological test patterns result from a wide variety of causes. Indeed, virtually all diffuse diseases of the lungs and airways that compromise pulmonary performance can be categorized into four distinctive patterns: (1) obstructive disease of the airways, (2) restrictive lung disease, (3) obliterative vascular disease, and (4) alveolar hypoventilation due to malfunctioning of the chest bellows or control mechanisms.

SUGGESTED READING Adams L, Guz A: Dyspnea on exertion, in Wasserman K, Whipp BJ, (eds), Exercise: Pulmonary Physiology and Pathophysiology. New York, Dekker, 1991, pp. 449–494. Bonica J: Painful disorders of the respiratory system, in The Management of Pain. Philadelphia, Lea & Febiger, 1990, pp 1043–1061. Fraser R, Muller NL, Colmman N, et al: Diagnosis of Disease of the Chest, 4th ed. Philadelphia: WB Saunders, 1999, p 384. Goodwin S, Glenny RW: Nonsteroidal anti-inflammatory drug-associated pulmonary infiltrates with eosinophilia: Review of the literature and Food and Drug Administration Adverse Drug Reaction reports. Arch Intern Med 152:1521–1524, 1992. Hilman B: Evaluation of the wheezing infant. Allergy Proc 15:1–5, 1994. Holden D, Mehta AC: Evaluation of wheezing in the nonasthmatic patient. Cleve Clin J Med 57: 345–352, 1990. Holt G, Kelsen SG: Dyspnea, in Tierney SD (ed), Current Pulmonology, vol 14. St. Louis, Mosby-Year Book, 1993 pp 293–320. Irwin R, Curley FJ, French CL: Chronic cough: The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 141:640–647, 1990. Irwin RS, et al: Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest 129(1 Suppl):1S–23S, 2006. Jaakkola M, Jaakkola, JJK, Ernst P, et al: Respiratory symptoms should not be overlooked. Am Rev Respir Dis 147:359–366, 1993. Johnson B, Badr MS, Dempsey JA: Impact of the aging pulmonary system on the response to exercise. Clin Chest Med 15:229–246, 1994.

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Johnson D, Osborn LM: Cough variant asthma: A review of the clinical literature. J Asthma 28: 85–90, 1991. Koster M, Baughman RP, Loudon RG: Continuous adventitious lung sounds. J Asthma 27:237–249, 1990. Lacourciore Y, Lefebvre J: Modulation of the reninangiotensin-aldosterone system and cough. Can J Cardiol 11(Suppl F): 33F–39F, 1995. Loudon R: The lung exam. Clin Chest Med 8:265–272, 1987. Loureno R, Turino GM, Davidson LAG, et al: The regulation of ventilation in diffuse fibrosis. Am J Med 38:199–216, 1965. Mahler D, Horowitz MB: Clinical evaluation of exertional dyspnea. Clin Chest Med 15:259–269, 1994. Maisel AS, et al: Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 347(3):161–167, 2002. Manning H, Schwartzstein RM: Pathophysiology of dyspnea. N Engl J Med 333:1547–1553, 1995. Fitzgerald, FT, Murray J: History and physical examinations, in Mason R, Broaddus VC, Murray J, Nadel JA (eds), Textbook of Respiratory Medicine, vol 1. Philadelphia, Saunders pp 493–538, 2005. Muza S, Silverman MT, Gilmore GC, et al: Comparison of scales used to quantitate the sense of effort to breathe in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 141:909–913, 1990. O’Connell SD, Moradoghli-Faftvani A, et al: Abnormal intraepithelial airway nerves in persistent unexplained cough? Am J Respir Crit Care Med 152:2068–2075, 1995. Patrick H, Patrick F: Chronic cough. Med Clin North Am 79:361– 372, 1995. Piirila P, Sovijarvi AR, Kaisla T, et al: Crackles in patients with fibrosing alveolitis, bronchiectasis, COPD, and heart failure. Chest 99:1076–1083, 1991.

Approach to the Patient with Respiratory Symptoms

Richter J: Gastroesophageal reflux as a cause of chest pain. Med Clin North Am 75:1065–1080, 1991. Schwartzstein R: The language of dyspnea, in Mahler D, O’Donnell DE (eds) Dyspnea: Mechanisms, Measurement, and Management. New York, Marcel Dekker, Inc, 2005, pp 115–146. Schwartzstein RM: Physiology of dyspnea, in Rose B (ed). UpToDate. Wellesley, MA, 2006. Schwenk N, Schapira RM, Byrd JC: Laryngeal carcinoma presenting as platypnea. Chest 106:1609–1611, 1994. Sharma O: Symptoms and signs in pulmonary medicine: Old observations and new interpretations. Dis Mon 41:577– 638, 1995. Simon P, Schwartzstein RM, Weiss JW, et al., Distinguishable types of dyspnea in patients with shortness of breath. Am Rev Respir Dis 142:1009–1014, 1990. Snider G: History and physical examination, in Baum G, Wolinsky E (eds), Textbook of Pulmonary Diseases, 5th ed. New York, Little, Brown, 1993, pp 243–272. Stark R, McGinn AL, Wilson RF: Chest pain in cardiac transplant recipients: Evidence of sensory reinervation after cardiac transplantation. N Engl J Med 324:1791–1794, 1991. Tunkel D, Zalzal GH: Stridor in infants and children: Ambulatory evaluation and operative diagnosis. Clin Pediatr (Phila) 31:48–55, 1992. Weinberger SE: Etiology and evaluation of hemoptysis in adults, in Rose B (ed), UpToDate. Wellesley, MA. Wilson R, Jones PW: Differentiation between the intensity of breathlessness and the distress it evokes in normal subjects during exercise. Clin Sci 80:65–70, 1991. Widdicombe J: Physiology of cough, in Braga PC, Allegra L (eds), Cough. New York, Raven, 1989, pp 3–25.

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28 Skin Disease in Patients with Pulmonary Disease Jeffrey P. Callen

I. ATOPIC DERMATITIS II. COLLAGEN VASCULAR DISORDERS Dermatomyositis Scleroderma III. INFECTIONS Blastomycosis Coccidioidomycosis Actinomycosis Tuberculosis IV. NEOPLASTIC DISORDERS Kaposiâ&#x20AC;&#x2122;s Sarcoma Lung Cancer and the Skin Lymphomatoid Granulomatosis V. REACTIVE DERMATOSES Clubbing and Hypertrophic Osteoarthropathy Erythema Nodosum

Examination of the skin can provide important clues in the diagnosis and treatment of persons with pulmonary disease. Some skin lesions either accompany pulmonary disease or complicate its treatment; occasionally, systemic diseases that affect both skin and lung first manifest themselves in the skin. In this chapter we deal briefly with processes in which there is prominence of cutaneous manifestations that might impact the care of the patient with pulmonary disease. The diagnosis and development of a differential diagnosis of cutaneous lesions is beyond the scope of this chapter and can be found in general dermatologic texts.

Neutrophilic Dermatoses: Sweet Syndrome and Pyoderma Gangrenosum Pruritus Urticaria Vasculitic Syndromes Yellow Nail Syndrome VI. MISCELLANEOUS DISORDERS Inherited Congenital and Developmental Disorder Hereditary Hemorrhagic Telangiectasia Nephrogenic Systemic Fibrosis Paraneoplastic Pemphigus Sarcoidosis Tuberous Sclerosis VII. TOXICITY OF MEDICATIONS Cutaneous Toxicity from Therapies for Pulmonary Disease Pulmonary Toxicity from Dermatologic Therapies

ATOPIC DERMATITIS Atopy refers to a group of disorders, including asthma, allergic rhinitis, and atopic dermatitis, in which immune and pharmacologic responses are abnormal. The atopic person usually has a family history of one or more of these disorders. Atopic dermatitis is a common disorder, affecting 1 to 3 percent of the population in the United States. In 85 percent of affected subjects, the skin lesions appear before 5 years of age. The dermatitis often resolves as the patient reaches adulthood; in

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have been used as an adjuvant or as a replacement for topical corticosteroids. Full discussions of the therapy of atopic dermatitis are available elsewhere.

COLLAGEN VASCULAR DISORDERS Dermatomyositis

Figure 28-1 Atopic dermatitis is characterized by lichenification, excoriations and slight scale.

the adult, either the skin lesions or respiratory systems may predominate. In infants, the skin lesions often begin as dry, erythematous plaques on the cheeks; excoriations and scaling may be prominent. In older children, the lesions localize in flexures; lichenification and excoriated papules are prominent features (Fig. 28-1). In adults, the lesions favor the hands and extremities. Atopic subjects also manifest prominent folds of the lower eyelids, periorbital hyperpigmentation with facial pallor, generalized dry skin, and white dermatographism. At any age, pruritus may be prominent and become secondarily infected, leading to bacterial impetigo within the lesions. In some patients, increased itching may be a prodrome to exacerbation of asthma. The cause of atopic dermatitis is unknown. In all likelihood, the pathogenesis is multifactorial, probably including disordered immune regulation as a causative factor. In persons with atopic dermatitis, abnormalities in cell-mediated immunity and lymphocyte function increase the risk of disseminated viral and fungal skin lesions. The role of food or environmental antigenic challenge in flares of atopic dermatitis is unsettled, but it is known that asthma can be precipitated by such challenges. The relationship between atopic dermatitis and lung disease is imperfect. Although hyposensitization is useful for asthma, it is either not helpful or is detrimental in atopic dermatitis. Treatment of atopic dermatitis in adults is multifaceted. The patient should avoid irritants. Bathing can occur on a daily basis, but should be followed by the application of emollients. Patients with atopic dermatitis frequently harbor or develop infections, particularly Staphylococcus aureus and eradication of infection is useful in those instances. Topical therapy with corticosteroids of an appropriate strength and in an appropriate vehicle for the site on the body that is being treated is a standard form of therapy. Recently topical calcineurin inhibitors, including pimecrolimus and tacrolimus,

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by proximal, symmetrical, slowly progressive muscle weakness and characteristic cutaneous lesions. The skin lesions that are pathognomonic include a heliotrope eruption, which consists of erythematous to violaceous periorbital changes that may be accompanied by edema (Fig. 28-2). Gottronâ&#x20AC;&#x2122;s papules are also pathognomonic for DM and consist of erythematous papules over the bony prominences on the dorsal hands (Fig. 28-3). In addition, patients might manifest a photodistributed poikiloderma

Figure 28-2 Heliotrope eruption of dermatomyositis.

Figure 28-3 Gottronâ&#x20AC;&#x2122;s papules in dermatomyositis: Erythematous to violaceous lesions are most prominent over the joints. In addition, this patient demonstrates cuticular and periungual changes that are frequent in dermatomyositis.

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Figure 28-4 Photodistributed poikiloderma in a patient with dermatomyositis.

(Fig. 28-4), nail fold changes, and an erythematous to violaceous scaly alopecia. Patients with dermatomyositis frequently complain of marked itching. Patients with dermatomyositis may also have other systemic manifestations, including arthritis, esophageal disease, and cardiopulmonary disease. Some patients with dermatomyositis have a malignancy. Others with the characteristic cutaneous lesions of DM are not weak and do not have an increase in musclederived enzymes. These patients are said to have amyopathic dermatomyositis. Pulmonary disease occurs in dermatomyositis and polymyositis (PM) in approximately 15 to 65 percent of patients. Interstitial pneumonitis is a primary process in DM/PM. Kang et al. have demonstrated that interstitial lung disease also occurs in patients with amyopathic dermatomyositis; in this subset of patients survival is poor. Pulmonary involvement is more frequent in patients with esophageal dysfunction. Lung disease may also occur as a direct complication of the muscle disease, such as hypoventilation or aspiration in patients with dysphagia, or may be a result of treatment, such as opportunistic infections or drug-induced hypersensitivity pneumonitis. In a retrospective review of 70 patients with myositis-associated interstitial lung disease seen at the Mayo Clinic between 1990 and 1998, most presented with either symptoms of lung disease or symptoms of myositis alone; in only 15 did the involvement occur simultaneously. The lung disease was originally felt to be a pneumonitis that was antibiotic resistant. Biopsy of the lung revealed non-specific interstitial pneumonitis or diffuse alveolar damage in a majority of those who were biopsied. Only two patients had bronchiolitis obliterans organizing pneumonia (BOOP). It is unclear how many of the patients had dermatomyositis; perhaps between 8 and 12. Therapy included corticosteroids with or without an immunosuppressive agent. However, the prognosis is poorer for these patients than for unselected patients with myositis, as demonstrated by a 5-year survival of 60.4 percent. Patients with Jo-1 antibodies (19 of 50 who were tested) had roughly

Skin Disease in Patients with Pulmonary Disease

Figure 28-5 Acrosclerosis characterized by marked contractures and sclerodactyly.

the same features and prognosis as those who did not have these antibodies.

Scleroderma Scleroderma refers to hard skin. This process may be localized to the skin or may be part of a systemic disease. Localized scleroderma may occur as limited plaques of morphea, generalized morphea, deep morphea, or linear scleroderma. Despite the fact that the disease occurs primarily on the skin, in rare instances pulmonary disease in the form of interstitial pneumonitis may complicate the course of the disease. There are two principal forms of progressive systemic sclerosis (PSS): limited scleroderma (acrosclerosis) and diffuse scleroderma. Acrosclerosis is the more common of the two, and is characterized by sclerosis of the skin of the fingers (sclerodactyly) (Fig. 28-5) and Raynaudâ&#x20AC;&#x2122;s phenomenon (Fig. 28-6). A variant known as the CREST syndrome includes esophageal dysfunction, telangiectasia, and calcinosis. In contrast, patients with diffuse scleroderma have widespread sclerosis beyond the acral areas of sclerodactyly. The prognosis for diffuse scleroderma is much worse than for acrosclerosis. Both types of scleroderma are often preceded by Raynaudâ&#x20AC;&#x2122;s phenomenon, diffuse arthralgias, or arthritis. The skin manifestations begin with transient, recurrent swelling of the hands and progress to tapered fingers with shiny, hidebound skin (sclerodactyly). The feet, chest, face, and scalp are often involved in the sclerotic process. In time, the skin becomes taut, leading to contractures of the large and small joints that culminate in a claw-like deformity of the hand. A variety of pigmentary disturbances may occur in scleroderma, including generalized hyperpigmentation that resembles adrenal insufficiency, focal hyperpigmentation, and hypopigmentation, and areas of perifollicular pigmentation that resemble vitiligo (Fig. 287). Raynaudâ&#x20AC;&#x2122;s phenomenon leads to small pitted scars at the fingertips or frank ulceration, with or without gangrene of the fingertips, toes, knuckles, and ankles, especially the malleoli.

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as lorsartan and most recently with phosphodiesterase type 5 inhibitors such as sildenafil or tadalafil. Ulcerations from scleroderma might be treated with the endothelin receptor antagonist bosentan. Localized scleroderma (morphea) might be treated with topical application of superpotent corticosteroids or calcipotriene. Systemic therapy with methotrexate seems promising in patients with progressive skin disease, although the therapy of systemic sclerosis is beyond the scope of this chapter. Over time the sclerosis that involves the skin seems to improve naturally; therefore, studies that suggest benefit based on improvement of the cutaneous disease should be interpreted cautiously.

INFECTIONS Blastomycosis Figure 28-6 Raynaudâ&#x20AC;&#x2122;s phenomenon in this patient was so severe that autoamputation of the distal digits occurred.

The face often undergoes distinctive changes, leading to a fixed stare and inability to wrinkle the forehead. As the facial tissues shrink, the nose becomes pinched, the cheeks sunken, the mouth narrows, and the lips thin. In diffuse scleroderma, cutaneous sclerosis, accompanied by a yellowish-brown hue, spreads from the chest to the head and extremities. Sharply delineated, broad telangiectatic macules appear on the face, buccal mucosa, lips, and hands. PSS is associated with interstitial pneumonitis. This is more common in patients with diffuse disease than in patients with limited disease. Pulmonary hypertension has been reported to occur in patients with CREST syndrome. Treatments for the cutaneous disease are multiple, but few have been tested in double-blind, randomized trials. Raynaudâ&#x20AC;&#x2122;s phenomenon is treated by avoidance of exposure to cold, and with calcium channel-blocking agents such as nifedipine, angiotensin-2 receptor antagonists such

Skin lesions are as common as pulmonary lesions in patients with blastomycosis. Cutaneous disease usually represents dissemination from a pulmonary focus that is often small and may be inapparent. The typical presentation is as a solitary nodule or multiple papules or nodules on the face, wrists, hands, or feet, which subsequently ulcerate and discharge pus (Fig. 28-8). The lesions grow eccentrically at the periphery and atrophy centrally over a period of months, eventually forming an arciform or serpiginous contour with sharply elevated and verrucous borders. Miliary abscesses occur along the borders of the lesions. In addition to the cutaneous involvement, osteolytic lesions may occur in the bones. Patients with cutaneous blastomycosis should be treated with antifungal therapies such as itraconazole, fluconazole, ketoconazole, or amphotericin B.

Coccidioidomycosis Coccidioidomycosis is usually manifest as a pulmonary infection. In its acute form, it is often associated with cutaneous symptoms; roughly 20 percent of patients develop erythema nodosum. Erythema nodosum is often accompanied by fever, arthritis, and eosinophilia. In patients with progressive pulmonary disease and eventual disseminated disease, the skin may be affected; subcutaneous granulomatous eruptions form and undergo necrosis and ulceration. After several months, the lesions tend to become verrucous. A third form is primary cutaneous disease, which occurs in farmers and laboratory workers as a chancriform lesion with sporotrichotic spread. This variant is extremely rare. Acute disease is often self-limiting and requires only symptomatic management; however, disseminated disease requires aggressive antifungal therapy and is associated with a poor prognosis.

Actinomycosis Figure 28-7 Vitiligo-like dyspigmentation associated with progressive systemic sclerosis.

The thoracic form of this disease presents as a pulmonary parenchymal process that sometimes forms multiple draining sinus tracts. Diagnosis is often difficult, but identification

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Figure 28-8 A–B. Blastomycosis: verrucous lesions on the face (A) and trunk (B).

of sulfur granules in the draining exudates is helpful. Treatment with penicillin or tetracycline may eliminate the need for surgery.

Tuberculosis Cutaneous involvement results from direct inoculation with the tubercle bacillus, via either the skin or mucous membranes or as a consequence of widespread organ involvement that begins in the respiratory tract. When the tubercle is introduced via the skin or mucous membranes by a contaminated syringe or a wound in a previously unexposed host, a nodule usually develops at the site of injury. Within several weeks, the nodule evolves into a chancre, a well-circumscribed ulcer. Particularly if host defenses are impaired, these chancriform lesions, which are typically located on the extremities, develop associated regional lymphadenitis, followed by systemic dissemination of the organism. A person who was previously infected with M. tuberculosis is apt to develop tuberculosis verrucosa cutis after receiving a cutaneous inoculation. The characteristic lesion in a sensitized person is a papule or a pustule, which becomes verrucous. On occasion, this disorder produces plaque-like lesions of the extremities consisting of verrucoid–indurated papules surrounded by an erythematous halo. Lupus vulgaris is the most common form of cutaneous post-primary tuberculosis that follows inoculation or lymphatic or hematogenous spread of M. tuberculosis. Patients with this disorder typically present with reddish-brown plaques surrounded peripherally by yellowish nodules, especially on the neck or extremities. The skin lesions tend to spread centrifugally as the center becomes atrophic. Papillary growths also occur in the nasal, buccal, and conjunctival mucosa. Histologically, lupus vulgaris generally shows epithelioid tubercles with caseation necrosis. Chronic cutaneous eruptions tend to involute, leaving considerable scar-

ring. Chemotherapy with the usual antituberculosis drugs is effective in treating these skin manifestations. Disseminated miliary tuberculosis can result in macules, papules, or vesicles. In children, especially those who are debilitated, subcutaneous nodules or gummas appear, ulcerate, and eventually develop draining sinus tracts, especially in the extremities and trunk. Scrofuloderma, which occurs following the necrosis of cervical nodules, is associated with fistula and sinus tract formation in the overlying cutaneous tissues. Tuberculids are skin lesions that are considered to represent either a hypersensitivity reaction to M. tuberculosis or an embolic response to atypical Mycobacteria. Erythema nodosum also occurs in association with primary tuberculosis.

NEOPLASTIC DISORDERS Kaposi’s Sarcoma Early in the epidemic of HIV infection, the incidence of Kaposi’s sarcoma (KS) increased. However, since the advent of HAART therapy, KS again became less common. KS can occur in any immune-suppressed individual whether the immune dysfunction is due to HIV infection, age, or iatrogenic immunosuppression in transplant recipients. Human herpesvirus-8 (HHV-8) has been identified and linked to all forms of KS. In addition, a recent report has documented that HHV-8 viremia is associated with progression on KS in both classic and endemic forms. In the elderly population, KS has an indolent course and occurs primarily on the lower extremities. At the outset, the lesions are dark-blue, purplish, or reddish papules, macules, and nodules (Fig. 28-9). After months to years, plaques evolve in association with thickening of the skin from midtibia to ankle and lymphedema. In patients with immune dysfunction, including AIDS, KS is more aggressive and is often widespread in its cutaneous manifestations.

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Figure 28-9 Kaposi’s sarcoma in an HIV-positive patient.

Figure 28-10 Tripe palms. (Courtesy of Dr. Jon Dyer.)

The respiratory tract is second only to the gastrointestinal tract in frequency of systemic involvement. Tumors may involve the larynx, trachea, bronchi, pulmonary parenchyma, and pleura. Accordingly, local manifestations of respiratory tract involvement range from hoarseness, signs of airway obstruction, cough, and hemoptysis, to dyspnea. When the parenchyma of the lung is affected, chest radiographs usually show many small nodules; occasionally, parenchymal infiltration of the lung is massive. On bronchoscopic examination, bronchial and tracheal lesions appear as small bluish nodules. Bloody pleural effusions are rare. Treatment of KS associated with immune suppression involves correction of the dysfunction by discontinuing immunosuppressive drugs when feasible or reconstitution of immune function in the HIV-infected individual. Local therapies for skin lesions include topical application of alitretinoin gel, liquid nitrogen cryotherapy, local irradiation, intralesional interferon, systemic interferon-α2a, or systemic chemotherapy. Liposomal doxorubicin or paclitaxel infusions are reserved for patients with extensive skin disease or systemic disease.

Patients with Bazex syndrome (acrokeratosis paraneoplastica) develop an erythematous to violaceous psoriasiform eruption primarily on acral surfaces (Fig. 28-11). The ears, nose, cheeks, hands, feet, and knees are most often affected, but the nails may become dystrophic and the palms and soles may develop a keratoderma in later stages of the disease. The disorder may develop in stages, and is associated primarily with carcinomas of the upper respiratory and digestive tracts (larynx, pharynx, trachea, bronchus, and/or upper esophagus); the malignancy is often detected concurrently. If the tumor is effectively treated the eruption may resolve, but may return with tumor recurrence. There is no known effective treatment for the cutaneous eruption, although corticosteroids and keratolytic agents have been used. Ectopic ACTH-producing tumors cause many of the typical signs and symptoms of Cushing’s syndrome. Intense hyperpigmentation, present in only 6 to 10 percent of patients with Cushing’s disease, is especially common in association with ectopic ACTH production and should alert the clinician to the possibility of a hormone-secreting tumor. Although

Lung Cancer and the Skin Several paraneoplastic syndromes may occur in patients with lung cancers. In most instances the dermatosis is not specific for lung cancer; other sites may be involved. The following are some of the more ominous manifestations of potential pulmonary malignancy. Tripe palms is a paraneoplastic condition that is manifest as rugose thickening of the palms and occasionally the soles (Fig. 28-10). Patients often have coexistent acanthosis nigricans (AN) and sometimes the sign of Leser-Tr´elat. Patients with tripe palms and AN usually have adenocarcinomas of the gastrointestinal tract; however, when tripe palms occurs in the absence of AN, patients often have squamous cell carcinoma of the lung. There is no known treatment for the cutaneous changes other than removal of the tumor.

Figure 28-11 Acrokeratosis paraneoplastica (Bazex’s syndrome). This patient was thought to have psoriasis prior to the diagnosis of a squamous cell carcinoma of the tonsillar pillar.

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the cause of the hyperpigmentation is unclear, it may be related to tumor production of the peptide β-lipotropin, which contains within its sequence of 91 amino acids the 22–amino acid sequence of β-MSH. A myasthenia gravis– like syndrome, including profound proximal muscle weakness, may be a striking clinical feature and may reflect either underlying hypokalemia or polymyositis. Oat cell carcinoma of the lung is the tumor most often associated with ectopic ACTH production, although other malignancies have been reported. The carcinoid syndrome is a second example of a hormonal syndrome associated with a nonendocrine tumor. The disorder is probably most often caused by the release of the enzyme kallikrein from tumor cells with subsequent conversion of kininogen to vasoactive kinin peptides, including bradykinin; in addition, increased blood levels of histamine may be important in the rare metastatic gastric carcinoid. The most striking cutaneous manifestations are episodes of flushing, initially lasting 10 to 30 minutes and involving only the upper half of the body; as the flush resolves, gyrate and serpiginous patterns may be noted. With successive attacks more extensive areas may be affected and the redness takes on a cyanotic quality, eventually leading to a more permanent facial cyanotic flush with associated telangiectasia, resembling rosacea. Persistent edema and erythema of the face may result in leonine facies. A pellagra-like picture, which has been noted in some patients, may be due to abnormal tryptophan metabolism. Systemic symptoms associated with the cutaneous flushing include abdominal pain with explosive watery diarrhea, shortness of breath, and hypertension. Carcinoid tumors are usually found in the appendix or small intestine; extraintestinal carcinoid tumors may arise in the bile ducts, pancreas, stomach, ovaries, or bronchi. The carcinoid syndrome occurs primarily when an intestinal carcinoid tumor metastasizes to the liver or with extraintestinal tumors; flushing attacks can be provoked by palpation of hepatic or abdominal metastases or by alcohol ingestion, enemas, emotional stress, or sudden changes in body temperature. When the syndrome is associated with bronchial adenomas of the carcinoid variety, the flushing is more prolonged and often associated with fever, marked anxiety, disorientation, sweating, salivation, and lacrimation. Migratory superficial thrombophlebitis and multiple deep venous thrombosis have been noted in cancer patients, especially those with tumors arising in the pancreas, lung, stomach, prostate, or hematopoietic system. The neck, chest, abdominal wall, pelvis, and limbs are most frequently affected.

Skin Disease in Patients with Pulmonary Disease

Figure 28-12 Lymphomatoid granulomatosis. This young woman developed the acute onset of multiple erythematous plaques on her face, accompanied by dyspnea and fever. She died within a month from pulmonary disease.

ease of biopsying the skin, and characteristic histology of these disease, careful dermatologic examination should be carried out in patients suspected of having lymphomatoid granulomatosis. The characteristic cutaneous lesions in lymphomatoid granulomatosis are 1- to 4-cm erythematous-to-purplish dermal papules, or subcutaneous nodules, with or without ulceration. The lesions generally occur over the buttocks, thighs, and lower extremities (Fig. 28-12), but may occur anywhere. Healing is often accompanied by scarring and hyperpigmentation. This histopathology of the skin lesions is similar to that of the lesions in the lungs, and is characterized by a marked angiocentric and angiodestructive lymphohistiocytic infiltrate composed predominantly of CD4-positive T cells. EBV-positive B cells are often present. This disorder is presumed to be a T-cell–rich B-cell lymphoproliferative disease. The papules or nodules in lymphomatoid granulomatosis sometimes clear spontaneously; more often, they recur or progress. The skin lesions seem to respond to therapy with systemic corticosteroids and cyclophosphamide. Recently the use of rituximab has been associated with a favorable outcome in some patients. Localized radiation therapy has been used for some refractory skin lesions.

REACTIVE DERMATOSES

Lymphomatoid Granulomatosis

Clubbing and Hypertrophic Osteoarthropathy

The skin is the most commonly affected extrapulmonary site in lymphomatoid granulomatosis, occurring in 40 to 50 percent of patients. In 10 to 25 percent of patients, the skin lesions are the first clinical evidence of the disorder; the skin lesions precede involvement of the lungs by 2 weeks to 9 years. Because of the frequent occurrence of skin lesions,

Pachydermoperiostosis is a syndrome in which hypertrophic osteoarthropathy is associated with cutaneous changes of the face and extremities that are similar to those that occur in patients with acromegaly. Although this disorder is generally benign, it is occasionally associated with bronchogenic carcinoma.

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Figure 28-13 Erythema nodosum. Red tender subcutaneous nodule on the leg.

Erythema Nodosum A relatively common process, erythema nodosum (EN) is usually acute and self-limited. The typical clinical presentation is the sudden onset of one or more, tender, erythematous nodules on the anterior legs, which are more easily palpated than visualized (Fig. 28-13). The eruption is often preceded by a prodrome of fever, malaise, and/or arthralgias. As the lesions age, they may develop an ecchymotic appearance. Over a 4- to 6-week period they eventually heal without scar formation. Ulceration of the primary process is rare. Although EN is usually an acute process, patients with chronic or recurrent disease have been described using such terms as chronic EN, EN migrans, subacute nodular migratory panniculitis (Vilanova’s disease), or septal granulomatous panniculitis. Chronic or recurrent EN most commonly occurs in middleaged women. The disease is often present for several years, and is most common on the legs. Etiologic or associated conditions are present in about 50 percent of patients with EN. The associated conditions can be divided into three broad categories: infections, drugs, or systemic diseases (usually inflammatory disorders). The infectious agents associated with EN tend to primarily affect the respiratory or gastrointestinal tract and are most often bacterial or fungal in origin. The most common drugs are antibiotics and oral contraceptives. Pregnancy, particularly in its second trimester, is a known association, and the EN will recur with subsequent pregnancies or with the administration of oral contraceptives. EN-like lesions may occur in Behc¸et’s disease and are accompanied by oral and genital ulcerations, pathergy, uveitis, and/or central nervous system (CNS) disease or other systemic manifestations. A specific variant of sarcoidosis associated with EN is known as L¨ofgren’s syndrome. This is an acute, self-resolving process in which EN occurs with bilateral hilar lymphadenopathy, arthritis, and anterior uveitis. Granulomatous colitis (Crohn’s disease), regional enteritis, and ulcerative colitis have been associated with EN. In patients with inflammatory bowel disease, it appears that the EN parallels the activity of the bowel disease. At least half of the cases of EN are not found to have an associated or underlying process.

The treatment of EN first involves assessment of a causative disease and its treatment. In the absence of a treatable disorder, therapy is symptomatic. Acute EN is often selflimited, thus non-toxic therapies are advised. Bed rest and leg elevation are very helpful in controlling symptoms. In patients who need to continue to be ambulatory, support stockings or tights may be helpful. Aspirin or other NSAIDs may be helpful. Sometimes, however, treatment with aspirin does not produce results prior to toxicity; therefore, oral indomethacin (25–75 mg/day) is recommended. In patients with chronic EN or frequent recurrences, oral potassium iodide 300 to 900 mg/day has been useful in open clinical trials. When the drug is stopped or the dose is lowered the disease often relapses, only to respond again to the reinstitution of therapy. Other therapies that may be considered include oral corticosteroids, colchicine, hydroxychloroquine, or an immunosuppressive agent.

Neutrophilic Dermatoses: Sweet Syndrome and Pyoderma Gangrenosum Sweet syndrome (Fig. 28-14) and pyoderma gangrenosum (Fig. 28-15) are distinct dermatoses, but share common associations and are often managed with similar therapies. In addition, a condition known as neutrophilic dermatosis of the dorsal hands (Fig. 28-16) often has characteristics that overlap between a superficial variant of pyoderma gangrenosum (also termed atypical pyoderma gangrenosum) and Sweet syndrome. The associated diseases include inflammatory bowel disease, rheumatoid arthritis, and myelogenous malignancy and pre-malignancy. Extracutaneous neutrophilic inflammation has been reported in multiple organs, but the most frequently reported are the lungs. The inflammatory reaction can cause infiltrates including cavitary disease. It is critical that infectious diseases be excluded with appropriate culture prior to initiating therapy with corticosteroids with or without immunosuppressive therapy.

Figure 28-14 Acute febrile neutrophilic dermatosis (Sweet syndrome): erythematous plaque with what appears to be vesiculation on the surface.

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plastic cause for the urticaria. This happens in less than 25 percent of patients.

Vasculitic Syndromes

Figure 28-15 Pyoderma gangrenosum: large ulceration on the leg with a violaceous, undermined border. This patient had active Crohn’s disease.

Pruritus Pruritus is a symptom that accompanies many dermatoses, but may also accompany systemic diseases. Patients without an obvious cause for their itching require a systemic evaluation, which usually includes a chest x-ray. Causes for pruritus are not commonly found, but Hodgkin’s disease and other malignancies might be uncovered during the evaluation. Effective treatment of an underlying malignancy will result in a disappearance of the pruritus.

Urticaria Urticaria is a reactive cutaneous disease manifest by transient urticarial skin lesions. Acute urticaria is almost always due to the ingestion of a food or medication and usually subsides within several days. The presence of chronic urticaria requires a thorough evaluation and at times the pulmonary evaluation might reveal an infectious, inflammatory, or neo-

Churg-Strauss Syndrome The clinical picture of allergic rhinitis, asthma, peripheral eosinophilia, and pulmonary infiltrates concomitant with systemic vasculitis has been designated the Churg-Strauss syndrome. However, the histologic finding of necrotizing granulomas and tissue eosinophilia is not unique to this clinical syndrome. Indeed, the same histologic appearance may be seen in a wide variety of systemic diseases, including allergic granulomatosis, Wegener’s granulomatosis, rheumatoid arthritis, and lymphoproliferative disease. One or more types of skin lesions develop in 70 percent of patients with Churg-Strauss syndrome. Most common is palpable purpura of the extremities; histologically, these lesions show necrotizing vasculitis without granuloma formation. In one-third of the patients, the cutaneous lesions are nonspecific—i.e., erythematous and urticarial. In another one-third, however, the skin lesions are distinctive—i.e., tender red to violaceous, indurated nodules, measuring 0.5 to 2 cm, which develop central crusting or become infarcted. These nodules occur most often over the scalp or symmetrically over the extensor surfaces of the extremities. It is these nodules that are most likely to have the histologic picture of necrotizing granulomatous vasculitis and eosinophilic infiltration; immunofluorescence staining may show vascular deposition of fibrin and complement. The skin lesions in Churg-Strauss syndrome generally respond to systemic corticosteroids or adjuvant cytotoxic therapy. Wegener’s Granulomatosis About 45 percent of patients with Wegener’s granulomatosis have cutaneous manifestations, most often small vessel vasculitis. Occasionally, biopsy of the skin lesions reveals a granulomatous vasculitis. In addition, the presence of cutaneous disease is usually indicative of active systemic involvement; therefore, such patients should be carefully evaluated and aggressively treated. Polyarteritis Nodosa Patients with polyarteritis nodosa frequently have cutaneous lesions. The skin disease may represent small vessel vasculitis as in Wegener’s granulomatosis or may represent mediumsized vessel involvement. In the latter case the manifestation is livedo reticularis or ulceration. Treatment of polyarteritis should include corticosteroids along with an immunosuppressive agent.

Figure 28-16 Neutrophilic dermatosis of the dorsal hands (aka atypical pyoderma gangrenosum). Such patients often have a hematologic malignancy or pre-malignant process.

Urticarial Vasculitis Urticarial lesions can occur in patients as a manifestation of small vessel vasculitis. McDuffie et al. first described urticarial vasculitis in four patients with recurrent attacks of erythematous urticarial and hemorrhagic skin lesions associated with synovitis and, sometimes, abdominal distress. Their patients

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did not have lupus erythematosus or paraproteinemia, but did have hypocomplementemia; two had nephritis. Urticarial lesions may also be an early clinical manifestation of lesions that become typical palpable purpura. The spectrum of urticarial vasculitis has also grown, in recent years, to include the presence of lung disease characterized by asthma or obstructive lung disease. Patients with hypocomplementemic urticarial vasculitis often have or develop obstructive pulmonary disease, whereas most patients with normal complement levels, chronic urticaria and vasculitis have little or no systemic involvement. The burning or itching of the lesions most often irritates patients with urticarial vasculitis. The patient should be first treated with antihistamines. Histamine 1 receptor (H1 ) antagonists can be combined with H2 antagonists, but the doses required often result in drowsiness. In some cases, the use of doxepin hydrochloride, which has effects on both H1 and H2 receptors, is effective. Lastly, the newer, less-sedating agent, cetirizine, or non-sedating agents such as fexofenadine or loratadine, can be used during waking hours and as a soporific agent before retiring. Patients are also often treated with corticosteroids and/ or immunosuppressive agents. Although these agents are useful in controlling the cutaneous lesions, they do not seem to have any impact of the progression of pulmonary disease. Toxic Epidermal Necrolysis Toxic epidermal necrolysis (TEN) is one of the true dermatologic emergencies. This disorder is most often due to drug administration and develops acutely. Patients often have a prodrome followed shortly by widespread skin involvement with a superficial blistering (Fig. 28-17). Multiple mucosal surfaces are affected (Fig. 28-18). Prognosis is dependent upon the extent of the blistering, age, and the presence of co-morbid diseases. Lung involvement is unusual, but these patients often are treated in an intensive care unit or burn unit and frequently end up on a ventilator. Infections are a frequent complication and can result in death. Pulmonary infection is one of the more frequent sites. Therapy of TEN is controversial, but in the United States treatment with high-dose

Figure 28-17 Stevens-Johnson syndrome/toxic epidermal necrolysis.

Figure 28-18 Mucosal lesions of Stevens-Johnson syndrome/toxic epidermal necrolysis.

intravenous immune globulin (0.75 g/kg per day for 4 days) has become a â&#x20AC;&#x153;standardâ&#x20AC;? therapy. The use of corticosteroids or other immunosuppressive agents is controversial. Prophylactic antibiotics are contraindicated, but prompt therapy of an identified infection should occur.

Yellow Nail Syndrome Thick, yellow discoloration of all 20 nails occurs in the yellow nail syndrome (Fig. 28-19). The nails are thick, but there is no onycholysis and no subungual debris, allowing clinical differentiation from onychomycosis. The nails are not clubbed and there are no underlying bony abnormalities. This disorder is almost always associated with pulmonary abnormalities, including pleural effusions, lymphoma, and sleep apnea. There is no known therapy for the nail changes in this disorder, but improvement of the associated pulmonary disease can result in improvement of the nails.

Figure 28-19 Yellow nail syndrome. All 20 nails were affected in this patient.

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MISCELLANEOUS DISORDERS Inherited Congenital and Developmental Disorders α1 -Antitrypsin Deficiency α1 -Antitrypsin deficiency is regularly associated with pulmonary and hepatic disease. Cutaneous manifestations may also occur in some patients with this inherited disorder and most commonly manifests as a panniculitis or rarely as a cutaneous vasculitis. Although the panniculitis is a lobular panniculitis in contrast to the septal panniculitis that is found in erythema nodosum, the clinical disease is similar except that these patients’ lesions might ulcerate. Therapy with replacement of the hormone will temporarily result in control of the panniculitic lesions. Cutis Laxa Cutis laxa is caused by a disorder in the formation of elastin that is transmitted as a dominant hereditary trait. In children with this disorder, skinfolds of the abdomen and face are large and pendulous. The pulmonary manifestations of cutis laxa are emphysema and pulmonary artery stenosis. Cystic Fibrosis and the Skin Cystic fibrosis (CF) is an inherited disorder that frequently affects the lungs and results in premature death. The skin is often useful for the diagnosis of this condition, but in addition there are patients in whom skin disease is due to CF. Specifically, cutaneous vasculitis seems to be more frequent in CF patients, probably due to the frequent formation of circulating immune complexes in the CF patient. Treatment of the patient with CF with cutaneous vasculitis is similar to other patients with cutaneous vasculitis.

Figure 28-20 Flesh-colored central facial papules in a patient with Birt-Hogg-Dube´ syndrome.

lead to discovery of renal tumors prior to spread to other organs. In addition to study of the patient, family members should be examined clinically and perhaps genetically.

Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Rendu-Weber syndrome, is an autosomal dominant disorder that is manifested by vascular ectasia in various organs, including the skin and mucous membranes (Fig. 28-21). HHT often is first manifest as nosebleeds. Eventually lesions affect the lips, tongue, nasal mucosa, palate, and palms. On rare occasions, patients with HHT have arteriovenous malformations of the lungs or CNS. Epistaxis, melena, and hemoptysis are common in adults. There is no known therapy for HHT at present, but if an A-V malformation is found, surgical consultation is indicated.

Nephrogenic Systemic Fibrosis Ehlers-Danlos Syndrome The most important disorder of collagen affecting the skin and lungs is Ehlers-Danlos syndrome (cutis hyperelastica), a hereditary disorder of collagen in which the skin and blood vessels are unduly elastic and fragile and the joints are hyperextensible. The skin is smooth, rubbery, and bruisable; the joints are hypermobile. Associated systemic abnormalities include megaesophagus, megacolon, dissecting aortic aneurysm, and diaphragmatic and inguinal hernias. Among the pulmonary disorders are spontaneous pneumothorax, arteriovenous fistulas, mega-trachea, and bronchial ectasia. Birt-Hogg-Dube´ Syndrome Birt, Hogg, and Dub´e described an autosomal dominant condition that was manifest by multiple facial flesh-colored papules that were characterized histologically as trichodiscomas (Fig. 28-20). These patients have been subsequently found to have frequent renal cell carcinomas, particularly oncocytomas. In addition, these patients frequently develop spontaneous pneumothorax at a young age. Although there is no known therapy for BHD patients, their recognition can

Nephrogenic systemic fibrosis is a recently recognized disorder of the skin in which a rapid onset of skin hardening (Fig. 28-22) occurs in patients with some form of renal disease. Often the onset of the fibrosis is preceded by anasarca. The cause of this disease is not known, but possibilities include vascular

Figure 28-21 Mucosal telangiectasia in a patient with hereditary hemorrhagic telangiectasia.

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therapies include high-dose daily corticosteroids, cyclophosphamide, and rituximab.

Sarcoidosis

Figure 28-22 Peau ‘d orange changes in a patient with nephrogenic systemic fibrosis.

thrombosis and recent surgical interventions. Recent identification of gadolinium in tissue following its use for MRI or MRA has suggested that this radiocontrast agent may be implicated in the etiology of nephrogenic systemic fibrosis. Initial descriptions of the disease focused on the cutaneous findings, but it has become evident that patients may also have systemic fibrosis, including pulmonary fibrosis. There is no known effective therapy for these patients, but with time the fibrosis does seem to lessen.

Paraneoplastic Pemphigus Paraneoplastic pemphigus (PNP) is a severe mucocutaneous disease with a specific pattern of immunofluorescence. It is a rare vesiculobullous disorder. Patients with PNP often present with severe oral erosions and polymorphous cutaneous lesions, including targetoid lesions, bullae, and erosions (Fig. 28-23). Patients with PNP often have a lymphoproliferative disorder with a high prevalence of Castleman’s disease. In addition to the mucocutaneous disease, these patients frequently have bronchiolitis obliterans. There is no therapy for PNP that is uniformly effective; however, if a coexisting tumor is removed, the disease will remit. Suggested

Sarcoidosis is a multisystem disorder with protean manifestations. The pulmonary manifestations and other aspects of the disease are well covered elsewhere in this text and we focus solely on the cutaneous disease. Skin lesions occur in about 25 percent of patients with sarcoidosis and may be “histopathologically specific” or “non-specific.” The most common nonspecific manifestation is erythema nodosum. Histopathologically, specific lesions are manifestations of granulomatous inflammation in the skin. Although associated with chronic disease in the past, it now appears that there are many patients with self-limiting granulomatous disease of the skin. Skin lesions are most commonly papules, plaques, or nodules. Rarely is there a great deal of surface change, and ulceration is uncommon. Several clinical variants are worth noting. Papular lesions on the knees (Fig. 28-24) are commonly associated with EN and are self-limiting. Lesions on the nasal ala (Fig. 28-25) are frequently associated with sarcoidosis of the upper respiratory tract (SURT) and a thorough otolaryngologic evaluation is indicated. Erythematous to violaceous plaques on the face are known as lupus pernio (Fig. 28-26) and residual scarring is possible. In addition, these patients tend to have accompanying chronic disease in the lungs. Finally, lesions of sarcoidosis frequently occur within scars or tattoos (Fig. 28-27). In this circumstance it may be difficult to distinguish sarcoidosis from foreign body granulomas. Management of cutaneous sarcoidosis is often challenging. Patients with chronic disease are often treated with systemic corticosteroids, but at times these are ineffective or are associated with toxicity. Oral tetracyclines have been used in open-label studies and are at times effective. Oral hydroxychloroquine 200 to 400 mg/day (less than 6.5 mg/kg per day based on ideal body weight) has been effective for cutaneous disease in small case series, but when the therapy is discontinued the disease often relapses. Methotrexate is the most commonly reported immunosuppressive agent, although azathioprine, mycophenolate mofetil and other agents have also been utilized. With methotrexate in doses of 15 to 25 mg per week, about 80 percent of patients with cutaneous lesions respond; however, chronic therapy in sarcoidosis patients has been associated with hepatic abnormalities that limit the use of methotrexate. Anti-tumor necrosis factor-α therapy with thalidomide or biologic agents has been reported to be effective. Infliximab is regularly effective; the use of etanercept has rarely resulted in improvement and the use of adalimumab has only been reported in several individual cases.

Tuberous Sclerosis

Figure 28-23 Paraneoplastic pemphigus.

Tuberous sclerosis is a hereditary disorder that is characterized by mental retardation, epilepsy, and skin lesions, including adenoma sebaceum, Shagreen patches, and ash leaf macules. Also seen as part of this disorder are retinal phakomas, calcification of basal ganglia, and ungual fibromas.

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Figure 28-24 Aâ&#x20AC;&#x201C;B. Sarcoidosis: acute onset of papular lesions (A) on the knees and feet (B) were associated with a self-limited course in these patients.

Approximately 9 percent of patients with visceral tuberous sclerosis have pulmonary manifestations; some of the pulmonary lesions are cystic and may be associated with recurrent spontaneous pneumothorax and hamartomas. Certain poorly understood diseases, such as fibrocystic pulmonary dysplasia, may represent a forme fruste of tuberous sclerosis.

TOXICITY OF MEDICATIONS Cutaneous Toxicity from Therapies for Pulmonary Disease Epidermal Growth Factor Receptor Inhibitors Epidermal growth factor receptor inhibitors are now being used for the treatment of solid tumors, including lung cancers.

Figure 28-25 Sarcoidosis affecting the nasal ala is regularly associated with granulomatous disease in the upper respiratory tract (SURT).

These agents are regularly associated with the development of an acneiform eruption on the face. The presence and severity of this eruption appear to correlate with survival. A variety of therapies have been suggested for prevention or treatment of this eruption, including oral tetracycline, oral isotretinoin, topical corticosteroids, and topical sulfacetamide. None of these therapies has been regularly reported to be effective. Consequences of Immunosuppressive Therapy in Lung Transplant Recipients Patients who are organ recipients are regularly treated with corticosteroids in combination with various immunosuppressive agents. Therapy with corticosteroids has well-known dermatologic consequences, including striae, steroid-acne, and/or folliculitis, and an increased risk of superficial fungal infections. The intensity of the immunosuppression and duration of therapy are associated with increasing risk of cutaneous malignancy, specifically non-melanoma skin cancer (NMSC) and Kaposiâ&#x20AC;&#x2122;s sarcoma. Squamous cell carcinoma is

Figure 28-26 Lupus pernio (sarcoidosis).

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Figure 28-27 Sarcoidosis within tattoos.

overrepresented in comparison to basal cell carcinoma; in addition the tumors appear to be more aggressive in the presence of immunosuppressive therapy. Therefore, in patients who develop multiple squamous cell carcinomas immunosuppressive therapy should be less intense if possible or substitution of cyclosporin and azathioprine by other “less” toxic agents should be considered. In addition, the use of oral retinoids such as acitretin might lessen the frequency of NMSC.

Pulmonary Toxicity from Dermatologic Therapies Methotrexate Methotrexate is a common systemic therapy for patients with psoriasis. In addition, it is regularly used for cutaneous dermatomyositis, cutaneous sarcoidosis, and cutaneous lymphomas. Pulmonary toxicity is not common and is believed to be idiosyncratic. Most of the dermatologic use is for psoriasis vulgaris and psoriatic arthritis; fortunately, pulmonary disease appears to be quite rare in these patients. No specific monitoring is recommended. Tumor Necrosis Factor-α Inhibitors There are three available tumor necrosis factor (TNF) antagonists: infliximab, etanercept, and adalimumab. These therapies have revolutionized our approach to psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis. All have been associated with an increased risk of infection, particularly pneumonitis. In addition, these agents may rarely cause or exacerbate cardiac failure.

SUGGESTED READING Akoglu G, Karaduman A, Boztepe G, et al: A case of lupus vulgaris successfully treated with antituberculous therapy despite negative PCR and culture. Dermatology 211:290– 292, 2005.

Beaty MW, Toro J, Sorbara L, et al: Cutaneous lymphomatoid granulomatosis: Correlation of clinical and biologic features. Am J Surg Pathol 25:1111–1120, 2001. Bolognia JL, Jorizzo JL, Rapini RP (eds): Dermatology. Edinburgh, Mosby, 2003. Brown TS, Marshall G, Callen JP: Cavitating pulmonary infiltrate in an adolescent with pyoderma gangrenosum: A rarely recognized extracutaneous manifestation of a neutrophilic dermatosis. J Am Acad Dermatol 43:108–112, 2000. Butnor KJ, Guinee DG Jr: Pleuropulmonary pathology of Birt-Hogg-Dub´e syndrome. Am J Surg Pathol 30:395–399, 2006. Callen JP: Pyoderma gangrenosum. Lancet 351:581–585, 1998. Callen JP: Dermatomyositis. Lancet 355:53–57, 2000. Callen JP: Neutrophilic dermatoses. Dermatol Clin 20:409– 419, 2002. Callen JP, Jorizzo JL, Bolognia JL, et al: Dermatological Signs of Internal Disease, 3rd ed. London, Saunders, 2003. Cowper SE, Boyer PJ: Nephrogenic systemic fibrosis: An update. Curr Rheumatol Rep 8:151–157, 2006. Douglas WW, Tazelaar HD, Hartman TE, et al: Polymyositisdermatomyositis-associated interstitial lung disease. Am J Respir Crit Care Med 164:1182–1185, 2001. Eichenfield LF: Consensus guidelines in diagnosis and treatment of atopic dermatitis. Allergy 59:86–92, 2004. English JC 3rd , Patel PJ, Greer KE: Sarcoidosis. J Am Acad Dermatol 44:725–743, 2001. Fazeli MS, Bateni H: Actinomycosis: A rare soft tissue infection. Dermatol Online J 11:18, 2005. Fradin MS, Kalb RE, Grossman ME: Recurrent cutaneous vasculitis in cystic fibrosis. Pediatr Dermatol 4:108–111, 1987. Freedberg IM, Eisen AZ, Wolff K, et al (eds): Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York, McGrawHill, 2003. French LE, Trent JT, Kerdel FA: Use of intravenous immunoglobulin in toxic epidermal necrolysis and StevensJohnson syndrome: Our current understanding. Int Immunopharmacol 6:543–549, 2006. Gallitelli M, Pasculli G, Fiore T, et al: Emergencies in hereditary haemorrhagic telangiectasia. QJM 99:15–22, 2006. Guillevin L, Pagnoux C, Mouthon L: Churg-strauss syndrome. Semin Respir Crit Care Med 25:535–545, 2004. Harris RB, Heaphy MR, Perry HO: Generalized elastolysis (cutis laxa). Am J Med 65:815–822, 1978. Kang EH, Lee EB, Shin KC, et al: Interstitial lung disease in patients with polymyositis, dermatomyositis and amyopathic dermatomyositis. Rheumatology (Oxford) 44:1282– 1286, 2005. Lynch JP 3rd, White E, Tazelaar H, et al: Wegener’s granulomatosis: Evolving concepts in treatment. Semin Respir Crit Care Med 25:491–522, 2004. Marie I, Hachulla E, Cherin P, et al: Interstitial lung disease in polymyositis and dermatomyositis. Arthritis Rheum 47:614–622, 2002.

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McDuffie FC, Sams WM Jr, Maldonado JE, et al: Hypocomplementemia with cutaneous vasculitis and arthritis. Possible immune complex syndrome. Mayo Clin Proc 48:340– 348, 1973. Mendoza FA, Artlett CM, Sandorfi N, et al: Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 35:238–249, 2006. Molinari E, De Quatrebarbes J, Andre T, et al: Cetuximabinduced acne. Dermatology 211:330–333, 2005. Ortiz PG, Skov BG, Benfeldt E: Alpha-1-antitrypsin deficiency-associated panniculitis: Case report and review of treatment options. J Eur Acad Dermatol Venereol 19:487– 490, 2005. Patel A, Teixeira F, Redington AE: Palmoplantar keratoderma (“tripe palms”) associated with primary pulmonary adenocarcinoma. Thorax 60:976, 2005. Patterson CC, Ross P Jr, Pope-Harman AL, et al: Alpha-1 anti-trypsin deficiency and Henoch-Schonlein purpura associated with anti-neutrophil cytoplasmic and antiendothelial cell antibodies of immunoglobulin-A isotype. J Cutan Pathol 32:300–306, 2005. Pellet C, Kerob D, Dupuy A, et al: Kaposi’s sarcoma-associated herpesvirus viremia is associated with the progression of classic and endemic Kaposi’s sarcoma. J Invest Dermatol 126:621–627, 2006. Requena L, Requena C: Erythema nodosum. Dermatol Online J 8:4, 2002. Rigau NC, Daele JJ: The yellow nail syndrome. Acta Otorhinolaryngol Belg 57:221–224, 2003. Safdar Z, O’Sullivan M, Shapiro JM: Emergent bullectomy for acute respiratory failure in Ehlers-Danlos syndrome. J Int Care Med 19:349–351, 2004.

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Scnirer II, Yao JC, Ajani JA: Carcinoid: A comprehensive review. Acta Oncol 42:672–692, 2003. Sehgal VN, Srivastava G: Toxic epidermal necrolysis (TEN) Lyell’s syndrome. J Dermatolog Treat 16:278–286, 2005. Serraino D, Angeletti C, Carrieri MP, et al: Kaposi’s sarcoma in transplant and HIV-infected patients: An epidemiologic study in Italy and France. Transplantation 80:1699–1704, 2005. Sowers JR, Lippman HR: Cushing’s syndrome due to ectopic ACTH production: Cutaneous manifestations. Cutis 36:351–352, 354, 1985. Steen VD: The lung in systemic sclerosis. J Clin Rheumatol 11:40–46, 2005. Trent JT, Kirsner RS: Identifying and treating mycotic skin infections. Adv Skin Wound Care 16:122–129, 2003. Wang J, Zhu X, Li R, et al: Paraneoplastic pemphigus associated with Castleman tumor: a commonly reported subtype of paraneoplastic pemphigus in China. Arch Dermatol 141:1285–1293, 2005. Webb KG, Malone JC, Callen JP: Acral psoriasiform eruption in a man with squamous cell carcinoma of the tonsillar pillar. Arch Dermatol 141:389–394, 2005. Wisnieski JJ, Baer AN, Christensen J, et al: Hypocomplementemic urticarial vasculitis syndrome. Clinical and serologic findings in 18 patients. Medicine (Baltimore) 74: 24–41, 1995. Yosipovitch G, Greaves MW, Schmelz M: Itch. Lancet 361:690–694, 2003. Zulian F, Vallongo C, Woo P, et al: Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 52: 2873–2881, 2005.

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29 Pulmonary-Systemic Interactions Alfred P. Fishman

I. THE LUNG AS AN ENDOCRINE ORGAN The Pulmonary Endocrine System Paraneoplastic Syndromes II. PULMONARY VASCULAR ENDOTHELIUM III. THE GUT-LIVER-LUNG AXIS Dietary Pulmonary Hypertension Ventilation and Circulation in Liver Cirrhosis IV. SEPSIS-INDUCED MULTIPLE ORGAN FAILURE

VI. GENERAL SYSTEMIC EFFECTS OF PULMONARY DISEASE Fever, Chills, Sweating Body Wasting VII. SPECIFIC SYSTEMIC EFFECTS OF PULMONARY DISEASE Clubbing of the Digits and Hypertrophic Osteoarthropathy VIII. CONCLUSIONS

V. INJURY BY OXYGEN-DERIVED PRODUCTS Mechanisms of Action Generation of Toxic Reactive Oxygen Species

The lungs are incorporated into the body in such a way as to serve a variety of functions other than external gas exchange. These include hemodynamic, metabolic, endocrine, and immunologic activities. Inadequacy or failure on the part of any of these functions can have serious systemic repercussions. Moreover, as part of the total body fabric, the lungs share in diverse pathological processes, such as collagen vascular diseases, and inherit susceptibility to others, such as cystic fibrosis, in which a generalized defect in ion transport across epithelial surfaces affects the liver, gastrointestinal tract, and pancreas, as well as the lungs. Because of its strategic location between the two ventricles and as the recipient of the entire output of the right ventricle, the pulmonary circulation is uniquely situated to transmit the products of pulmonary metabolism and injury to systemic organs and tissues. Its position at the exit of the right ventricle also enables the pulmonary vascular bed to serve as a filter for particulate matter arising in the systemic venous circulation (e.g., thromboemboli). Finally, the arrangement in series of the gastrointestinal tract, liver, and lungs enables interdependence in the handling of biologically active materials that release in health (Fig. 29-1) and disease (e.g., hepatic cirrhosis, gastrointestinal disorders, and splenic dysfunctions).

The diversity of cells that constitute the pulmonary parenchyma, the vasculature, and the airways, coupled with the ready access of blood constituents to the structures in the lungs, affords great opportunity for the lungs to influence systemic organs and vice versa. For example, the endothelial cells that line the enormous expanse of pulmonary vessels can release vasodilator or vasoconstrictor substances, anticoagulants, and a wide variety of enzymes and cytokines into the circulation. Mast cells in the vicinity of the pulmonary vessels can release a variety of substances that can influence both intrapulmonary and extrapulmonary vessels and structures. Chloride-secreting cells, not only in the airways but also in other glandular structures (e.g., sweat glands, pancreas), can suffer inherited defects that disturb different kinds of bodily functions. Immunologically competent cells in the lungs that are part of natural body defenses can open the way for serious systemic infections if their guard is dropped or if environmental pollutants are overwhelming. The large pulmonary blood flow and the brief pulmonary transit time ensure virtually instantaneous exposure to biologically active substances originating in the lungs. Among these substances are hormones (e.g., angiotensin II), mediators (e.g., nitric oxide), and neurotransmitters. Disease,

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cells (i.e., pulmonary endocrine cells) which are part of a widespread system that is contained within other organs as well as within the lungs. The so-called pulmonary endocrine cells have attracted the attention of clinicians more because of their potential for undergoing neoplastic transformation than because of recognizable biologic functions.

The Pulmonary Endocrine System

Figure 29-1 The sequential processing of serotonin.

such as pneumonia, can promote the release of inflammatory and immunologic mediators from both the resident cells and the migratory blood cells (e.g., leukocytes). Another access route to the lungs is the bronchial circulation. This systemic blood supply can undergo remarkable proliferation in some diseases (e.g., bronchiectasis), but remain small in others (e.g., primary carcinoma of the lung). As is noted below, proliferation of the bronchial circulation often accompanies clubbing of the digits.

Pulmonary endocrine cells, or pulmonary neuroendocrine cells, have been found in a wide variety of species, ranging from the African lungfish to humans. These cells can be found in the respiratory epithelium from trachea to alveolar walls, where they may appear as single cells, as clusters associated with nerve terminals (neuroepithelial bodies), or in mounds (tumorlets). The typical pulmonary endocrine cell is usually argyrophilic and is characterized ultrastructurally by a densecore vesicle surrounded by clear scant cytoplasm; within the core are granular chromatin bodies and prominent nucleoli. Histochemistry and immunochemistry have displayed a large spectrum of biologically active mediators, including serotonin, calcitonin, substance P, cholecystokinin, somatostatin, calcitonin gene-related peptide, and bombesinlike peptides. Although these substances have been identified in cells and in serum, few have yet proved to be of clinical significance, although a variety of physiological functions (i.e., vasomotor, bronchomotor, secretomotor, and inflammatory) have been attributed to them. The basal aspect of these cells is often closely related to nerve endings or nerve varicosities. Acute hypoxia has been shown to cause exocytosis of the dense-core vesicles in neuroepithelial bodies, presumably a reflection of a receptor or effector function. Cells of the pulmonary endocrine system can give rise to neoplasms with endocrine characteristics. These endocrine tumors can be pictured as a continuum of neoplasms that range from benign to malignant (i.e., from carcinoid to small cell carcinoma). The carcinoids mark one end of the continuum: they are the more highly differentiated, and their endocrine features are the most marked. Toward the opposite end are the small cell carcinomas, which are poorly differentiated. Nonâ&#x20AC;&#x201C;small cell carcinomas are less apt to show endocrine differentiation. In this continuum, carcinoids are generally indolent, whereas small cell carcinomas are very aggressive.

THE LUNG AS AN ENDOCRINE ORGAN In addition to its roles in gas exchange and water exchange, the lung is active metabolically. The metabolic processes entail uptake, storage, and elaboration of substances, many of which (such as nitric oxide) function locally, whereas others, such as angiotensin II (Fig. 29-2), exert their effects on remote tissues and organs (i.e., they enter the bloodstream and influence systemic tissues and organs). In addition to such chemical messengers, the lungs secrete amines and peptides, whose functions are far less well defined. These messengers are released by a system of epithelial

Paraneoplastic Syndromes Pulmonary neoplasms are more commonly associated with paraneoplastic syndromes than are any other types of neoplasms. Three types of paraneoplastic syndromes illustrate the systemic effects of pulmonary neoplasms: the carcinoid syndrome, Cushingâ&#x20AC;&#x2122;s syndrome, and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Clubbing of the digits is considered below. The carcinoid syndrome is attributed to the release of various mediators from the neoplasm, owing to either

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Figure 29-2 The renin-angiotensin system. The interplay among kidney, liver, and lungs results in the formation of angiotensin II. This hormone, generated in the lungs from precursors in the kidneys and blood, is active in the regulation of systemic blood pressure. It does so by way of its effects as a systemic vasoconstrictor and as a regulator of the circulating blood volume. The latter operates through the salt- and water-retaining effects of aldosterone.

a carcinoid tumor or, less often, a small cell carcinoma. Various mediators have been implicated, including serotonin, histamine kinins, and prostaglandins. The systemic effects include flushing, diarrhea, bronchospasm, and heart disease. Cushingâ&#x20AC;&#x2122;s syndrome is due to excessive secretion of adrenocorticotropic hormone (ACTH) or ACTH-like peptides by the neoplasm, generally a small cell carcinoma. The systemic effects are hypokalemic alkalosis, systemic hypertension, impaired carbohydrate tolerance, muscle weakness and wasting, edema, and weight loss. SIADH generally occurs in association with pulmonary tuberculosis or bronchial carcinoma. The clinical syndrome, caused by inappropriate secretion of arginine vasopressin and antidiuretic hormone, is manifested by hyponatremia (not attributable to drugs), water retention, hyperosmolar plasma accompanied by disproportionately high hyperosmolarity of the urine, persistent natriuresis without volume depletion, and hypouricemia. These disorders may lead to altered mental state, lethargy, confusion, psychosis, or coma. Other familiar syndromes involving pulmonary neoplasms in association with systemic effects are clubbing of the digits, gynecomastia, a variety of cutaneous disorders (e.g., acanthosis nigricans), neurological disorders (e.g., cerebellar degeneration), and autonomic disturbances (e.g., orthostatic hypotension).

PULMONARY VASCULAR ENDOTHELIUM The lungs contain the largest expanse of endothelium in the body. This lining of the pulmonary circulation is engaged in a variety of vital functions (Table 29-1). Some, such as pulmonary vasodilation, are served by local mediators, such as nitric oxide and prostacyclin. Countering these effects are local vasoconstrictors, such as the endothelins. As noted above, other products, such as angiotensin II, exert their effects on remote functions (e.g., in the regulation of systemic blood pressure). Endothelin (ET-1) is a powerful vasoconstrictor peptide which is synthesized by vascular endothelium. Increased circulating levels of ET-1 have been reported in pulmonary arterial hypertension. Endothelin contributes to setting pulmonary vascular tone by counterbalancing the vasodilatory effects of prostacyclin and other endothelium-derived relaxing substances. In addition to its vasoconstrictor actions, endothelin exerts a variety of other biologic effects depending on the cell type on which the receptors are found: positive inotropic and chronotropic effects on the heart, decrease in renal blood flow and filtration rate, and release of atrial natriuretic peptide (ANP). Among its deleterious effects are vasoconstriction, vascular hypertrophy, cell proliferation, fibrosis, and inflammation. ET-1 has been implicated in the

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Table 29-1 The Processing of Certain Vasoactive Substances by the Lungs Metabolized at the luminal surface Angiotensin I Bradykinin Adenine nucteotides Uptake by endothelium and then metabolized Serotonin Norepinephrine Prostaglandins E and F Released by endothelium Lipoprotein lipase Heparin Prostacyclin Kallikrein Leukotrienes Unaffected in traversing the lungs Angiotensin II Epinephrine Dopamine Vasopressin Prostaglandin A Vasoactive intestinal polypeptide Oxytocin The Generation of Vasoactive Substances by the Lungs Endothelins Nitric oxide Prostacyclin Hyperpolarizing factor

pathogenesis of systemic hypertension, pulmonary hypertension, and heart failure. Bosentan, a non-selective ET-1 receptor antagonist, is currently used in the treatment of pulmonary hypertension. Nitric oxide is a highly reactive gas. It is synthesized within cells by nitric oxide synthase (NOS). The human genome contains three different genes that encode NOS, one of which, NOS-3, is found in endothelial cells. NOS is produced from arginine with the aid of molecular oxygen and nicotinamide adenine dinucleotide phosphate (NADPH). Nitric oxide acts as a vasodilator and anti-aggregator of platelets. The feasibility of direct measurements of the release of nitric oxide into expired air by vasoactive drugs has been demonstrated in both pigs and humans. Thrombin is another interactive substance. It plays a key role in coagulant processes: on the one hand, it is procoagulant (i.e., it activates platelets, stimulates monocyte and

neutrophil chemotaxis, cleaves fibrinogen, stimulates the endothelial release of tissue factors, and releases von Willebrand factor from Weibel-Palade bodies); on the other, it can serve as an anticoagulant molecule that stimulates protein C activity, promotes prostacyclin secretion, and causes the liberation of tissue plasminogen activators. Thrombin is also a potent growth factor that initiates proliferation of smooth-muscle cells at the site of injury. These diverse effects are due to the prevalence of thrombin receptors in many cell types. A variety of strategies to inhibit thrombin are being tested for therapeutic purposes: hirudin has been used to prevent the cleavage of fibrinogen and activation of thrombin receptors; peptides that act as antagonists for thrombin receptors are being tested; monoclonal and polyclonal antibodies are being developed that prevent activation of thrombin receptors; antisense oligonucleotides are being tried to block expression of thrombin receptors. Chronic injury to the pulmonary vascular endothelium can evoke proliferation of the intima, invasion of the endothelial lining by underlying smooth muscle and adventitial cells, and accumulation of blood cells at the blood-endothelial interface. The end result is replacement of the single endothelial lining layer by occlusive heaps of endothelial, smooth-muscle connective-tissue cells (Figs. 29-3 and 29-4). How well the heaped-up endothelium preserves the functions of normal endothelial function (e.g., anticoagulation) is not clear. The pulmonary circulation, like the systemic venous circulation, remains virtually free of atherosclerotic lesions unless pulmonary arterial blood pressures increase to hypertensive levels. Acute injury to endothelium can provide access of circulating proteins, such as fibrinogen, and blood cells to the pulmonary interstitium, thereby setting the stage for interstitial fibrosis. Aside from leakage, endothelial injury can stimulate a complex array of local reactions: circulating white blood cells and platelets are drawn to the injured site, undergo activation, and release factors that contribute to the response.

THE GUT-LIVER-LUNG AXIS Perhaps nowhere is the principle of effluent from one organ influencing the behavior of its neighbor better illustrated than in the gut-liver-lung axis (Fig. 29-5). Misbehavior by any one of the series can seriously derange the workings of the next in line and the entire organism. For example, in liver failure, not only are noxious substances added to its effluent but also injurious substances from the gut, spleen, and other systemic organs, which are normally detoxified by the liver, gain access to the pulmonary circulation. The remote consequences of liver injury, such as clubbing of the digits in patients with liver cirrhosis, are considered below.

Dietary Pulmonary Hypertension In 1974, the concept of dietary pulmonary hypertension was proposed. The idea stemmed from the ability of the drug

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Figure 29-3 Normal and abnormal endothelium. Various endothelial abnormalities illustrating the different surfaces encountered by the perfusing blood.

aminorex in humans and the plant crotalaria in animals to elicit pulmonary hypertension. The generalization from this experience with drugs and plants taken by mouth was that other medications, foods, and herbs, taken by mouth, might injure the pulmonary circulation sufficiently to evoke pulmonary hypertension. Since then, ample evidence has accrued in support of this hypothesis (e.g., the toxic oil syndrome; fenfluramine derivatives; female â&#x20AC;&#x153;crack-cocaineâ&#x20AC;? users). The outbreak of primary pulmonary hypertension attributed to aminorex occurred in Austria, Switzerland, and Germany, and came to a close after the sale of the over-thecounter drug was stopped. Aminorex is a catechol derivative that acts by releasing norepinephrine at nerve terminals and synapses. One important lesson from the aminorex experience was that individual susceptibility was prerequisite for developing pulmonary hypertension: of the many thousands who used the drug, only a few developed the findings of primary pulmonary hypertension. History repeated itself in April 1996, when another anorexigenic agent, dexfenfluramine, became available in drugstores throughout the United States. Its use spread widely. Dexfenfluramine exerts its pharmacologic effects by its enhancing effects on serotonin-mediated neurotransmission: it blocks serotonin reuptake, whereas its principal metabolite, dexnorfenfluramine, not only releases serotonin into synapses but also activates 5-HT2 receptors. After sporadic case reports in the early 1980s of the association of pulmonary hypertension with the use of fenfluramine, Brenot and colleagues published a retrospective analysis that linked fenfluramine use with primary pulmonary hypertension. A follow-up, case-controlled study under the auspices of the Medical Research Council of Canada confirmed

the higher incidence of primary pulmonary hypertension in people taking anorexigens, predominantly fenfluramine or dexfenfluramine. Moreover, the use of the anorexigen for more than a few months was associated with increased risk of primary pulmonary hypertension. Because of the widespread use of anorexigens, an outbreak of primary pulmonary hypertension seems inevitable. Indeed, a registry set up to keep track of such cases has already received reports of people in whom the use of anorexigens is associated with primary pulmonary hypertension.

Ventilation and Circulation in Liver Cirrhosis Liver cirrhosis, and the accompanying portal hypertension, is often associated with striking changes in the pulmonary circulation. Some of these changes appear to be diametrically opposite. Thus, on the one hand the minute vessels of the lungs often show evidence of vasodilation in the pulmonary microcirculation (e.g., dilated arterioles and capillaries), whereas on the other hand the pulmonary microcirculation may be affected in obliterative vascular disease. The mechanisms at work are speculative. For example, the commonly held view that the obliterative pulmonary disease originates in pulmonary vasoconstriction, presumably because of some unknown vasoconstrictor mechanism, is unproven. Three aspects of the lung-liver relationship in liver cirrhosis have received special attention: pulmonary vasomotor control, pulmonary vasodilation, and pulmonary hypertension. Ventilatory Responses to Hypoxia in Liver Cirrhosis Hypoxic pulmonary vasoconstriction is blunted in patients with chronic liver disease, indicating a defect in intrinsic autonomic control. This blunting is in the face of the characteristic

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Figure 29-4 Microscopic appearance of small pulmonary muscular arteries and arterioles, illustrating different degrees of intimal proliferation and vascular occlusion. Plexiform lesion is at bottom right.

high-cardiac-output state that is a feature of patients with liver cirrhosis. The mechanism responsible for both the highoutput state and the blunted hypoxic pulmonary pressor response is unknown. Nitric oxide is the most recent candidate to explain the high-output state associated with liver cirrhosis.

CIRCULATORY ADAPTATIONS IN LIVER CIRRHOSIS Mild arterial hypoxemia is found in 30 to 70 percent of patients with hepatic cirrhosis. This arterial hypoxemia is attributable to â&#x20AC;&#x153;anatomicâ&#x20AC;? venous admixture (i.e., to anatomic shunts or to their equivalent; the rapid passage of unoxygenated blood past the gas-exchanging surfaces of the lungs).

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Portal-Pulmonary Hypertension The association of pulmonary hypertension with liver cirrhosis has attracted considerable attention. The pulmonary hypertension is due to obliterative pulmonary vascular disease. In the 1960s, the obliterative pulmonary vascular disease in patients with liver cirrhosis was attributed to organized pulmonary emboli that originated in thrombi in the portal vein. Since then, this possibility has largely been discounted, and it is now generally recognized that the pulmonary vascular lesions are identical with those of primary pulmonary hypertension. The etiology of portal-pulmonary hypertension remains speculative. Among the possibilities being entertained is the prospect that vasoconstrictor substances or autoimmune substances, or other injurious agents, might start the obliterative process by injuring pulmonary vascular endothelium. The arrangement of the gut, liver, and lungs in series nurtures this hypothesis. One intriguing aspect of this proposition is why the endothelium of pulmonary resistance vessels should be extensively affected by the injury while the more extensive endothelium of the pulmonary capillary bed is spared.

SEPSIS-INDUCED MULTIPLE ORGAN FAILURE

Figure 29-5 The gut-liver-lung axis.

This abbreviated transit time is, in turn, due to a combination of high-cardiac output and dilation of the pulmonary precapillaries and capillaries. Dilatation of microvessels in liver cirrhosis is not confined to the lungs. Instead, it occurs throughout the body, including the skin and kidneys. In the fingers, it contributes to the rare occurrence of clubbing in patients with liver cirrhosis. Inexplicably, the blood vessels on the pleural surface are more affected by dilatation than are the intrapulmonary vessels. The spider nevi on the pleural surface are fed by the pulmonary circulation. They are composed of short vessels, less than 1 mm in diameter, and are generally quite conspicuous. Although anatomic dilation of intrapulmonary microvessels has often been seen at autopsy, as a rule such dilatation is rare compared to that on the surface of the lung.

Probably the most striking impact of the lungs on the rest of the body is exemplified by multiple-organ failure that complicates the adult respiratory distress syndrome (ARDS). Indeed, most patients who die of ARDS do so because of multipleorgan failure rather than from the lung disease. In recent years, the liver, as well as the kidneys, has been recognized to be a major determinant of the outcome of ARDS. In its systemic effects, ARDS behaves like sepsis elsewhere in the body, overwhelming host defenses by the release into the circulation of inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). TNF continues to be the major center of attention. Endotoxin is the most potent stimulus known for the production of TNF. Instead of acting directly to cause injury, endotoxin (or its lipopolysaccharide) prompts the formation of host factors that cause the damage. Macrophages are deeply implicated in generating these host factors. In addition to releasing injurious agents, sepsis interferes with the biologic inactivation of mediators of inflammation. Novel therapies have been directed at countering the role of TNF in the septic shock syndrome. These include anti-TNF monoclonal antibodies, soluble TNF receptors, and soluble TNF receptor-immunoglobulin G heavy-chain fusion proteins. These approaches are still under development. Recently, attention has turned to attempts at blocking the production of nitric oxide, an endogenous vasodilator and immune modulator that may be active in inducing the systemic hypotension associated with sepsis. The target has been nitric oxide synthase (NOS), the enzyme that produces nitric

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oxide. Blocking NOS affords promise not only of relieving systemic hypotension but also of favorably influencing other harmful processes that may contribute to organ failure, including direct tissue injury, myocardial depression, derangement of cellular metabolism, and release of inflammatory cytokines (e.g., TNF) from macrophages. However, the therapeutic role of inhibiting nitric oxide has not yet been settled because nitric oxide may have beneficial as well as harmful properties.

INJURY BY OXYGEN-DERIVED PRODUCTS Mechanisms of Action In recent years, mounting evidence has implicated oxidative injury in the pathogenesis of a wide array of biologic processes, ranging from the normal aging process to a variety of disease states, including atherosclerosis, carcinoma, and ischemia-perfusion injury. Oxidative injury has also been increasingly held responsible for diverse diseases of the lungs and airways, such as emphysema, interstitial pulmonary fibrosis, asthma, and ARDS. The relationship between cigarette smoking and the development of emphysema illustrates one pathway: oxygen-derived products, either contained in cigarette smoke or generated by activated leukocytes attracted to the lungs by smoking, oxidize the methionine residue of α1 -antitrypsin, an antiprotease, thereby inactivating it and enabling the destruction by proteases of alveolar walls (see Chapter 41). The abnormal pulmonary function that ensues exerts systemic effects by way of abnormal blood gases and mechanics of breathing, stimulation of respiratory control mechanisms, and the sensation of dyspnea. The oxidant injury may be aggravated by administration of supplementary oxygen in the form of O2 -enriched inspired air mixtures. Sensitized asthmatics respond to an allergen by degranulation of mast cells, which causes the release of TNFα. In turn, TNFα prompts the migration of neutrophils and eosinophils to the site of the allergic reaction. At this site, the leukocytes release toxic oxygen products, which contribute importantly to the inflammatory response. Most of the molecular oxygen entering the body is reduced sequentially to water via the respiratory chain. However, in the course of the serial reductions that are part of normal intermediary metabolism, superoxide anion (O2– ) and hydrogen peroxide (H2 O2 ) are generated as undesirable by products.

Generation of Toxic Reactive Oxygen Species Cells that respire aerobically generate toxic reactive oxygen species. These reactive species are produced not only in the course of normal aerobic metabolism but also as by products of inflammatory reactions. The toxic reactive species known as free radicals include the superoxide anion and hydroxyl

Figure 29-6 The generation of oxygen free radicals by the addition of electrons.

radicals and hydrogen peroxide (Fig. 29-6). Cellular damage is inflicted by these species on proteins, nucleic acids carbohydrates, and lipids. Damage to the lungs inflicted by free radicals (e.g., ARDS) can exert disastrous effects on systemic organs (e.g., renal failure). In turn, the cell damage causes the induction of antioxidant genes that prompt the elaboration of enzymes directed at scavenging the reactive oxygen species. Among the clinical situations in which free radicals feature prominently are reperfusion injury and the adverse immunologic responses elicited by organ transplant action. In the lungs, reactive oxygen species from the environment can inflict damage. Oxygen toxicity, produced by breathing O2 -enriched inspired air, affords a traditional example of injury produced by O2 -derived products. Within 24 h of the start of oxygen breathing, the endothelium of the pulmonary microcirculation is damaged and becomes “leaky,” enabling blood plasma to gain access to the interstitial spaces and alveoli. Along with excess fluid and serum proteins, inflammatory cells accumulate in the lungs. Should exposure to the O2 -rich inspired gas continue, the end point can be ARDS. One experimental strategy for mimicking the pathological and pathophysiological changes in the lungs induced by oxygen toxicity is the administration of endotoxin. Another mechanism for causing oxidant injury involves nitric oxide (see Chapter 25). Nitric oxide, a mediator of signal transduction with diverse physiological functions, is categorized as a free radical because of its unpaired electron. Because of this property, it has biologically important reactivities with certain kinds of proteins, carbohydrates, and other free radicals (e.g., superoxide radicals). In its reactions with other free radicals, it can yield even more potent oxidants (e.g., peroxynitrite). Some toxic reactions, originally attributed to its chemical precursors, superoxide and nitric oxide, are now attributed to peroxynitrite. Oppositely, nitric oxide can also exert a protective action against free radicals, such as the superoxides. Thus, nitric oxide can either inflict damage or ward

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it off, depending on the oxidative environment in which the reactions are taking place. An intense research effort is currently directed at unraveling the nature of reactions involving nitric oxide and peroxynitrite with proteins, lipids, carbohydrates, and gene expression in a variety of pathological processes. The amino acid homocysteine is operative in another mechanism by which oxidative injury can damage endothelium. This mechanism is mediated primarily by autooxidation, which generates the superoxide anion radical (Oâ&#x20AC;&#x201C;2 ) and H2 O2 and the hydroxyl radical (OHÂˇ). Abnormally high levels of homocysteine in plasma blunt the responses of endothelium to endothelium-dependent vasodilators (e.g., nitric oxide) by way of the damage caused by products of homocysteine oxidation. The antithrombotic function of endothelium and the migration and proliferation of vascular smooth-muscle cells are also affected by high levels of homocysteine. Two other clinical areas in which oxidant-produced injury features prominently are the inhalation or ingestion of oxidants (e.g., paraquat) and the chronic injury caused by smoking, which predisposes to low-level inflammation, pulmonary damage, and neoplasm.

Pulmonary-Systemic Interactions

Table 29-3 Some Substances from Pulmonary Endocrine Neoplasms That Can Affect Systemic Organs and Tissues Adrenocorticotropin Calcitonin and calcitonin gene-related peptide Arginine vasopressin Growth hormone Serotonin Pituitary gonadotropins Thyroid-stimulating hormone Vasoactive intestinal polypeptide Insulin Parathyroid hormone

GENERAL SYSTEMIC EFFECTS OF PULMONARY DISEASE

Somatostatin Renin

Pulmonary infections and neoplasms are notorious for the systemic effects that they can elicit (Table 29-2). Pneumonias caused by bacteria, mycoplasma, viruses, or fungi can cause a spectrum of disturbances, ranging from mild fever to bacteremia and circulatory collapse. Viral infections commonly induce leukopenia, anemia, and thrombocytopenia. Metabolic derangements are also the rule in these acute

Table 29-2 General Systemic Effects of Nonrespiratory Diseases of the Lung Disturbances in the control of body temperature (fever, chills, sweating) Central nervous system abnormalities (euphoria, irritability, confusion, delirium) Faintness, reduced alertness, syncope (postural hypotension, arrhythmias, decreased blood flow to the brain) Anorexia, asthenia, cachexia Remote organ failure

Gastrin Prolactin Bombesinlike peptides

disorders; abnormal hepatic and bone marrow functions are the bases for common abnormalities (e.g., high erythrocyte sedimentation rate and leukocytosis). The span of disturbances is just as great for neoplasms, not only because they encroach on adjacent structures and functions but also because of derangements in remote bodily functions that they cause by releasing biologically active materials (Table 29-3; see also Chapter 134). The impact of pulmonary disease on the rest of the body rises exponentially when infectious organisms or neoplastic cells escape the confines of the lungs to enter the bloodstream. Bacteremia, viruses, fungi, and other microorganisms can invade the bloodstream from the lungs. Such infections gain in virulence with increasing numbers of organisms and their products; the elderly are particularly vulnerable to the systemic effects of pulmonary infections. Among the common consequences of diseases that begin in the lungs and affect the rest of the body are fever and body wasting.

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Fever, Chills, Sweating There are many causes of fever. Among the most common are infections, inflammation, injury to the central nervous system, thrombosis, hematoma, vasculitis, and necrosis. Fever is generally regarded as harmful. However, fever has enhancing functions. For example, in infections, it enhances neutrophil migration and the production of antibiotic substances by neutrophils. The body is constructed to keep internal core temperature stable at about 37.1◦ C (corresponding to a rectal temperature of about 37.6◦ C) and equipped with automatic feedback devices that minimize fluctuations in the core temperature. Regulation of the core temperature is accomplished almost entirely by neural feedback mechanisms, virtually all of which are controlled by temperature-regulating mechanisms in the hypothalamus. Fever represents an upward shift in the thermostatic set point. The automatic attempt by the body to restore body temperature to normal includes cutaneous vasodilatation, sweating, decreased chemical thermogenesis, and a widespread decrease in muscle tone due to reflex inhibition of the primary motor center for shivering. Chills are a response to an abrupt disparity between the set point of the thermostat in the hypothalamus and the temperature of the blood. Certain substances, notably pyrogens and products of tissue destruction (see next paragraph), can suddenly raise the hypothalamic set point without raising body temperature. Until the body temperature catches up, mechanisms to raise it are turned on, and the subject feels cold and experiences chills—even while the body temperature is increasing to match the hypothalamus set point: the cold sensation is a consequence of cutaneous vasoconstriction, whereas shivering causes the “shakes.” When the body temperature reaches the higher set point, chills cease and the subject feels neither cold nor hot. Until the factor responsible for increasing the set point stops, the febrile state is maintained by the usual mechanisms. Precipitous discontinuance of the initiating factor results in widespread cutaneous dilatation and flushing and intense sweating (i.e., “the crisis”). Pyrogens feature prominently in causing clinical fevers. They do so, directly or indirectly, by raising the thermostatic set point in the hypothalamus. Particularly effective in this regard are endotoxins produced by gram-negative bacteria. Leukocytes and macrophages act as intermediaries in this process: these phagocytic cells, after digesting the bacterial products, release leukocyte or endogenous pyrogen, which, in minute amounts, stimulates the hypothalamus to raise its set point; prostaglandin E1 is presumably the intermediary within the cells of the hypothalamus that effects the febrile response. Blockage of prostaglandin formation, as by aspirin, can prevent or reduce the febrile response. Chills, fever, and sweating are familiar manifestations of the syndrome of pneumococcal pneumonia and its complications. Some infecting organisms tend to be associated with distinctive diurnal fever patterns. Although these patterns were once regarded as diagnostic clues to the etiological agent, not much clinical attention is now paid to patterns,

although the peaks and valleys in the fever curves can suggest clues to origin, and undue persistence of fever may signal a complication.

Body Wasting Progressive infection or the growth of a neoplasm often elicits anorexia, weight loss, and cachexia. Cachexia is characterized by an inexorable loss of weight that is inordinate for the degree of anorexia and the decrease in food intake. Both adipose tissue and muscle mass are depleted; death usually is the end result of progressive depletion of lean body tissue. Anorexia and underlying metabolic abnormalities appear to be at work in the pathogenesis of cachexia. Anorexia regularly accompanies weight loss. Although the initiating mechanism for anorexia seems to relate to the infection or neoplasm, in time other mechanisms supervene. Among these are depression, continued immobilization, and comorbid conditions. Appetite suppression is often aggravated further by medications. Attempts to reverse cachexia by nutritional supplements are rarely successful. Key factors in the production of cachexia fall into three categories: (1) metabolic products of the pathogen or neoplasm; (2) catabolic hormones and a lipid-mobilizing factor (LMF) produced by neoplasms that acts to cause breakdown of adipose tissue; and (3) cytokines, such as TNFα and interleukin-6 (IL-6), which seem to affect adipose tissue by inhibiting lipoprotein lipase. TNFα plays a pivotal role. It is produced by macrophages, monocytes, and T cells, and its toxic effects are exceedingly diverse: it is a pyrogen, directly damages endothelium, can suppress adipose-specific enzymes, and is a mediator of the inflammatory process. Since the 1994 discovery of leptin, a hormone active in the control of body weight, interest in starvation has taken a new turn. Leptin is a hormone produced by the obesity gene (ob), manufactured by adipocytes, and delivered to receptors in the hypothalamus (arcuate nucleus and paraventricular nucleus). Leptin functions as a lipostat: when fat stores increase, adipocytes produce leptin, which tells the brain to decrease appetite and increase activity. Leptin exerts its effects via a complex interplay that involves neuropeptide Y and the melanocortins, a family of peptides. Decreased leptin levels work through neuropeptide Y to deal with the stresses of starvation; high levels may work through melanocortins to resist overweight. One feature of starvation is altered endocrine activity (e.g., decreased production of thyroid and sex hormones and increased production of adrenal stress hormones). Low levels of leptin elicit starvation-induced changes in endocrine function. The components of the hormone-neuropeptide system and their interplay in the control of body weight are currently under intense investigation. Most studies have been conducted in the rat, however, and their implications for human disorders, such as starvation, are incompletely understood. Some success in reversing cachexia has been accomplished by the use of two groups of agents: those that stimulate

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intake of food (e.g., megestrol acetate, which can also stimulate tumor growth) and those that inhibit LMF (e.g., eicosapentaenoic acid).

SPECIFIC SYSTEMIC EFFECTS OF PULMONARY DISEASE Certain systemic manifestations, although not unique to pulmonary disease, occur often enough to warrant special mention. Among these is clubbing of the digits.

Clubbing of the Digits and Hypertrophic Osteoarthropathy The characteristic and preferential bulbous enlargement of the distal segment of the digits (Fig. 29-7) and the distinctive bony lesions of secondary hypertrophic osteoarthropathy are generally explained in terms of humoral mediators that cause selective vasodilatation of the digital precapillary vessels. As is noted in Chapter 108, this explanation seems

Pulmonary-Systemic Interactions

to suffice in certain disorders (e.g., the clubbing of the digits and the hypertrophic osteoarthropathy that accompany carcinoma of the lungs) but not in others (e.g., subacute bacterial endocarditis). One other intriguing aspect of clubbing is its association both with chronic bronchiectasis, in which the adjacent collateral circulation of the lungs undergoes remarkable proliferation, and with carcinoma of the lung, in which the collateral blood supply is modest.

CONCLUSIONS Once the metabolic functions of the lungs were fully appreciated, it became evident that interplay between the lungs and systemic tissues and organs was part of normal body functioning and that more than nervous connections is operative. This interplay became even more evident in clinical syndromes that involved the transport by the circulation (and possibly lymph) of products of inflammation from one part of the body to the other. Syndromes such as the hepatorenal syndrome and organ failure in ARDS underscored the interplay. Others, such as coexistent portal and pulmonary hypertension, remain enigmas to be resolved. With these insights came the realization that understanding of the interplay between the lungs and other organs is still in its infancy.

SUGGESTED READING

Figure 29-7 Casts of clubbed fingers. A. The second right finger of an 18-year-old woman with tetralogy of Fallot before and after surgery. Upper: Preoperatively, showing marked clubbing. Middle: Two months later, showing partial reversal of changes. Lower: Regression of the clubbing. B . The third right finger of a 40-yearold woman with digital clubbing (above), compared with that of a normal 36-year-old woman (below). (Mellins RB, Fishman AP: Digital casts for the study of clubbing of the fingers. Circulation 33:143–145, 1966.)

Abenheim L, Moride Y, Brenot F, et al: Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 335:609–616, 1996. Barie PS: Organ-specific support in multiple organ failure: Pulmonary support. World J Surg 19:581–591, 1995. Becker KL, Gazdar AF: The Endocrine Lung in Health and Disease. New York, Saunders, 1984. Bernard ER, Artigas A, Brigham KL, et al: The AmericanEuropean Consensus Conference on ARDS. Am J Respir Crit Care Med 149:818–824, 1994. Berthelot P, Walker JC, Sherlock S, et al: Arterial changes in the lungs in cirrhosis of the liver-lung spider nevi. N Engl J Med 274:291–298, 1966. Blackwell TS, Christman JW: Sepsis and cytokines: Current status. Br J Anaesth 77:110–117, 1996. Bone RC: Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome. Crit Care Med 24:163–172, 1996. Braun-Moscovici Y, Nahir AM, Balbir-Gurman A: Endothelin and pulmonary arterial hypertension. Semin Arthritis Rheum 34(1):442–453, 2004. Casale TB, Costa JJ, Galli SJ: TNFα is important in human lung allergic reactions. Am J Respir Cell Mol Biol 15:35–44, 1996. Castro M, Krowka MJ, Schroeder DR, et al: Frequency and clinical implications of increased pulmonary artery

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pressures in liver transplant patients. Mayo Clin Proc 71:543–551, 1996. Chaouat A, Weitzenblum E, Higenbottam T: The role of thrombosis in severe pulmonary hypertension. Eur Respir J 9:356–363, 1996. Demling RH: The modern version of adult respiratory distress syndrome. Annu Rev Med 46:193–202, 1995. Dupuis J: Increased endothelin levels in congestive heart failure: Does it come from the lungs? Does it matter? Cardiovasc Res 63(1):5–7, 2004. Espat NJ, Moldawer LL, Copeland EM 3rd, et al: Cytokinemediated alterations in host metabolism prevent nutritional repletion in cachectic cancer patients. J Surg Oncol 58:77–82, 1995. Griffin JA: The thrombin paradox. Nature 378:337–338, 1995. Kerr ME, Bender CM, Monti EJ: An introduction to oxygen free radicals. Heart Lung 25:200–209, 1996. Kunichika N, Landsberg JW, Yu Y, et al: Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes. Am J Respir Crit Care Med 170(10):1101–1107, 2004. Lentz SR, Sobey CG, Piegors DJ, et al: Vascular dysfunction in monkeys with diet-induced hyperhomocyst(e)inemia. J Clin Invest 98:24–29, 1996.

Li L, Zhang J, Block ER, et al: Nitric oxide-modulated marker gene expression of signal transduction pathways in lung endothelial cells. Nitric Oxide 11(4):290–297, 2004. Livingston DH, Deitch EA: Multiple organ failure: A common problem in surgical intensive care unit patients. Ann Med 27:13–20, 1995. Loprinzi CL: Management of cancer anorexia/cachexia. Support Care Cancer 3:120–122, 1995. Loscalzo J: The oxidant stress of hyperhomocyst(e)inemia [Editorial]. J Clin Invest 98:5–7, 1996. Malmstrom RE, Tornberg DC, Settergren G, et al: Endogenous nitric oxide release by vasoactive drugs monitored in exhaled air. Am J Respir Crit Care Med 168:114–120, 2003. Mandelli MS, Groves BM: Pulmonary hypertension in chronic liver disease. Clin Chest Med 17:17–34, 1996. Matuschak GM: Liver-lung interactions in sepsis and multiple organ failure syndrome. Clin Chest Med 17:83–98, 1996. Ottery FD: Supportive nutrition to prevent cachexia and improve quality of life. Semin Oncol 22:98–111, 1995. Schiffrin EL: Vascular endothelin in hypertension. Vascul Pharmacol 43:19–29, 2005. Schraufnagel DE, Kay JM: Structural and pathologic changes in the lung vasculature in chronic liver disease. Clin Chest Med 17:1–15, 1996.

SECTION SEVEN

Diagnostic Procedures

30 CHAPTER

Radiographic Evaluation of the Chest Wallace T. Miller

I. GENERAL ASPECTS Routine Examination Supplementary Plain Radiographs Laminography Fluoroscopy Computed Tomography Nuclear Magnetic Resonance Contrast Examinations Pulmonary Angiography Aortography and Systemic Arteriography Air Contrast Studies II. PULMONARY ARTERIES AND VEINS Distribution of Pulmonary Blood Flow III. DISTRIBUTION OF AIR WITHIN THE LUNGS Obstructive Airway Disease Heart Failure Complicating Chronic Bronchitis and Emphysema

Radiographic evaluation of the chest constitutes an important component in assessment of the patient with known or suspected pulmonary disease. In fact, the chest radiograph may provide the earliest or only clue to the presence of clinically significant respiratory disease. This chapter provides a brief overview of chest radiology. First, general aspects are covered; use of more specialized techniques, including computed tomography, nuclear magnetic resonance, and arteriography,

IV. DISEASES AFFECTING THE PULMONARY PARENCHYMA Localized Alveolar Disease Diffuse Alveolar Disease Interstitial Lung Disease The Solitary Nodule Multiple Pulmonary Nodules Left Ventricular Failure V. THE MEDIASTINUM VI. DIAPHRAGM AND CHEST WALL VII. PLEURA Pleural Effusions Pleural Thickening Pleural Nodules Pneumothorax VIII. PORTABLE CHEST EXAMINATION

is highlighted. Subsequently, radiographic manifestations of diseases that affect the distribution of pulmonary blood flow, the airways, and the lung parenchyma are considered. Finally, disorders are reviewed that are predominantly or exclusively confined to anatomically distinct areas of the thorax, including the mediastinum, diaphragm and chest wall, and pleura. Throughout the presentation, examples of radiographs are provided to highlight the principles and disorders discussed.

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Figure 30-1 The lateral view in uncovering a solitary nodule. A. PA view. No nodule is discernible. B . Lateral view. A small nodule (arrow) overlies the left hilus. The nodule proved to be a granuloma.

Although significant emphasis is placed on plain film findings, computed tomography has emerged as the most useful radiographic means of investigating chest disorders. Furthermore, although digital radiography is supplanting traditional film-based radiography in most departments, the descriptions provided about film-based radiography apply equally to digital studies.

GENERAL ASPECTS In recent years, fresh concepts and new techniques have greatly expanded the diagnostic armamentarium of chest radiology. As a rule, the new approaches have strengthened the underpinnings of conventional methods and our diagnostic abilities. Evaluation invariably begins with routine chest radiographs, supplemented, as indicated, by more specialized techniques. Many of these specialized techniques are largely historical, since computed tomography (CT) and magnetic resonance imaging (MRI) produce a more detailed and sensitive evaluation of chest abnormalities.

demonstrable in this view. Ideally, a lateral view should also be part of the routine examination. The lateral view adds valuable information about areas that are not well seen in the PA projection. This is particularly true of the anterior portion of the lung, adjacent to the mediastinumâ&#x20AC;&#x201D;an area that may be obscured by the overlying heart and aortic shadows (Fig. 30-1). The vertebral column is also seen to better advantage on the lateral view. A small pleural effusion is best seen, and often only seen, as blunting of a costophrenic sulcus posteriorly (Fig. 30-2). In determining which costophrenic angle is blunted, correct identification of each hemidiaphragm on the lateral view is helpful. If the lateral radiograph is taken in the left lateral position, as is usual, the magnified ribs are on the right side; the unmagnified ribs are on the left side and are associated with the corresponding left hemidiaphragm (Fig. 30-2). In addition, the outline of the left hemidiaphragm is often obscured anteriorly because it merges with the heart shadow. Finally, the left hemidiaphragm may be recognized from its proximity to the stomach bubble, especially if the left hemidiaphragm is higher than the right.

Routine Examination

Supplementary Plain Radiographs

In asymptomatic patients, a posteroanterior (PA) chest radiograph may be used as the sole screening procedure. This projection is easiest to interpret, since the anatomy is quite familiar, and most pathological respiratory conditions are

In addition to the PA and lateral chest radiographs, other projections serve special purposes, although routine use of CT scanning has markedly diminished the frequency of use of these special films.

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Figure 30-2 The lateral view in uncovering a small pleural effusion. A. PA view. No evidence of a pleural effusion. B . Lateral view. The right costophrenic sulcus is blunted (arrow). C. Lateral view. After treatment for heart failure, the effusion is gone. Note the magnification of the posterior (right) ribs.

Oblique views are sometimes invaluable in confirming or delineating a pulmonary mass or infiltrate from structures that overlie it on the PA and lateral views. Barium in the esophagus serves as a useful adjunct in clarifying the location of middle mediastinal lesions on oblique films. In interpreting oblique films, the clinician will find it useful to keep in mind that a pulmonary lesion that maintains a fairly constant relationship to the heart as the patient is rotated lies in the anterior portion of the chest; a lesion

that maintains a constant relationship to the spine is in the posterior portion if the chest. The lateral decubitus projection (Fig. 30-3C ) is often used to identify the presence of a pleural effusion. As little as 25 to 50 ml of pleural fluid can be visualized, even though 300 ml may be required to blunt the costophrenic sulcus on the PA view. The decubitus view is particularly useful in determining if blunting of the costophrenic sulcus is due to a freely mobile pleural effusion or pleural thickening. Although a pleural effusion may be an important finding,

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Figure 30-3 Infrapulmonary effusion. Neither the PA view (A) nor the lateral view (B ) shows blunting of the costophrenic sulcus. However, elevation of the right hemidiaphragm suggests the presence of an infrapulmonary effusion. A right lateral decubitus film (C ) shows the presence of a free pleural effusion on the right. The effusion was secondary to congestive heart failure.

pleural thickening most often is a sequel to a remote exudate or blood in the pleural space; usually it is clinically unimportant. Distinction between pleural thickening and loculated fluid may be difficult. On the PA film, shadows created by the first rib and clavicle may make interpretation of the lung apices difficult (Fig. 30-4A). The lordotic projection enables evaluation of the apices by displacing these overlying shadows (Fig. 304B). The lordotic view may also be useful in demonstrating collapse of the right middle lobe. The over-penetrated grid radiograph (Fig. 30-5A) is useful for evaluating densities that lie behind the heart or diaphragm and are poorly seen on routine radiographs. Using digital imaging, the same effect can usually be obtained by appropriate windowing; hence, use of the over-penetrated

grid radiograph is now seldom made. Expiratory films may disclose air trapping or a pneumothorax that is poorly shown on the inspiratory film.

Laminography Historically, a technique known as laminography (also known as tomography, body section radiography, or planigraphy) utilized movement of the radiography tube and film about a fixed point to generate a radiograph of a tissue plane that is several millimeters thick; the designated plane is in focus, while surrounding anatomic details are blurred. In effect, this technique provided a view of a thin slice of lung and affords a â&#x20AC;&#x153;close lookâ&#x20AC;? at a suspected abnormality. It was useful in demonstrating the presence of calcification within a

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Figure 30-4 Carcinoma of the left upper lobe. A. PA view. A small nodule is present in the left upper lobe adjacent to the mediastinum, just above the aortic knob. B . Lordotic view. The nodule is much more apparent. It proved to be a primary adenocarcinoma of the lung.

pulmonary nodule and, occasionally, in providing insight into its benign or malignant cause (e.g., the presence of scattered, â&#x20AC;&#x153;popcornâ&#x20AC;? calcifications, implying a benign process). Laminography has been supplanted completely by CT imaging.

Fluoroscopy Fluoroscopy of the chest may be used for examining the movement of pulmonary and cardiac structures and for localizing a pulmonary lesion that is visible in only one of the two conventional radiographic projections. It is particularly

Figure 30-5 Pulmonary arteriovenous malformation. A. Overpenetrated grid (Bucky) radiograph shows a nodule behind the diaphragm (closed arrow) with feeding artery in draining veins (open arrows). B . Pulmonary angiogram confirmed the diagnosis of arteriovenous malformation. Also visible bilaterally on the overpenetrated Bucky film are the posterior paraspinal lines (small arrows). The left posterior paraspinal line is medial to the aorta. The right paraspinal line is ordinarily not discernible; however, it can be seen in this patient because small osteophytes arising from the vertebral bodies displace the pleura laterally on the right.

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sion, and other procedures, particularly ultrasound, CT, and MRI, are generally used to confirm a suspected pericardial effusion. In the past, fluoroscopy was used as a screening procedure for routine examination of the chest. This is no longer acceptable for several reasons: (1) the patientâ&#x20AC;&#x2122;s x-ray exposure is much greater during a short fluoroscopic examination than during the performance of standard chest radiographs; (2) small lesions in the lung fields are easily overlooked at fluoroscopy; and (3) no permanent record of the fluoroscopic examination is created.

Computed Tomography

Figure 30-6 Partial eventration of the diaphragm. The lateral view shows elevation of the posterior portion of the right hemidiaphragm (open arrow). The normal contour of the left hemidiaphragm (closed arrow) appears immediately beneath. This partial eventration is due to a localized weakness in the posterior aspect of the right hemidiaphragm.

helpful for examining diaphragmatic motion. When one is searching for diaphragmatic paralysis, the patient is best fluoroscoped in the lateral projection, allowing motion of both hemidiaphragms to be observed simultaneously. A paralyzed hemidiaphragm moves paradoxically. This paradoxical motion may not be present during quiet breathing, but it usually becomes readily apparent during a quick, short â&#x20AC;&#x153;sniff â&#x20AC;? (sniff test). Localized weakness of part of one hemidiaphragm (i.e., diaphragmatic eventration) (Fig. 30-6) is often misinterpreted as diaphragmatic paralysis. This error can be avoided by performing fluoroscopy with the patient in the lateral projection; partial eventration is then readily observed as paradoxical motion of one portion of the hemidiaphragm, while the remainder of that hemidiaphragm moves normally. Eventration of an entire hemidiaphragm is impossible to distinguish from paralysis, since in both instances the entire hemidiaphragm moves paradoxically. Fluoroscopy is sometimes useful in determining whether a nodule is truly in the lung. In an upright subject, nodules that are in the lung move in the caudal direction with inspiration, while nodules in the chest wall or ribs move in the cephalad direction. CT has largely supplanted fluoroscopy for this use; however, it is significantly more expensive, and fluoroscopy remains an option for evaluating certain pulmonary nodules. Fluoroscopy of the heart may be useful in demonstrating calcifications in cardiac valves and in coronary arteries, but these areas are much better evaluated by CT or MRI. Fluoroscopy may suggest the presence of pericardial effusion much more convincingly than does the chest radiograph. However, fluoroscopy is rarely definitive for detecting a pericardial effu-

Computed tomography (CT) is a radiologic technique for scanning cross-sections of the entire body. The underlying principle is the production of radiographic absorption profiles that are made at different angles in the same crosssectional plane. A pencil-thin beam or beams of x-rays passes through the body as the radiographic tube rotates around the patient, and the transmitted radiation is detected by a sodium iodide crystal. By means of electronic transformation, the signals are fed into a computer, which synthesizes them into a radiographic image that displays the relative absorption coefficients of each small area in the plane of the scan. The technique is highly accurate, and its sensitivity to differences in density is considerably greater than that of the standard radiograph. Multidetector CT scanners now use multiple beams, so that 4 to 64 images are created simultaneously and at a much faster rate than when a single detector is used. While the plain chest radiograph remains the primary radiologic technique in evaluating the chest, CT has added tremendous insight into disorders of the lungs, mediastinum, and chest wall. Cross-sectional images depicted by CT provide a huge added dimension in the investigation of chest pathology, and the increased resolution permits identification of many findings that are not visible on the plain radiograph (Fig. 30-7). This increased sensitivity is particularly true for small nodules, although the heightened sensitivity

Figure 30-7 CT showing lung carcinoma not seen on routine chest radiograph. A large mass narrowing the right main stem bronchus can be seen in the right lower lobe. The mass contains some calcification.

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Figure 30-8 CT demonstrating Hodgkin’s disease obstructing the superior vena cava. A. A mass is seen in the anterior mediastinum, just beneath the sternum. The mass completely obstructs the superior vena cava, which cannot be seen. However, the accessory azygos vein (arrow) is unusually bright, since it is carrying blood that would ordinarily pass through the superior vena cava. B . A lower section shows contrast material crossing into the azygos vein, where it then enters the superior vena cava, adjacent to the right atrium.

for unimportant small nodules is the bane of chest CT. In addition, the mediastinum, which is somewhat of an “occult” area on the plain radiograph, is seen in wonderful anatomic detail. Lymphadenopathy may be readily seen, and mediastinal lesions of uncertain nature may be elucidated (Fig. 30-8). The use of intravenous contrast material as part of the examination permits separation of vascular from nonvascular

mediastinal lesions and identification of vascular invasion by neoplasm (Fig. 30-9). The technique is also extremely useful in investigating chest wall lesions or the extension of pulmonary or pleural tumors into the chest wall (Fig. 30-10)— an important consideration, since the chest wall is not readily studied with the plain radiograph unless bone destruction is present.

Figure 30-9 CT demonstration of extent of left upper lobe carcinoma. A mass is seen invading the pulmonary artery (large arrow) and left main stem bronchus (small arrows).

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CT Angiography CT angiography is an exciting application of helical (spiral) CT technology which has been made especially useful since the emergence of multidetector imaging. Axial, multiplanar, reformatted, and three-dimensional images of the vascular system are possible using this technique. CT angiography has emerged as an excellent tool for identifying pulmonary embolism and has largely supplanted pulmonary angiography and scintigraphic ventilationperfusion lung scanning. Direct visualization of pulmonary emboli by CT angiography carries a specificity similar to pulmonary angiography and a sensitivity similar to ventilationperfusion scanning (Fig. 30-11). The technique is also useful in identifying chronic thromboembolic disease. Various aortic lesions, such as aortic dissection (Fig. 30-66), traumatic

Figure 30-10 Mesothelioma extending into the chest wall. A pleural mesothelioma is seen on the right side; it directly invades the chest wall (arrow). The nodular character of the pleural involvement is characteristic of mesothelioma.

Figure 30-11 Spiral CT showing pulmonary embolus. A and B. Axial tomographic cuts at two levels show multiple central pulmonary emboli (arrows). C. Lung windows demonstrate a pulmonary infarct in the left lower lobe.

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Figure 30-12 High-resolution CT of interstitial lung disease due to pancreatic carcinoma. Pulmonary lobules are nicely outlined by an interstitial process that affects the interlobular septae. This pattern is characteristic of lymphangitic spread of carcinoma, which, in this patient, was due to pancreatic carcinoma.

pseudoaneurysm, penetrating aortic ulcers, aortic aneurysms (Fig 30-24), and vascular anomalies of the aorta are well visualized using CT angiography. In addition, pulmonary venous malformations are readily recognized noninvasively. CT also has great usefulness in recognition and evaluation of cardiac disease. High-Resolution CT High-resolution CT is a special method for evaluating pulmonary pathology. The technique is based on generation of images of very thin anatomic slices (1 mm vs. 7 to 10 mm for the usual CT slice) and a special â&#x20AC;&#x153;bone algorithmâ&#x20AC;? for reconstruction of the information obtained in each slice. The result is a very high-contrast image that provides excellent insight into certain pulmonary disorders. High-resolution CT is primarily useful in identifying interstitial lung disease and bronchiectasis (Figs. 30-12 and 30-52). This technique has supplanted bronchography in evaluation of bronchiectasis (Fig. 30-13), as it is of comparable diagnostic accuracy and is noninvasive. In addition, highresolution CT is helpful in identifying low-grade interstitial lung disease which may not be visible on the plain radiograph. While useful in stratifying differential diagnostic considerations in interstitial lung disease, high-resolution CT does not, at this time, completely supplant tissue biopsy. However, some clinicians will establish a diagnosis of usual interstitial pneumonitis (UIP) on the basis of clinical presentation and a characteristic CT appearance. In general, the technique serves mainly as an adjunct diagnostic method. While not ideal for studying mediastinal and chest wall lesions, high-resolution CT images are adequate to investigate these areas if the main

Figure 30-13 Bronchiectasis. A. Focal areas of tubular bronchiectasis are demonstrated in the middle lobe and lingula. This is a common manifestation of nontuberculous mycobacterial infection, in this case Mycobacterium avium intracellulare (MAI). B. High-resolution scan from another patient demonstrates more subtle bronchiectasis, with many small areas of invasion in the lingula. This was also secondary to MAI infection.

objective is delineation of the extent of the pulmonary process. In most instances, a routine, unenhanced CT study is performed prior to the high-resolution study to better evaluate the mediastinum, bones, and small pulmonary nodules that can be overlooked on the high-resolution images (since only samples of the lung are imaged, rather than consecutive contiguous slices).

Nuclear Magnetic Resonance Magnetic resonance imaging (MRI) or nuclear magnetic resonance (NMR) is a technique that uses radiowaves modified by

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Figure 30-14 Pulmonary embolus demonstrated by ‘‘time of flight” MRI. This technique shows the blood vessels in detail, rivaling images obtained with pulmonary arteriography. A. Pulmonary embolus can be seen in the right upper lobe (arrow). B. Reproductions in various degrees of obliquity show that the defect of the pulmonary embolus remains constant.

a strong magnetic field to produce a diagnostic image. The images generated are somewhat similar to CT images. However, using MRI, vascular structures are usually well seen without the use of contrast material, although intravenous gadolinium can be administered for better vascular evaluation. In addition, with MRI, different images and different information

can be obtained by manipulation of the radiowave frequency and timing of the impulses delivered. Although MRI has not had quite as great an impact as CT in the investigation of pulmonary lesions, it has great usefulness in the study of vascular lesions of the pulmonary vessels and mediastinum. In some institutions, MRI has

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Figure 30-15 MRI demonstration of partial anomalous pulmonary venous return. Time of flight image shows the pulmonary arteries (straight arrow), pulmonary veins (curved arrow), and an anomalous pulmonary vein entering the superior vena cava (small arrow).

become the primary technique used in the study of aortic dissection (Fig. 30-62), although CT is equally good, somewhat faster, and much more readily available. MRI may also have a major role in the investigation of pulmonary embolism, either acute or chronic (Fig. 30-14). Finally, MRI has become a major means of investigation of congenital heart disease and shows great promise in the evaluation of myocardial ischemia. In addition to use of intravenous administration of gadolinium as a “contrast agent” to allow better visualization of vascular structures, a variety of MRI scanning techniques (e.g., “time of flight” imaging, etc.) further enhance the technique’s utility (Figs. 30-15 and 30-16). Scanning can now be done extremely quickly, almost rivaling CT in rapidity of image acquisition. MRI provides a unique feature in investigating the thorax and other body parts: the images obtained can be reconstructed in any one of several anatomic planes. While the standard MR image is usually an axial view, similar to that obtained with CT, sagittal and coronal images can be easily created from the information obtained at the time of the study (Fig. 30-14) and are usually routinely obtained. With the newer multidetectors, reformatted coronal and sagittal images with CT rival those of MRI.

Contrast Examinations Air in the bronchi and alveoli is a superb contrast medium, outlining the pulmonary vasculature, heart, aorta and other mediastinal structures, diaphragm, and chest wall. In addition, pathological processes in the lung often produce characteristic changes in the pattern of the pulmonary vessels or air-filled alveoli. Hence, the plain chest film is a very useful

Figure 30-16 MRI of metastatic renal cell carcinoma (arrows) to the right lower lobe pulmonary veins and left atrium. A. Tumor in the left atrium (T1 image). B. Tumor in the pulmonary veins and left atrium (T2 image).

tool in the diagnosis of pulmonary disease, and more sophisticated radiographic techniques are often not necessary. Supplementary information can be gained by placement of contrast material into different components of the chest. Positive contrast material, such as barium sulfate suspension, is commonly introduced into the esophagus; other suitable media are used to visualize cardiac chambers, the trachea and bronchi, pulmonary vessels, vena cava and mediastinal veins, and mediastinal lymphatics. These techniques are very efficient in increasing the information that can be gained on a CT scan. Historically, carbon dioxide and nitrous oxide have been used to outline the right-sided cardiac chambers. With CT, intravenous contrast material is especially useful in investigating mediastinal lesions and vascular structures. Oral contrast agents (e.g., Gastrografin) may be used to outline the esophagus and the gastrointestinal tract in the

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Pulmonary Angiography

Figure 30-17 Enlarged left atrium. The esophagus is displaced posteriorly by an enlarged left atrium (arrow).

upper abdomen. Similarly, using MRI, administration of intravenous gadolinium is frequently used to better depict vascular structures or highly vascular organs, such as the liver. Of all the contrast examinations available, the barium swallow, generally carried out under fluoroscopic guidance, is the simplest to perform. A thick mixture of swallowed barium sulfate, with or without gas, outlines the esophageal contour, making it easy to detect displacement of the esophagus by adjacent mediastinal structures, such as tumor-containing lymph nodes or a large left atrium (Fig. 30-17). Abnormalities of the esophagus itself, such as achalasia or tumor, are also easily seen. While CT demonstrates most lesions of the esophagus, especially when oral contrast is administered, the barium swallow is much more sensitive for mucosal diseases, as it sometimes demonstrates esophageal carcinoma which is not well seen on CT. Although the trachea and major bronchi are readily visualized in the mediastinum and hila on the plain film, bronchography or CT is necessary to better demonstrate the trachea, main stem bronchi, and peripheral bronchi. Historically, bronchography was performed with special contrast material to perform this function, but this has been replaced by CT and is no longer used. Figures 30-18 and 30-19 are bronchograms obtained using oily Dionosil as a contrast agent instilled in the airways.

Pulmonary angiography and related interventional radiographic techniques are also discussed in Chapter 32. When used as a diagnostic tool, pulmonary angiography entails rapid injection of a radiopaque dye into the pulmonary circulation through a catheter introduced into the pulmonary arterial tree or into a large systemic vein leading into the right atrium. In the past, angiography, was the gold-standard in investigation of pulmonary thromboembolic disease (Figs. 30-20 and 30-21) (see Chapter 34); however, CT yields comparable information and is much less invasive. Ventilation-perfusion lung scans using radioactive isotopes are also useful in detecting pulmonary embolism (see Chapter 82), but they, too, are currently used less frequently than CT. Congenital abnormalities of the pulmonary vascular tree, such as hypoplasia or agenesis of the pulmonary artery, arteriovenous malformation, pulmonary varix, or anomalous pulmonary venous return, are also identified using pulmonary angiography (Fig. 30-5B). These abnormalities are often suspected on the basis of routine radiographs, but angiography may be used for confirmation. As with pulmonary embolism, both CT and MRI have largely supplanted pulmonary angiography in investigating these lesions (Figs. 30-11 and 30-15). Pulmonary angiographic procedures may also be used therapeutically (see Chapter 34). Arteriovenous malformations can be treated with pulmonary artery embolization using a variety of embolic materials, as can bleeding from the pulmonary or bronchial arteries. A strategically placed pulmonary artery catheter may be used to infuse streptokinase or other lytic agents to dissolve an acute pulmonary embolus. Similarly, techniques are available to fragment and extract pulmonary emboli through pulmonary artery catheters.

Aortography and Systemic Arteriography Puzzling shadows in the vicinity of the middle (visceral) compartment of the mediastinum can be explored with aortography, a technique that takes advantage of the fact that the aorta is within the middle mediastinal compartment. Opacification of the aorta using contrast material usually requires retrograde catheterization of the aorta for direct injection. Middle mediastinal masses frequently prove to be vascular (e.g., dissecting aneurysms of the aorta), saccular or fusiform aneurysms of the aorta (Fig. 30-22), or anomalies or unusual tortuosity of the aorta or great vessels. In current practice, CT or MRI usually makes arteriography unnecessary (Figs. 30-23 and 30-24). Owing to the dual blood supply of the lung, pulmonary arteriography may not be rewarding in the evaluation of some pulmonary lesions; in these cases, bronchial arteriography may be more useful. In patients with massive hemoptysis due to tumor or infection (e.g., tuberculosis, bronchiectasis, or aspergillosis), the major pulmonary blood supply is usually the bronchial circulation. Embolization of feeding bronchial arteries may yield temporary, or even permanent, control of the bleeding.

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Bronchial arteries supply most lung tumors. Infusion of various chemotherapeutic agents into these tumors via the bronchial circulation has been attempted for palliative control of nonresectable malignancies. So far, this has not been a very fruitful approach.

Radiographic Evaluation of the Chest

Venography can also be helpful in the diagnostic evaluation of pulmonary abnormalities. After injection of radiopaque material into a large vein of one or both upper extremities, displacement or obstruction of the superior vena cava by mediastinal masses or scarring due to inflammatory

Figure 30-18 Normal bronchogram. The normal bronchial anatomy of the right lung is shown in the PA (A), oblique (B ), and lateral (C ) projections. The corresponding anatomy of the left lung is demonstrated in the PA (D ) and oblique (E ) projections. The lateral projection for the left lung appears in Figure 30-19, which also illustrates bronchiectasis. A schematic representation of the bronchial tree in the PA projection appears in Figure 30â&#x20AC;&#x201C;38.

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Figure 30-18 (Continued) Figure 30-20 Large pulmonary embolus. A large pulmonary embolus is lodged in the right main pulmonary artery (arrow) and has compromised blood flow primarily to the arteries of the right upper lobe. The peripheral vessels in the right mid lung zone are not filled (Westermarkâ&#x20AC;&#x2122;s sign).

Figure 30-19 Bronchiectasis. The lateral view shows extensive bronchiectasis of the left lung. All the bronchi that contain contrast medium show saccular dilatation of their segments. This was secondary to nonspecific infection.

Figure 30-21 Small pulmonary emboli. Angiography shows small filling defects in the posterior basal artery (open arrows). Several of the other basal divisions are cut off (closed arrow). Blood flow to the left upper lobe is well preserved. Angiography was helpful diagnostically in this patient because the lung scan was equivocal.

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processes can be identified (Fig. 30-25). The azygos vein can also be opacified, and visualization of this structure is occasionally helpful in evaluating mediastinal lesions or suspected bronchogenic carcinoma. Once again, these techniques have been largely supplanted by CT (Fig. 30-9) and MRI.

Air Contrast Studies

Historically, air has been introduced into various compartments of the chest for diagnostic purposes. For example, deliberate introduction of air into the pleural space (diagnostic pneumothorax) has been used to demonstrate pleural lesions. Diagnostic pneumothorax has fallen out of vogue because other methods, such as thoracoscopy, yield much more definitive and reliable information. Diagnostic pneumothorax and diagnostic pneumoperitoneum have been used to investigate masses in the vicinity of the diaphragm. Air in the peritoneal may also demonstrate a subphrenic abscess. CT or MRI is much less invasive and more definitive.

PULMONARY ARTERIES AND VEINS

The pulmonary arteries are recognized as structures that accompany the bronchi and branch in a similar fashion (Fig. 3026A). In contrast, the pulmonary veins take a somewhat different course (Fig. 30-26B). In the lower lobes, the pulmonary veins are considerably more caudal than the corresponding arteries; the veins are situated at the level of the eighth to tenth ribs posteriorly, whereas the arteries are at the level of the seventh and eighth ribs. In the upper lobes, the pulmonary veins are lateral to the pulmonary arteries (Fig. 30-15). On the plain film, the direction taken by a pulmonary vessel is the most useful basis for establishing its identity. Near the hili, particularly in the lower lobes, the pulmonary veins are more horizontal than the pulmonary arteries. At the hili, the pulmonary veins lie below and lateral to the arteries (Figs. 30-15 and 30-26). Although it is often possible to distinguish arteries from veins by plain film, this distinction is seldom useful, and the generic terms pulmonary vessels and pulmonary vasculature are used. CT and MRI more readily depict the pulmonary arteries and veins. The pulmonary arteries arise from the main pulmonary artery trunk, while the pulmonary veins enter the left atrium (Figs. 30-15 and 30-26).

Distribution of Pulmonary Blood Flow

Figure 30-22 Aortic aneurysm. A. PA view. A large mass is in the left upper mediastinum. B. Lateral view. This mass appears to be within the middle mediastinal (visceral) compartment. C. Aortogram. The dye column is irregular at the site of the aortic aneurysm (closed arrow), most of which is filled with clot (open arrows).

Blood flow is not uniform in the normal, upright human lung. Moreover, the blood flow pattern shifts with changes in posture, during exercise, and in a variety of heart and lung diseases. In the normal pulmonary circulation, gravity is the predominant determinant of the pattern of blood flow. Under the influence of gravity, hydrostatic pressure in pulmonary arteries, capillaries, and veins decreases by approximately 1 cm H2 O per centimeter of distance from the bottom to the top of the lung. Accordingly, in the upright position, blood flow

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Figure 30-23 Aortic aneurysm shown by CT. A saccular aneurysm of the aortic arch (arrow) is readily demonstrated.

is minimal at the apex and maximal at the base. In the supine position, blood flow becomes much more uniform. If the lung is inverted, the normal pattern is reversed, so that flow to the apex, now dependent, increases considerably and exceeds blood flow to the base (Fig. 30-27). During walking or with any mild exercise in the upright position, total pulmonary flow increases, but flow to the lung apex increases proportionately more than flow to the base, resulting in a more uniform distribution. If pulmonary arterial pressure at the top of the lung fails to exceed alveolar pressure, capillaries in the apices collapse. In the normal lung, pulsatile pulmonary blood flow suffices

to perfuse the apices; but when pulmonary arterial pressure falls, as in hemorrhagic hypotension, the normal marginal perfusion of the apices may give way to cessation of blood flow. Gravity plays less of a role once an increase in pulmonary vascular resistance has raised pulmonary arterial pressure to hypertensive levels. Lung disease often modifies the pattern of pulmonary blood flow by mechanical means and by development of pulmonary vasoconstriction (Fig. 30-28). Heart disease may also affect the pattern of flow. For example, in left-to-right intracardiac shunts, pulmonary blood flow not only increases but also becomes more uniform than normal. The pattern

Figure 30-24 Aortic pseudoaneurysm demonstrated by CT. Anterior mediastinal infection led to development of a pseudoaneurysm at an aortotomy site. The CT not only demonstrates the pseudoaneurysm (arrow) but also shows masses caused by infection in the anterior mediastinum and chest wall.

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Figure 30-25 Superior vena caval invasion by metastatic tumor. A superior venacavogram shows invasion of the superior vena cava in several places (arrows) by metastatic tumor involving the mediastinal lymph nodes. Today, this would be identified by CT.

is quite similar to that in exercise. In heart disease associated with high pulmonary venous pressure (e.g., chronic left ventricular failure or mitral stenosis), the distribution of blood flow tends to become more uniform early in the disease.

Radiographic Evaluation of the Chest

In time, the apices become relatively hyperperfused as a result of interstitial edema, pulmonary fibrosis, and hypoxic vasoconstriction of the lung bases. As a consequence, pulmonary vascular resistance at the lung bases is increased in the setting of pulmonary venous hypertension, and blood flow is directed toward the apices (Fig. 30-29). In prolonged, severe pulmonary venous hypertension, further constriction of the pulmonary vasculature occurs diffusely through the lungs, resulting in the “pruned tree” appearance of pulmonary arterial hypertension. Chronic lung disease or idiopathic pulmonary hypertension (Fig. 30-30A) may also result in the radiographic findings of pulmonary arterial hypertension. In general, the diagnostic accuracy of the plain film is much greater for pulmonary venous hypertension than for pulmonary arterial hypertension. CT and MRI may suggest the presence of pulmonary arterial hypertension. Ordinarily, the aortic diameter is greater than the pulmonary artery, but in pulmonary hypertension, the situation is reversed (Fig. 30-30B). The influence of gravity on the distribution of blood flow bears on the interpretation of the chest radiograph. The mainstay of the concept, illustrated in Fig. 30-31, is that in the normal upright lung, although gravity causes pulmonary arterial and venous pressures to increase from top to bottom of the lung, alveolar pressure remains virtually constant (see Chapter 11). Alterations in the normal relationships among pulmonary arterial, pulmonary venous, and alveolar pressures from top to bottom of the upright lung cause derangements in the pattern of blood flow. For example, a regional increase in alveolar pressure may arise because of “ball-valve” physiology as a result of bronchoconstriction or bronchial obstruction by a foreign body or mucus plug. In chronic obstructive airway disease, this mechanism contributes to

Figure 30-26 Pulmonary arteries and veins. A. The early phase of the pulmonary angiogram depicts the normal course of the pulmonary arteries. B. The late phase shows the normal course of the pulmonary veins. The veins have a more horizontal course than the arteries and enter the hilus below the arteries.

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rearrangement of blood flow, adding a functional component to the anatomic effect of obliteration of parts of the pulmonary vascular bed by disease. Other disease processes also cause a characteristic redistribution of pulmonary blood flow. For example, although uncommonly seen, the oligemic pattern distal to a large pulmonary embolus (Westermarkâ&#x20AC;&#x2122;s sign) is of great diagnostic

Figure 30-27 Effect of gravity on the pulmonary vasculature. Vascular patterns are compared in a normal subject in the erect, supine, and upside-down positions. A. Erect posture. The vascular pattern is more prominent at the bases. B. Supine position. The vascular pattern is more uniform. C. Upside-down position. The vascular pattern is more marked at the apices.

value (Fig. 30-32). In primary pulmonary hypertension, the peripheral vessels are small and the central vessels are quite large, resulting in the pruned-tree appearance of the pulmonary vasculature described earlier (Fig. 30-30A). In emphysema, local destruction of pulmonary vasculature results in bizarre and unpredictable patterns of pulmonary blood flow (Fig. 30-28A).

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Figure 30-28 Severe pulmonary emphysema. A. PA view. Both lungs appear to be hyper-radiolucent. Blood flow to the left lower lobe is particularly reduced. B. Lateral view. The marked hyper-radiolucency is associated with a flat diaphragm, a wide anteroposterior diameter of the chest, and an increase in the retrosternal space. These changes represent advanced emphysema. In mild emphysema, the chest radiograph is usually normal. C. CT showing moderate centrilobular emphysema with incidental left upper lobe carcinoma. Multifocal, asymmetric hyperinflation is present. A small nodular infiltrate in the left upper lobe proved to be a primary lung carcinoma. D. CT showing panlobular emphysema in Îą1 -antitrypsin deficiency. Diffuse emphysematous changes are present, primarily at the lung bases.

DISTRIBUTION OF AIR WITHIN THE LUNGS Just as is the case for pulmonary blood flow, the distribution of ventilation is affected by gravity. Normally, ventilation to the base is greater than to the apex because of the greater alveolar distention caused by gravity and a higher transpul-

monary pressure at the apex (see Chapter 11). Changes in ventilation from top to bottom of the upright lung are much more modest than are changes in blood flow. When the lung is supine, ventilation, as well as blood flow, is much more uniform. If the lung is turned upside down, the normal pattern is reversed, so the apex is better ventilated than the base.

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Figure 30-29 Pulmonary vasculature (venous hypertension) in mitral stenosis. A. PA view. The enlarged left atrium is seen as a double density within the cardiac shadow. Cephalization of the pulmonary blood vessels is also present as a result of an increase in blood flow to the apices, in conjunction with a decrease in flow to the lung bases. B. Close-up view. The increase in vascular markings at the apices is more striking.

Radiographic techniques can be of considerable value in providing information about the distribution of air within the lungs. For example, fluoroscopy of the chest and comparison of chest radiographs taken during inspiration and expiration are useful in detecting and localizing air trapping; blebs and bullae appear as avascular, excessively radiolucent areas. Expiratory CT is much more sensitive in demonstrating air trapping, especially in small airways disease and is also much more sensitive in showing disproportionate blood flow to the two lungs. Extensive pleural encasement of one lung often is associated with a disproportionately small hemithorax and diminished ventilation and perfusion of the affected side. Marked reduction in pulmonary vascular markings also occurs in unilateral hypoventilation or hypoplasia of the pul-

monary artery (Swyer-James or Macleodâ&#x20AC;&#x2122;s syndrome); the hemithorax on the affected side is also usually small. Syndromes associated with unilateral hypoplasia often show air trapping on the affected side.

Obstructive Airway Disease The plain film generally has little to offer in the early diagnosis of obstructive disease of the airways, but CT, especially high-resolution expiratory CT, can be quite useful. Chest radiographs are nearly always normal in patients in whom the airway obstruction is reversible. For example, in asthma, the chest radiograph is usually normal except during an acute episode, when the lungs often appear hyperinflated.

Figure 30-30 A. Primary pulmonary arterial hypertension. The pulmonary trunk and its right and left main bronchi are markedly enlarged. In contrast, the peripheral vasculature is sparse. B. Pulmonary hypertension by CT. Note that the pulmonary artery is much larger than the aorta. This is the reverse of the normal situation and is characteristic of pulmonary hypertension.

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Figure 30-31 Schematic representation of the behavior of small vessels in different parts of the lung. The lung is pictured as consisting of three vertical zones. In zone I, alveolar pressure is greater than arterial pressure, so collapsible vessels in the pulmonary microcirculation close; there is no blood flow. In zone II, arterial pressure exceeds alveolar pressure, which exceeds venous pressure. The pulmonary arterial-alveolar pressure difference determines the blood flow. Microvessels in this zone behave like Starling’s resistors. The arterial-alveolar pressure difference increases linearly from top to bottom of the lung and produces corresponding changes in blood flow. In zone III, blood flow is determined by the difference between pulmonary arterial and venous pressures, since venous pressure exceeds alveolar. The collapsible vessels are open, and the pressure difference is constant throughout the zone (From West JB: Regional Differences in the Lung. New York, Academic, 1977.)

Figure 30-32 Massive pulmonary embolus. The PA view demonstrates marked diminution of the pulmonary vasculature to the left lung, secondary to a chronic massive pulmonary embolus in the left main pulmonary artery (Westermark’s sign).

Expiratory CT may show localized air trapping or a “mosaic” perfusion pattern. Similarly, the diagnosis of chronic bronchitis is a clinical one, based upon a history of chronic sputum production

(see Chapter 40) and supplemented by characteristic abnormalities in pulmonary function tests (see Chapter 34). The radiograph rarely provides substantive help. Vascular markings throughout the lung fields are sometimes prominent, but this finding is nonspecific. Once again, expiratory CT may show air trapping which is indicative of small airways disease. The classic radiographic appearance of more advanced emphysema is hyperinflation and diminution of vascular markings (Fig. 30-28). Hyperinflation is manifested by increased radiolucency of the lungs; low, flat diaphragms; exaggerated verticality of the heart; increased anteroposterior diameter of the chest; and widening of the retrosternal space. Of all these criteria, diaphragmatic flattening is probably the most reliable in supporting a diagnosis of chronic obstructive airway disease, but is seen only in patients with severe emphysema. Hyperinflation can be simulated radiographically when a normal, robust person exerts a maximal inspiratory effort. The lungs also appear hyperinflated in very slender persons. Therefore, it is unwise to make the diagnosis of emphysema solely on the basis of the radiographic finding of hyperinflation. CT shows characteristic changes in centrilobular, panlobular, and paraseptal emphysema. In centrilobular emphysema, focal areas of hyperlucency are scattered throughout the lungs, often with an apical dominance. As emphysema

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the main pulmonary artery and of the hilar pulmonary arteries and oligemia of the peripheral lung fields. These findings constitute important evidence of the existence of pulmonary hypertension. Using CT, pulmonary hypertension is readily recognized when the diameter of the pulmonary artery is greater than the aorta, a reversal of the normal situation. Attempts have been made to use radiographic techniques to determine lung volumes in patients with chronic bronchitis and emphysema. Numerous measurements made on PA and lateral chest radiographs and on CT have served as the basis for the calculations; results have compared favorably with those obtained directly using body plethysmography. Recently, the radiographic approach has been reinforced by the availability of sophisticated computer techniques, especially with CT. These methods have not been widely adopted, however, because of the availability and accuracy of body plethysmography (see Chapter 34).

Heart Failure Complicating Chronic Bronchitis and Emphysema

Figure 30-33 Increased markings pattern. The vascular markings are prominent throughout the lung fields. The patient has chronic bronchitis and emphysema. Hyperaeration is minimal.

becomes worse, more lung is involved and bullae may be evident. In panlobular emphysema, there is diffuse hyperaeration of the lungs, often with a basilar predominance. This pattern is characteristic of α1 -antitrypsin deficiency. In paraseptal emphysema, there are focal areas of hyperlucency in the periphery of the lungs. Paraseptal emphysema usually coexists with centrilobular emphysema. CT is especially useful in demonstrating the presence and location of bullae when bullectomy or lung reduction techniques are planned (see Chapter 53). Supplemental plain film evidence for the diagnosis of emphysema can be afforded by examination of the pulmonary vessels. Two distinctly different vascular patterns have been identified in patients with chronic bronchitis and emphysema: arterial deficiency and increased lung markings. Patients who show the arterial deficiency pattern (Fig. 30-28) often have panlobular emphysema and manifest the clinical syndrome of the “pink puffer.” Those who have the pattern of increased lung markings (Fig. 30-33) often have centrilobular emphysema and manifest the “blue bloater” syndrome (see Chapter 40). Notably, these radiographic findings occur relatively late in the clinical course of emphysema. Patients with chronic bronchitis and emphysema who develop pulmonary hypertension usually show the characteristic features of hyperinflation and an abnormal vascular pattern. In addition, they may show distinctive enlargement of

Both right and left ventricular failure may occur in the patient with chronic obstructive airway disease, but the underlying mechanisms and radiographic appearances are different. Right ventricular failure in chronic obstructive airway disease is generally a consequence of pulmonary hypertension— which, in turn, is secondary to severe hypoxia and respiratory acidosis. As a consequence of right ventricular failure, lung water increases, but rarely to the point of overt pulmonary edema. In contrast, left ventricular failure is generally caused by unrelated disease of the coronary circulation or left ventricular myocardium; as a result, pulmonary venous pressure is abnormally high, resulting in the formation of hemodynamic pulmonary edema. Recognition of left ventricular failure in patients with chronic obstructive airway disease is difficult. The low diaphragm and rarefied lungs obscure enlargement of the heart. Changes in pulmonary vasculature that are associated with left ventricular failure are difficult to recognize in the patient with a pattern of increased lung markings. Moreover, pulmonary edema often assumes unusual appearances in patients with underlying structural lung disease. Most helpful is comparison of recent and old chest radiographs, with particular attention focused on changes in cardiac size and vascular pattern. Frequently the presence of left ventricular failure is recognized retrospectively, as heart size decreases and vascular markings become attenuated following diuretic therapy. Comparison with prior CTs is also useful in recognizing heart failure on CT.

DISEASES AFFECTING THE PULMONARY PARENCHYMA In sorting out the many diseases that can affect the lung parenchyma, knowledge of whether the process involves

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features include coalescence of densities and creation of large homogeneous shadows; presence of air bronchograms (i.e., visualization of peripheral bronchi due to consolidation of surrounding alveoli); fluffy, irregular margins of localized areas of consolidation; and usually rapid change in the areas of consolidation.

Localized Alveolar Disease

Figure 30-34 Right upper lobe pneumonia. The PA radiograph shows diffuse consolidation of the right upper lobe. The alveolar pattern is characteristic. The radiolucent streaks that run through the consolidation represent air in the bronchi (air bronchogram).

primarily the alveoli or the interstitium is useful. Frequently, but not invariably, this distinction can be made on the chest radiograph. An alveolar radiographic pattern is created when alveolar airspaces are filled with material (e.g., blood, pus, or fluid). Characteristic radiographic features of alveolar filling diseases are exemplified in Figs. 30-34 through 30-36. These

Localized alveolar disease assumes two primary patterns on the chest radiograph: patchy consolidation of airspaces without a decrease in the volume of the affected area, and consolidation of airspaces associated with a decrease in the volume of the affected area (atelectasis). The differential diagnosis depends largely on the extent to which lung volume is decreased. However, assessment of the magnitude of volume loss is not always useful. For example, while pneumonia usually is associated with minimal or no volume loss, occasionally, volume loss is considerable. On the other hand, atelectasis usually has moderate or severe loss of volume, but in some instances, there may be little or no loss of volume. Localized consolidation of alveolar airspaces without loss of lung volume, or with minimal loss, is usually a sign of pneumonia (Fig. 30-34). Consolidation may be localized to a lobe (Fig. 30-35) or a pulmonary subsegment, or it may be more diffuse (Fig. 30-36). Consolidation of a pulmonary subsegment causes a characteristic radiographic pattern (Figs. 30-37 and 30-38). Other causes of consolidation without loss of volume include pulmonary edema (which occasionally occurs as local consolidation, even though more often it is diffuse) and pulmonary infarction (Fig. 30-11C ). In most instances, localized pulmonary consolidation without loss of lung volume indicates an acute inflammatory process. If consolidation persists without change for several

Figure 30-35 Patterns of alveolar cell carcinoma. A. A large area of consolidation in the right lower lobe. The alveolar pattern suggests pneumonia, but was due to lobar alveolar cell carcinoma. B. The more distinctive pattern for alveolar cell carcinoma consists of multiple alveolar nodules. The nodules have irregular or fuzzy margins that are characteristic of alveolar, rather than interstitial, nodulation.

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Figure 30-36 Pulmonary edema. Pulmonary edema may be either localized or diffuse. A. Most distinctive, but not most common, is a ‘‘bat wing” pattern of central alveolar consolidation. B. Occasionally, pulmonary edema affects one or more areas of the lung and appears as patchy alveolar consolidation. C . CT of diffuse pulmonary edema secondary to acute respiratory distress syndrome (ARDS). In this instance, the pattern is indistinguishable from that of other causes of severe pulmonary edema. In some cases of ARDS, the pulmonary edema is very patchy.

weeks, however, a less common pathological process should be suspected, including alveolar cell carcinoma (Figs. 30-35A and 30-39); lymphoma; metastatic carcinoma, particularly from a breast primary; bronchiolitis obliterans organizing pneumonia; fungal infection; eosinophilic lung disease; or granulomatous vasculitis, such as Wegener’s disease. CT is frequently useful in distinguishing between the various causes of localized alveolar disease, although it may not be able to distinguish between atelectasis and pneumonia. The technique is especially useful in depicting the extent of the process (Fig. 30-39). CT is extremely useful in identifying cavitation (Figs. 30-40 and 30-41) and in demonstrating mediastinal adenopathy, which may not have been suspected on plain films.

Loss of volume is also associated with localized consolidation of the lung. In most instances, atelectasis detected radiographically is lobar in distribution, since collapse of anatomic pulmonary units smaller than a lobe (e.g., segments) is prevented by collateral air drift. Lobar patterns of atelectasis are illustrated in Figs. 30-42 through 30-46. The various patterns of lobar atelectasis are extremely important to recognize, since this radiographic finding is a very common manifestation of carcinoma of the lung or, occasionally, some other endobronchial neoplasm. Atelectasis is also common in the postoperative patient, presumably because of hypoventilation of dependent parts of the lungs and inadequate clearing of respiratory secretions. In this instance,

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Figure 30-37 Radiographic anatomy of the pulmonary subsegments. Schematic representations of characteristic patterns of consolidation for each of the pulmonary subsegments are shown. A. Left lung. B. Right lung.

Apical Right upper lobe

Posterior Anterior Anterior

Right lower lobe Right middl e lobe

Right lower lobe

Apical posterior

Superior

Superior (lingula)

Left upper lobe

Inferior (lingula)

Lateral Medial Anterior basal

Superior

Medial basal

Anteromedial basal

Lateral basal Posterior basal

Lateral basal

Left lower lobe

Posterior basal

Figure 30-38 Topographic anatomy of the tracheobronchial tree and pulmonary subsegments. A. Tracheobronchial tree. B . Left anterior. C . Left lateral. D . Left cutaway. E . Left posterior. F . Right anterior. G . Right lateral. H . Right cutaway. I . Right posterior.

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loss of volume may be minimal or absent. Atelectasis may also occur as a consequence of inflammatory disease of the airways or aspiration of a foreign body. CT is extremely useful in the evaluation of atelectasis, since the technique may clearly demonstrate the causeâ&#x20AC;&#x201D;for example, a primary carcinoma of the lung. Conversely, CT may demonstrate an open bronchus, strongly suggesting that

the atelectasis is not due to an endobronchial tumor. In this regard, it is important to note that some tumors (e.g., alveolar cell carcinoma and lymphoma) may cause consolidation with an open bronchus. Atelectasis also invariably accompanies pleural effusions and pneumothorax. With pleural effusions, atelectasis is greatest in the vicinity of the pleural effusion.

LUL, apical posterior LUL, apical posterior

LUL, anterior LLL, superior

LUL, anterior

LUL, superior (lingula)

LUL, inferior (lingula)

LUL, superior (lingula)

LLL, anteromedial basal

LUL, inferior (lingula)

LLL, anteromedial basal

LLL, posterior basal LLL, lateral basal

LUL, apical posterior LUL, apical posterior

LUL, anterior

LLL, superior

LUL, superior (lingula)

LUL, anterior LLL, superior

LUL, superior (lingula)

LLL, posterior basal LLL, anteromedial basal LLL, lateral basal

LUL, inferior (lingula)

LLL, anteromedial basal LLL, lateral basal

Figure 30-38 (Continued)

LLL, posterior basal

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RUL, apical

RUL, posterior

RUL, anterior RUL, anterior RLL, superior RML, lateral

RML, medial

RLL, posterior basal RML, medial

RLL, anterior basal RLL, lateral basal

RML, lateral RLL, anterior basal

RUL, apical RUL, apical

RUL, posterior RUL, anterior

RUL, anterior

RUL, posterior

RLL, superior

RML, lateral

RLL, posterior basal

RLL, medial basal RLL, lateral basal RLL, anterior basal RLL, anterior basal

RLL, anterior basal RLL, posterior basal

RML, medial RML, lateral

RLL, lateral basal

Figure 30-38 (Continued)

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Figure 30-39 CT image of localized alveolar cell carcinoma. A patchy right lower lobe infiltrate is present. The characteristic alveolar infiltrate is most suggestive of pneumonia, but it is consistent with lobar-type alveolar cell carcinoma. The findings are not specific, and in this instance, CT adds little to the diagnosis.

CT may also suggest the diagnosis of rounded atelectasis (Fig. 30-47) and is particularly useful in demonstrating mediastinal adenopathy or the extent of a tumor that invades the mediastinum or great vessels. These findings reveal the anatomic basis for the atelectasis.

Diffuse Alveolar Disease The prototype of a pathological process affecting the alveoli diffusely is pulmonary edema (Fig. 30-36). Most often,

pulmonary edema is secondary to left ventricular failure. However, noncardiac pulmonary edema is common and may have a number of underlying causes, including hypersensitivity reactions to drugs or inhaled toxins, uremia, drug overdose, oxygen toxicity, near-drowning, and, especially adult respiratory distress syndrome (ARDS) (Chapter 145). Cardiogenic pulmonary edema characteristically clears rapidly after appropriate therapy, whereas noncardiogenic pulmonary edema often requires days or weeks to clear. Other causes of diffuse alveolar disease may mimic pulmonary edema. Diffuse pneumonia and diffuse pulmonary hemorrhage may be indistinguishable and must be differentiated clinically. If diffuse alveolar consolidation persists for weeks or months, chronic disorders, such as pulmonary alveolar proteinosis (Fig. 30-48C ), alveolar cell carcinoma (Figs. 30-35 and 30-39), sarcoidosis, hypersensitivity pneumonitis, or desquamative interstitial pneumonitis should be considered. As with localized disease, CT is often useful in distinguishing one type of diffuse alveolar disease from another. The distribution of the alveolar infiltrates may sometimes be helpful. Multifocal, patchy disease is typical of aspiration pneumonia. ARDS also appears patchy, but is typically less focal. Diffuse pneumonia, pulmonary hemorrhage, and pulmonary edema may be indistinguishable. Diffuse alveolar disease or focal alveolar disease may be manifest on CT by “ground glass” changes. The term, ground glass opacification, refers to faint alveolar consolidation which is less dense than more extensive consolidation and has an appearance resembling ground glass. This finding is often not explained. If focal, it may be caused by pneumonia or aspiration, and if chronic, may be a manifestation of lung carcinoma or lymphoma. If more diffuse, pulmonary

Figure 30-40 CT demonstrating characteristic crescent sign of aspergillosis. A right upper lobe infiltrate is seen that, in this case, was due to tuberculosis. In the left upper lobe, a crescent of air is seen around the matted mycelia of a fungus ball. The finding is characteristic of ‘‘noninvasive” aspergillosis.

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Figure 30-41 CT showing gangrene of the lung due to a pulmonary artery thrombus in the left main and lower lobe pulmonary artery. The patient had a prior left upper lobectomy; in the postoperative period, consolidation of the remaining left lung developed. The scan shows a lung cavity that was not previously suspected, as well as a thrombus in the left pulmonary artery. The cavity represents a rapidly developing lung abscess due to lung infarction (gangrene).

edema or patchy pneumonia may be the cause. Ground glass changes may also be seen in desquamative interstitial pneumonitis, lymphoid interstitial pneumonitis, or nonspecific interstitial pneumonitis.

Interstitial Lung Disease The plain film features of interstitial lung disease differ from those of the alveolar disorders (Fig. 30-49). In interstitial disease, the pattern is discrete and sharp, rather than fluffy and irregular, and the lesions tend to be diffuse, rather than localized. In addition, coalescence is not a feature, and the small densities are characteristically nodular, reticular, or linear. Pathological interstitial processes may be acute or chronic, although the chronic causes are more common. Within the acute category, a pattern changing over hours to days usually represents interstitial pulmonary edema. Occasionally, a rapidly changing interstitial pattern represents pneumonia due to Pneumocystis carinii or cytomegalovirus. The acute interstitial disorders typically cause a linear or reticular pattern, which is characterized by prominent Kerleyâ&#x20AC;&#x2122;s lines throughout the lung fields (Fig. 30-49 A). In his original description in 1951, Kerley associated thin, radiographic parenchymal opacities with left ventricular failure. At first, Kerleyâ&#x20AC;&#x2122;s lines were thought to represent swollen pulmonary lymphatics. It is now recognized that Kerleyâ&#x20AC;&#x2122;s lines usually represent edematous septa within the pulmonary interstitium. Three patterns exist. Kerley type B lines are the most familiar and are particularly prominent at the lung bases, where they appear as straight, thin lines

approximately 1 cm long; they are oriented parallel to the diaphragm. Kerley type A lines represent septa deep within the substance of the lungs; they radiate from the hili. Kerley type C lines probably represent coalescence of A and B lines. Chronic interstitial lung diseases may be caused by a wide variety of diseases (Figs. 30-49 and 30-50), including pneumoconioses; sarcoidosis; lymphangitic spread of tumors; infections, such as miliary tuberculosis, interstitial pneumonia, and fungal diseases; allergic lung disease; collagen vascular diseases; eosinophilic granuloma; and idiopathic interstitial fibrosis. Characterization of the pattern of interstitial disease as nodular, reticular, or linear on the plain film may help in differential diagnosis, since many of the interstitial lung diseases assume, almost exclusively, one of these three patterns. Interstitial nodules range in size from minute to massive. Large nodules generally represent metastatic tumor (Fig. 30-51). Smaller nodules are found in pneumoconiosis or silicosis, miliary tuberculosis, sarcoidosis (Fig. 30-49B), and allergic lung disease. Linear densities, as noted previously, are more characteristic of acute lung disease (e.g., interstitial pulmonary edema [Fig. 30-49A] or interstitial pneumonia). A similar, but chronic, pattern occurs in lymphangitic spread of metastatic tumor (Figs. 30-12 and 30-49C ). A reticular pattern suggests collagen vascular disease when the reticular or cystic changes are tiny and are confined primarily to the lung bases (Fig. 30-49D). Asbestosis and UIP also cause a basilar reticular pattern (Fig. 3052A). Eosinophilic granuloma of the lung sometimes causes

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a similar pattern at the lung apices. A larger reticular pattern suggests idiopathic pulmonary fibrosis (IPF) or the end-stage lung pattern that often represents the final common denominator of a variety of chronic interstitial lung diseases. Most interstitial diseases cause loss of lung volume on the radiograph, since these disorders are restrictive in their pathophysiological effect. However, two interstitial diseases that produce diffuse, small bullous changes are characteristically associated with preserved lung volume: eosinophilic granuloma and lymphangioleiomyomatosis. These are relatively uncommon causes of interstitial lung disease. Notably, patients with interstitial lung disease may have concurrent chronic obstructive pulmonary disease, in which case lung volume may be preserved. High-resolution CT has emerged as a powerful technique for evaluating interstitial lung diseases. CT can often identify interstitial disease that is not seen on the plain radiograph, and it may also identify the underlying cause. Ma-

Figure 30-42 Right upper lobe atelectasis secondary to carcinoma of the lung. A. PA view. The minor fissure is elevated (arrow). B. Lateral view. The minor fissure is displaced upward (open arrow), and the major fissure is displaced anteriorly (closed arrows). C. Schematic representation of atelectasis of the right upper lobe.

jor indications for high-resolution CT are identification of suspected alveolar or interstitial disease, which is not seen on the chest radiograph, and characterization of the disease (Fig. 30-52). CT patterns of interstitial lung disease follow, to some degree, the patterns seen on the plain radiograph. Collagen vascular disease and IPF typically have reticular or cystic changes in the periphery of the lung and at the lung bases (Fig. 30-52A). These changes are so characteristic that many authors believe that further diagnostic efforts, such as lung biopsy, are unnecessary. The changes of IPF are virtually impossible to distinguish from those of collagen vascular disease. In most, but not all instances, the presence of collagen vascular disease is recognized prior to discovery of the lung disease. Asbestosis may also cause reticular and peripheral interstitial lung disease. However, invariably associated pleural plaques are noted, suggesting the diagnosis in a patient

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with a long history of asbestos exposure. Occasionally, pleural plaques and IPF can coexist. Asbestosis progresses very slowly; if progression is more rapid, IPF should be suspected. Sarcoidosis, interstitial pulmonary edema (Fig. 3052B), and lymphangitic spread of tumor (Fig. 30-12) demonstrate a bronchovascular (septal) distribution, with linear densities outlining the pulmonary lobule. This septal distribution is extremely characteristic of these three entities. Interstitial pulmonary edema is seen almost exclusively with heart failure or fluid overload and rapidly disappears with appropriate therapy. Lymphangitic spread of tumor improves only occasionally with chemotherapy and is usually progressive. While usually diffuse, the disorder is often unilateral when due to carcinoma of the lung, and it may occasionally be focal in lung cancer or when due to other tumors. The tumors that most frequently cause lymphangitic spread include carcinoma of the breast (the most common), lung, stomach, and pancreas, and, on occasion, other tumors.

Radiographic Evaluation of the Chest

Figure 30-43 Right middle lobe atelectasis secondary to right middle lobe syndrome. A. PA view. The middle lobe is collapsed against the right side of the heart. B. Lateral view. The major and minor fissures are drawn together (arrows), creating a density that overlies the cardiac shadow. C. Schematic representation of right middle lobe atelectasis.

Hypersensitivity pneumonitis frequently is associated with an alveolar or ground glass pattern, and commonly has a mosaic distribution (Fig. 30-52C ). In addition, hypersensitivity pneumonitis may cause multiple tiny nodules. Several other diseases usually exhibit a nodular pattern. Large nodules are seen almost exclusively in metastatic tumor, but occasionally they are also seen in silicosis. On the other hand, carcinoma of the thyroid may be seen as multiple tiny nodules, although tiny nodules are usually indicative of another process. Miliary tuberculosis and miliary fungus diseases are among those that present with a fine nodular pattern. Sarcoidosis, which usually has a bronchovascular distribution and linear septal pattern, may also be seen as fine nodules. Silicosis also has a fine nodular pattern and invariably is more prominent in the upper lobes than elsewhere. Occasionally, the nodules of silicosis are somewhat larger and may be confused with metastatic tumor. Massive progressive fibrosis, also seen in silicosis, may also be confused with primary or metastatic tumor. Finally, metastatic tumor (Fig. 30-51) and miliary tuberculosis usually are characterized by fine nodules.

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The Solitary Nodule A wide variety of pathological processes appear on the chest radiograph as a solitary nodule (see Chapter 103). Among the most common are primary carcinoma of the lung, granulomas due to tuberculosis or fungal infection, metastatic carcinoma, and organizing pneumonia. Less common are hamartoma, bronchogenic cyst, bronchial adenoma, arteriovenous malformation, pulmonary sequestration, necrobiotic nodule due to rheumatoid arthritis, Wegenerâ&#x20AC;&#x2122;s granulomatosis, lymphoma, inflammatory pseudotumor, and lipoid granuloma. Although the radiograph is invaluable for detection of a pulmonary nodule, it is usually of little help in elucidating the underlying cause. Although certain radiographic aspects of a nodule may suggest its benign or malignant nature, in most instances, histological or cytological proof is required. One radiologic clue to the origin of a pulmonary nodule is the character of its border. Ill-defined margins suggest an inflammatory lesion (e.g., tuberculosis or pneumonia) or primary lung carcinoma. A very sharply circumscribed pulmonary nodule with a regular contour is more likely to be a granuloma or hamartoma. However, metastatic tumor often

Figure 30-44 Atelectasis (severe) of the right lower lobe due to chronic inflammatory disease. A. PA view. Secondary signs of atelectasis are present in the right lung: small hemithorax, stretching of the pulmonary vessels, hyperlucent lung, and small hilus. In this instance, these secondary signs are important in suspecting atelectasis. In addition, there is downward displacement of the right hilus, and the collapsed lower lobe can be seen (poorly) through the right heart border (arrow). B. Lateral view. The entire right lower lobe appears only as a diffuse density overlying the spine (arrow). The posterior portion of the right hemidiaphragm cannot be identified (silhouette sign). C. Schematic representation of collapse of right lower lobe.

presents with a sharply circumscribed edge, and primary lung neoplasms may present either as sharply circumscribed nodules or nodules with ill-defined margins. The age of the patient is useful in stratification of the differential diagnosis of a solitary nodule. Primary carcinoma of the lung is extremely rare in patients under 30 years old, whereas in patients older than 50, more than half of solitary nodules on the plain film are primary carcinomas of the lung. Occasionally, the radiograph may be sufficiently convincing of the benignity of a pulmonary nodule to preclude the need for diagnostic evaluation, including possible thoracoscopy or thoracotomy. Extensive calcification within the nodule suggests that the process is benign; CT may be helpful in demonstrating such calcification. Benignity is suggested by calcification that is central, concentric, diffuse, or punctate (â&#x20AC;&#x153;popcornâ&#x20AC;? calcification). On the other hand, eccentric calcification is of no diagnostic help, since it occurs in both benign and malignant disease, presumably as a consequence of envelopment of a preexisting benign calcified focus within an expanding neoplastic process.

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Prominent vascular shadows extending from a nodule suggest that the nodule is an arteriovenous malformation; the shadows actually represent veins. Arteriography is useful in confirming the vascular nature of the lesion (Fig. 30-5B). CT and MRI are also helpful in diagnosing arteriovenous malformations and now constitute definitive imaging techniques. A basal lung nodule that is suggestive of a pulmonary sequestration can be definitively identified by CT, MRI, or arteriography if the study demonstrates that the mass is supplied by an anomalous artery arising from the abdominal aorta. The lung is uniquely suited for serial chest radiographs or serial CT to estimate the size of a solitary pulmonary nodule. This feature has led to the practical concept of doubling

Radiographic Evaluation of the Chest

Figure 30-45 Left upper lobe atelectasis secondary to carcinoma of the lung. A. PA view. The left superior mediastinum and left side of the heart are indistinct, due to collapse of the left upper lobe medially. B. Lateral view. The collapsed lung is seen as a density anterior to the major fissure, which is displaced anteriorly. C. Schematic representation of collapse of left upper lobe.

timeâ&#x20AC;&#x201D;the time required for a tumor to double in volume (not diameter). A previous radiograph in which the nodule was present, even if unrecognized, serves as a useful baseline for estimating the rate of nodule growth. If a nodule does not change in size for 2 years, it is likely that the process is benign. Conversely, any growth of the nodule within 1 year should raise suspicion of malignancy. Usually, malignant tumors grow quickly, with a doubling in volume between 1 and 15 months (Fig. 30-53C and D). Occasionally, a slowly growing nodule proves to be a primary carcinoma of the lung (Fig. 30-53A and B)â&#x20AC;&#x201D;usually adenocarcinoma or localized alveolar cell carcinomaâ&#x20AC;&#x201D;or sometimes a carcinoid tumor. The presence of cavitation within a pulmonary nodule is usually not helpful in determining whether the nodule is

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Figure 30-46 Left lower lobe atelectasis (postoperative). A. PA view. The collapsed left lower lobe is seen as a straight line (arrow) behind the left heart border. No vasculature can be seen through the heart shadow, and the medial border of the left hemidiaphragm is obscured by the collapsed left lower lobe (arrow). B. Lateral view. Density over spine and absence of left posterior diaphragm. This is difficult to differentiate from a pleural effusion. C. Schematic representation of collapsed left lower lobe.

Figure 30-47 CT showing rounded atelectasis. A mass with a ‘‘tail”can be seen in the anterior segment of the right upper lobe. Pleural thickening is seen on the left side, with transpulmonary bands extending into the left upper lobe. The mass on the right represents rounded atelectasis, a finding usually associated with asbestos exposure. The changes on the right probably represent an early stage in the development of rounded atelectasis.

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Figure 30-48 Anatomic changes in the pulmonary alveolar proteinosis. A. Sagittal section of the lung showing homogeneous filling of alveoli as though the lung had been embedded in the proteinaceous material. (Courtesy of Dr. S. Molten.) B. Alveolar spaces are filled with granular period acid-Schiff (PAS)–positive material. The alveolar septae are minimally thickened and are lined by hyperplastic type II pneumocytes. PAS stain, ×540. (Courtesy of Dr. G. G. Pietra.) C. CT of limited pulmonary alveolar proteinosis, showing the characteristic ‘‘crazy paving” pattern.

benign or malignant. Other radiographic features, including the presence of stranding, satellite lesions, or associated pleural disease, are seen in both benign and malignant processes and do not constitute bases for distinction.

A major use of CT is in determining whether a solitary nodule is, indeed, solitary. Many nodules that appear to be solitary on the plain radiograph are shown by CT to be multiple; many of these additional nodules are much smaller

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Figure 30-49 Diffuse interstitial disease. A. Linear interstitial pattern produced by interstitial pulmonary edema. The pattern is caused by fluid in the interstitial spaces of the lungs, particularly in interlobar septae. B. Nodular interstitial pattern due to sarcoidosis. Multiple small, discrete nodules involve both lung fields diffusely. Adenopathy is absent. C. Lymphangitic spread of tumor. The linear interstitial pattern was caused by metastatic carcinoma of the pancreas. D. Reticular or cystic interstitial lung pattern. The pattern is most marked at the bases and is characteristic of idopathic pulmonary fibrosis or collagen vascular disease, particularly scleroderma (as in this patient).

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Figure 30-50 Different types of interstitial pneumonia. A. Chest radiograph of fibrosing alveolitis (usual interstitial pneumonia). B. Usual interstitial pneumonia (UIP). The alveolar septa are irregularly thickened by collagen (blue) and mononuclear cells. The airspaces contain desquamated epithelial cells, macrophages, and newly formed fibrous tissue. Masson trichrome, ×540. C. Bronchiolitis obliterans (BO). The lumen of a small bronchus is obliterated by fibrin (bright red), collagenous tissue, and macrophages. H&E, ×540. D. Desquamative interstitial pneumonia (DIP). The airspaces are filled with desquamated epithelial cells and occasional eosinophils. The alveolar walls are lined by hyperplastic type II cells. Giant cells are also present. H&E, ×400. E . Lymphocytic interstitial pneumonia (LIP). The alveolar septa are infiltrated by mononuclear cells, primarily mature lymphocytes, and plasma cells. H&E, ×405. (B through E, courtesy of Dr. G. G. Pietra.)

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Figure 30-51 Metastatic tumor causing a nodular interstitial pattern. Multiple fine nodules can be seen throughout the lungs. The moderatesize nodules are characteristic of metastatic tumor. Finer nodules suggest miliary tuberculosis or other types of nodular interstitial disease.

Figure 30-52 High-resolution CT in various interstitial lung diseases. A. CT of reticular interstitial lung disease. The characteristic peripheral reticular pattern is from a patient with idiopathic pulmonary fibrosis. Collagen vascular disease causes an indistinguishable pattern. B. CT of interstitial pulmonary edema in congestive failure. Pleural effusions and prominent vessels are due to congestive heart failure. Linear densities are seen surrounding the lobules in the right lower lobe, adjacent to the right hemidiaphragm. These findings are characteristic of interstitial edema, but they might also be seen in lymphangitic spread of carcinoma. C. Chronic beryllium disease. CT shows ground glass changes in a mosaic distribution. D. Mosaic pattern due to small airways disease. This is frequently indistinguishable from hypersensitivity pneumonitis.

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Figure 30-53 Top: Carcinoma of the lung with a long doubling time. An interval of 18 months elapsed between A and B. The right upper lobe lesion, which enlarged minimally during that time, proved to be squamous cell carcinoma of the lung. Bottom: Carcinoma of the lung with a short doubling time. An interval of 4 months elapsed between C and D. The nodule was not detected on the first radiograph (C ). It proved to be a small cell carcinoma of the lung.

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than the original nodule identified. The presence of multiple nodules suggests the diagnosis of metastatic tumor. A major problem of chest CT is identification of one or several small nodules as an incidental finding. These nodules usually measure 5 mm or less in size and are almost always benign. Current thinking is that, in the absence of a known primary tumor, follow-up in 1 year is adequate to demonstrate stability of multiple nodules, and earlier follow-up is not necessary. However, with a solitary nodule, earlier followup (e.g., at 3 months) is prudent. Like the plain film, CT is only marginally helpful in characterizing a pulmonary nodule. A “stellate” or “crablike” nodule is highly likely to be a primary lung carcinoma, although not invariably so. CT is excellent in demonstrating calcification in a nodule, usually indicative of a benign process (see above). CT may also demonstrate fat in a nodule, characteristic of a hamartoma. It may also demonstrate the draining vein of an arteriovenous malformation or the feeding artery of a sequestration. Definitive diagnosis of the solitary pulmonary nodule is only rarely possible with radiographic techniques alone. Sputum cytology; bronchoscopy with bronchial washings, brushings, and biopsy; transthoracic lung aspiration or biopsy; thoracoscopic biopsy; or open lung biopsy may be necessary (see Chapters 36 and 37).

Multiple Pulmonary Nodules Although a solitary pulmonary nodule that is seen on the plain film may be benign or malignant, the presence of multiple nodules strongly suggests metastatic tumor. Occasional exceptions to this rule include rheumatoid nodules (Fig. 3054), fungal infections, alveolar sarcoidosis, and Wegener’s granulomatosis. CT is often not very helpful when multiple pulmonary nodules have already been identified on the plain chest radiograph. As previously noted, CT detects a large number of small pulmonary nodules which are not visible on the chest radiograph. If these are 5 mm or less and multiple, they are usually benign if the patient has no known primary tumor; radiographic follow-up is appropriate.

Left Ventricular Failure Failure of the left ventricle is generally easy to recognize on the chest radiograph. The heart is enlarged, and the pulmonary vasculature is prominent. Changes in the size of the heart and central vessels are most evident on consecutive radiographs. In chronic left ventricular failure, chronic dependent edema and interstitial fibrosis at the lung bases result in redirection of pulmonary blood flow from the bases to the apices; the vessels of the upper lobes become more prominent than those of the lower lobes, a finding referred to as cephalization. Interstitial edema often accompanies pulmonary venous congestion and is manifested by a diffuse increase in interstitial markings, usually in a linear distribution (Fig. 30-49A); Kerley’s lines are characteristic features of interstitial edema.

Figure 30-54 Rheumatoid nodules. The nodules in the left lung of this patient with rheumatoid arthritis regressed 4 months later.

Alveolar edema may follow the development of interstitial edema and is characterized by diffuse bilateral consolidation (Fig. 30-36). As on the plain film, heart failure on CT is first manifest as increased vascular markings. This is more easily recognized if a prior CT is available for comparison. As the heart failure progresses, interstitial pulmonary edema occurs, easily identified as increased interstitial markings with a septal pattern. Further progression leads to ground glass changes or frank alveolar edema. Pleural effusions often accompany biventricular heart failure. At first, the pleural effusions are associated with prominence of the pulmonary vascular markings, cephalization, or both. However, while the pulmonary congestion clears in response to therapy, the pleural effusions often remain after the pulmonary vessels have returned to normal size. Pleural effusions in congestive heart failure may be unilateral or bilateral. If unilateral, the effusion most commonly occurs on the right side. As noted previously, recognition of left ventricular failure is difficult in the patient with obstructive lung disease because hyperinflated lungs and an elongated heart make it difficult to recognize cardiomegaly and pulmonary vascular engorgement. Comparison with previous films is paramount in recognizing subtle changes in cardiac size and in pulmonary vascular engorgement.

THE MEDIASTINUM The anatomic delineations of “compartments” of the mediastinum are not defined consistently throughout the medical

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Figure 30-55 Compartments of the mediastinum. A. Anatomic view of the compartments of the mediastinum. The subdivisions in the small schematic (top left) correspond to those designated by the solid black lines in B. PA = pulmonary artery; ST = sympathetic trunk; SG = sympathetic ganglion; RC = ramus communicans. (From Jones KW, Pietra GG, Sabiston DC: Primary Neoplasms and Cysts of the Mediastinum, in Fishman AP (ed), Pulmonary Diseases and Disorders, New York, McGraw-Hill, 1980, pp 1490â&#x20AC;&#x201C;1521.) B. Radiographic division of the mediastinum. The closed lines delineate the anterior, middle, and posterior compartments. The dashed line represents the division of the middle and posterior mediastinum that is conventionally used by anatomists.

literature. For radiographic diagnosis, a simple classification has been employed (Fig. 30-55): (1) The anterior compartment, which extends from the sternum anteriorly to the heart, aorta, and brachiocephalic vessels posteriorly, comprises only the thymus and a few lymph nodes. (2) The middle, or visceral, compartment contains the heart, great vessels, trachea and its branches, esophagus, and descending aorta. It extends from the posterior border of the anterior compartment to the anterior border of the vertebral column. These boundaries differ from the anatomistâ&#x20AC;&#x2122;s classification (Fig. 30-55 A), which relegates portions of the esophagus and the descending aorta to the posterior mediastinum. (3) The posterior compartment contains the vertebrae and the paravertebral sulci. Applying this classification to the lateral chest radiograph, or to the CT, one may categorize mediastinal masses readily according to their position with the mediastinum. Abnormalities in the anterior compartment include enlarged lymph nodes, substernal goiter, thymus and thymic tumors, and teratomas. Distinction among these can be made

on the basis of their position within the anterior mediastinum and their appearance. Thyroid masses invariably lie high in the anterior mediastinum and displace the trachea and esophagus (Fig. 30-56A and B). On CT, the thyroid has characteristic enhancement. Small thyroid nodules, usually a goiter, are frequently detected by CT as an incidental finding. Benign, or minimally invasive, thymomas and teratomas generally lie below the aortic arch and present as single, well-demarcated masses (Fig. 30-56C and D). If the outline of the mass is irregular by plain film or CT, the capsule likely has been breached and the thymoma or teratoma is invasive. However, invasive tumor may be present and not be recognized by radiographic means. In addition, invasive thymoma or teratoma may be indistinguishable from a lymphoma which is confined to the anterior mediastinum. Lymph node enlargement is generally diffuse, often nodular or lumpy in character on the plain film (Figs. 3057 and 30-58), and evident as a characteristic appearance on

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Figure 30-56 Substernal thyroid. A. PA view. A large mass in the neck extends below the clavicle. The trachea and esophagus are displaced to the right. B. Lateral view. The trachea and esophagus are also displaced posteriorly. Several calcifications are present within the mass. Thymoma. C. PA view. A discrete mass (thymoma) lies along the right heart border. D. Lateral view. The mass also overlies the anterior portion of the cardiac shadow. Despite being radiographically well circumscribed, the mass may be either invasive or noninvasive thymoma.

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Figure 30-57 Hodgkinâ&#x20AC;&#x2122;s disease. A. PA view. A lobulated mass widens the mediastinum on both sides of the trachea. B. Lateral view. The mass lies anterior to the trachea.

Figure 30-58 Sarcoidosis. A. PA view. A mass is present in the right paratracheal area, and both hili are enlarged. B. Lateral view. The hilar enlargement (arrows) is striking. Enlargement in these three node-bearing areas is characteristic of sarcoidosis.

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Figure 30-59 Malignant teratoma. A poorly circumscribed, diffuse mass can be seen anterior to the great vessels. Although the mass could represent lymphadenopathy from a number of causes, it is also consistent with malignant thymoma or teratoma. In this patient with AIDS, the mass was shown to be a teratoma.

CT. Enlarged anterior mediastinal lymph nodes are usually accompanied by enlarged lymph nodes in the middle mediastinum, making it easy to separate lymphoma from invasive thymoma or teratoma. Occasionally, differentiation may be impossible (Fig. 30-59). Lymph node enlargement may be produced by metastatic tumor, particularly from a primary neoplasm of the lung, or by sarcoidosis, lymphoma, or primary tuberculosis. Less common causes of mediastinal lymphadenopathy include other inflammatory processes, such as fungal infection or infectious mononucleosis. The middle compartment of the mediastinum contains all of the mediastinal viscera, as well as lymph nodes. Lymphadenopathy in the middle compartment is quite common and is generally seen as a diffuse mass, often associated with enlargement of one or both hili (Fig. 30-58). CT often demonstrates mediastinal adenopathy which is not visible on the plain film (Fig 30-60). A localized middle mediastinal mass may be caused by an aneurysm or other anomaly of the aorta or great vessels (Fig. 30-61). Its vascular nature is suggested by proximity to the aortic shadow and is readily confirmed by CT, MRI, or aortography (Figs. 30-62 and 30-66). Duplication cysts of the esophagus and the tracheobronchial tree are also common in the middle compartment. These localized masses are smooth and well circumscribed; generally, they do not contain air. Bronchogenic cysts commonly occur at the tracheal carina, whereas esophageal duplication cysts are characteristically located near the distal end of the esophagus (Fig. 30-63 A and B). However, esophageal and bronchogenic cysts may occur anywhere within the middle compartment. On CT, a duplication cyst often has a fluid density (as measured in Hounsfield

units); however, not infrequently, fluid in the cyst is proteinaceous and of high density, erroneously suggesting that the cyst is a solid mass. A dilated esophagus is sometimes seen on the chest radiograph as a long tubular mass in the middle compartment (Fig. 30-63C and D) and is readily identified by CT. Tumors of the esophagus or trachea may also present as more localized mediastinal masses by chest radiograph; usually, CT is required for recognition. An esophageal tumor may involve primarily the mucosa and may not be well seen on the CT when it is clearly demonstrated on a swallowing study.

Figure 30-60 Mediastinal mass not seen on the routine chest radiograph. A large lymph node (arrow) is well seen on the CT scan lying just anterior to the descending aorta. This could not be seen on the routine chest radiograph. This node contained adenocarcinoma, and its presence on the scan was an important finding in staging a primary carcinoma of the left lower lobe.

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Figure 30-61 Mediastinal mass. A. Aortic aneurysm, PA view. A mass is seen to the left of the aorta. B. Aortic aneurysm, lateral view. The mass is also posterior to, and intimately associated with, the aorta. C. Aortic aneurysm, aortogram. An irregularity in the wall of the opacified aorta indicates the aneurysm. Most of the aneurysm is filled with clot. This type of mass may be mistaken for a neurogenic tumor in the posterior mediastinal compartment.

Radiographs taken with barium in the esophagus are particularly helpful in characterizing middle compartment masses on plain film and, occasionally, on CT. In the posterior (paraspinal) compartment, the most common radiographic abnormalities are neurogenic tumors

(Fig. 30-64). However, tumors or infections of the vertebral column may also present as masses in the posterior compartment (Fig. 30-65). CT or MRI usually distinguishes between a neurogenic tumor, which is unilateral and paraspinal in location, and lesions which erode or destroy the vertebrae and

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are generally present on both sides of the vertebral column. MRI findings are characteristic for neurogenic tumors. A variety of radiographic lines or stripes seen in and around the mediastinum on the PA radiograph can be very useful diagnostically. Most useful among these is the posterior paraspinal line, which is a pleural reflection to the left of the thoracic spine (Figs. 30-5 and 30-65). The posterior paraspinal line is related to the descending aorta; it is seen on the right side if the descending aorta is on the right. Tumors or inflammatory diseases in the vertebral bodies displace the posterior paraspinal line to the left, creating a pos-

Figure 30-62 Dissecting aortic aneurysm demonstrated by MRI. A. A large anterior mediastinal mass was suspected in the plain chest film. B. An axial MRI shows a huge dissecting aneurysm of the ascending aorta (arrows) containing multiple septations (arrows). C. A sagittal image is more graphic in its depiction of the huge ascending aortic aneurysm (arrows).

terior paraspinal line on the right, where one is not ordinarily present. Large spurs arising from the vertebral body on the right also push out the pleura, creating a paraspinal line (Fig. 30-5A).

DIAPHRAGM AND CHEST WALL The left hemidiaphragm is generally lower than the right; in only about 9 percent of subjects is the left hemidiaphragm

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Figure 30-63 Esophageal duplication cyst. A, B . The small round mass behind the heart (arrows) has the characteristic location and appearance for an esophageal duplication cyst. Achalasia. C. PA view. The dilated esophagus is visible as a mass along the right mediastinum. Air outlines the wall of the upper esophagus above the aortic arch (arrow). D. Lateral view. The mass consists of an amorphous cluster of material lying posterior to the trachea and the heart (debris in the esophagus), displacing the trachea anteriorly.

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Figure 30-64 Neurogenic tumor (pheochromocytoma). A. PA view. A small mass (arrow) lies to the right side of the spine. B. Lateral view. The mass overlies the spine. The location is typical for a neurogenic tumor, usually a schwannoma or ganglioneuroma. This mass proved to be a thoracic pheochromocytoma.

higher. Variations in diaphragmatic contour are common. Most common is a localized eventration of the diaphragm (Fig. 30-6), in which a segment of diaphragmatic muscle is replaced by a thin fibrous membrane. The use of fluoroscopy in identifying local eventration of the diaphragm was described previously. Foramina traverse the normal diaphragm to connect the thorax and abdomen. Sometimes the foramina enlarge sufficiently to allow herniation of abdominal viscera into the chest. The paired foramina of Morgagni lie anteriorly and medially; hernias through one of these foramina occur frequently on the right (Fig. 30-67A and B), but rarely on the left. Generally, diaphragmatic hernias contain only omentum or fat, but they may sometimes contain colon. Hernias through the centrally placed esophageal hiatus (Fig. 30-67Câ&#x20AC;&#x201C; E ) are much more common than those through the foramina of Morgagni. The stomach is the usual herniating viscus; less often, the hernia contains colon or small bowel. Traversing the diaphragm posteriorly and slightly laterally are the paired foramina of Bochdalek. The massive congenital hernias occasionally seen in newborns generally occur through a large foramen of Bochdalek, usually on the left side. Hernias through these foramina are unusual in adults; when present, they may contain a kidney. Traumatic diaphragmatic hernias occur secondary to traumatic rupture of the diaphragm, usually in the setting of a motor vehicle accident. Any viscus may protrude through

the rupture; stomach and colon are common (Fig. 30-67F ). The actual herniation may occur days, weeks, or many months after the diaphragmatic injury. Delayed hernias often create a confusing radiographic picture. These hernias may be difficult to recognize on axial CT. Coronal reconstructions or MRI may be useful. On the plain film, masses of the chest wall may cause bone destruction or erosion; if they do not, they may not be readily visualized. The masses also may be seen if they protrude into the lung as densities. Most lesions of the chest wall are metastatic tumors of the ribs, but primary tumors of the ribs and soft-tissue sarcomas also occur. Their encroachment into lung tissue causes a characteristic shadow that has smooth margins and tapering edges and is generally seen well in only one of the two standard views of the chest (Fig. 3068A). This characteristic configuration has been designated the extrapleural sign. Since many pleural lesions mimic the extrapleural sign, bone destruction is the key finding in accurate identification of an extrapleural mass. CT is extremely useful in the evaluation of chest wall lesions (Fig. 30-10), which often are not well seen or are poorly characterized on routine radiographs. CT readily shows bone destruction and the soft-tissue mass in the chest wall. Clinically palpable chest wall masses may not be visible on the plain film if they do not involve the ribs or protrude into the thoracic cage. In this instance, CT imaging is important. MRI also is an excellent technique for demonstrating chest wall masses.

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Figure 30-65 Tuberculosis. The normal left paraspinal line is displaced laterally (open arrow) by a paraspinal mass; the right paraspinal line, which is usually not seen, is present and displaced laterally (closed arrow). These findings are characteristic of infection involving the spine, in this case tuberculosis.

Figure 30-66 Dissecting aortic aneurysm shown by CT. A. A sagittal image shows a dissecting aneurysm in the descending aorta; a prominent flap is seen medially, crossing the aortic lumen. B. An oblique sagittal reconstruction of the image shows the flap in the proximal descending aorta.

Pleural Effusions In addition to hernias through the diaphragm, tumors of the diaphragm occasionally present as masses seen on the chest radiograph. MRI is ideally suited to demonstration of diaphragmatic lesions, since coronal sections are much better than transaxial ones for this anatomic region. This is also true for pleural lesions, such as a pleural fibroma. With axial images, clear demonstration that a pleural lesion is in the chest (above the diaphragm), rather than in the abdomen, may be difficult. Coronal images will usually clearly demonstrate the location of the lesion.

PLEURA The pleura and its disorders are considered in Chapters 85 through 88. Radiographic involvement of the pleura is generally manifested by pleural fluid, localized or diffuse pleural thickening, or pleural nodules.

Fluid in the pleural cavity appears radiographically as a homogeneous opacity that generally occupies a dependent position. A small pleural effusion that is barely perceptible or is overlooked on the PA view is often readily apparent on the lateral radiograph as blunting of the posterior costophrenic sulcus (Fig. 30-2). The best non-CT radiographic study for demonstrating small quantities of pleural fluid is the lateral decubitus film (Fig. 30-3C ). Using this technique, as little as 25 ml of fluid can be detected. Larger pleural effusions usually blunt the lateral costophrenic sulcus on the PA radiograph as well (Fig. 30-68B). Occasionally, pleural fluid remains between the diaphragm and the lung (i.e., is infrapulmonary or subpulmonic), displacing the lung upward, so that the lateral costophrenic angle remains sharp (Fig. 30-3). The presence of an infrapulmonary accumulation of fluid should be suspected if the diaphragm appears elevated, if the costophrenic sulcus is blunted posteriorly, or if the stomach bubble is separated from

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Figure 30-67 Foramen of Morgagni hernia. A. PA view. A mass containing a loop of bowel lies just to the right of the cardiac silhouette. B. Lateral view. The mass is also anterior to the cardiac silhouette. The location of the mass is characteristic for a foramen of Morgagni hernia. The hernia usually contains only omentum, but in this instance, it also contained a loop of colon. Hiatus hernia. C. PA view. An air-fluid level is present in the left chest and must be differentiated from an elevated diaphragm with underlying stomach. D. Lateral view. The mass is also posterior to the heart. E. An upper gastrointestinal series demonstrates the air-fluid level to be within the stomach, which has herniated into the chest and lies in an upside-down position. Traumatic hernia. F. PA film of the chest shows an air-fluid level in the left chest, quite similar to the above hiatal hernia. However, this was a traumatic hernia of the diaphragm with stomach herniated through the diaphragm and gangrenous at surgery.

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Figure 30-68 A. Rib metastasis (extrapleural sign). A smooth mass protrudes into the lung. This mass has tapering edges, characteristic of an extrapleural lesion. The destroyed anterior rib (arrows) is secondary to a metastatic tumor that is invading the rib. B. Rheumatoid effusion. The characteristic meniscus of a free pleural effusion is seen in the left hemithorax. This patient had rheumatoid arthritis. C. Pleural lipoma. A smooth mass along the left lateral chest wall proved to be a lipoma. D. Pleural metastases. A right pleural effusion, showing a meniscus, blunts the right costophrenic sulcus. The lobulation along the right lateral chest wall is characteristic of tumor nodulation (arrows).

the dome of the apparent hemidiaphragm by more than a few millimeters. CT is especially sensitive in identifying pleural effusions (Fig. 30-69). These effusions may be small and not visible on the plain film. In the intensive care unit, where most plain films are obtained in supine patients, CT imaging is helpful in the diagnosis of pleural effusions.

Pleural fluid sometimes is loculated and difficult to distinguish from localized pleural thickening. Loculated pleural fluid in an interlobar fissure assumes a cigar-shaped configuration on the lateral radiograph, and it sometimes simulates a mass. This mass, known as a â&#x20AC;&#x153;phantom tumor,â&#x20AC;? disappears as the fluid is eliminated. CT readily recognizes these loculated

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Figure 30-69 A small right pleural effusion (arrow) is identified by CT. This was not seen on the routine chest radiograph. Pleural thickening is seen in a similar location of the left side.

effusions. The loculation is usually indicative of a high concentration of protein in the fluid, frequently due to infection or tumor. Bilateral pleural effusions are usually caused by heart failure or ascites. Occasionally, they are due to collagen vascular disease or metastatic tumor. Common causes of unilateral pleural effusions include tuberculosis, pneumonia, pulmonary infarction, metastatic tumor, primary pleural tumor, lymphoma, collagen vascular disease, chest trauma, ascites, and intra-abdominal inflammatory processes, such as subphrenic abscess or pancreatitis. Thoracentesis and pleural biopsy may be necessary to establish the nature of a pleural effusion that has been recognized radiographically. CT and MRI are usually not useful in determining the exact cause of a pleural effusion. The lumpy, masslike character of a mesothelioma or metastatic tumor can be nicely demonstrated by CT (Figs. 30-68D and 3070); such findings are often apparent on the plain chest radiograph. Many mesotheliomas demonstrate only a pleural effusion, without any specific findings to indicate the malignant nature of the process. CT or MRI may show associated mediastinal adenopathy that was not suspected on the plain radiograph.

Pleural Thickening Fibrosis of the pleura may be localized or generalized. Localized pleural thickening is common at the lung apices and is suggestive of tuberculosis. Most often, however, apical scarring, commonly seen on CT, remains unexplained and is attributed to aging. Blunting of the costophrenic sulcus is occasionally the result of a previous pleural effusion. A costophrenic sulcus that appears to be blunted laterally on the PA radiograph, but not posteriorly on the lateral radiograph, usually represents pleural thickening, rather than pleural fluid.

Figure 30-70 Pleural mesothelioma. Asbestos-related pleural plaques are seen in the right chest; pleural thickening and pleural calcification are present. On the left side, the pleura is thickened and quite lumpy. This is characteristic of mesothelioma, but the finding is not specific for this disorder and could be due to metastatic tumor. Mesothelioma might also present as a nonspecific pleural effusion.

Generalized pleural thickening confined to one hemithorax is usually secondary to previous tuberculosis, empyema, or hemothorax. Bilateral pleural thickening, either localized or generalized, is strongly suggestive of asbestos exposure. Although such thickening is sometimes accompanied by pleural calcification or interstitial lung disease, pleural thickening may be the sole radiographic manifestation of asbestos exposure. Pleural plaques are more commonly seen using CT imaging, and the associated calcification is more readily appreciated than on the plain film.

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Figure 30-71 Hydropneumothorax. A. Posteroanterior view. A distinct air-fluid level is seen overlying the left hilus. B. Lateral view. The fluid and air are anterior to the hilus. This is difficult to differentiate from a lung cavity, but the very thin edge suggests that this is in the pleural space. This was a hydropneumothorax and was secondary to a postoperative bronchopleural fistula.

Pleural Nodules A localized pleural nodule suggests a benign pleural tumor, such as a fibrous tumor of the pleura or lipoma (Fig. 30-68C ). The nodule may be difficult to distinguish from a localized area of pleural thickening, but generally it is larger and more symmetric in contour. On CT, these nodules generally have a characteristic appearance: the greatest diameter of the mass is in its center, and its edges are flat and tapering; the appearance is similar to the extrapleural sign, described previously. Unilateral, diffuse pleural nodulation (Fig. 30-68D) usually indicates diffuse mesothelioma or metastatic malignancy, although empyema can sometimes be quite nodular in appearance. Mesotheliomas and pleural metastatic tumor are impossible to distinguish radiographically; they also may

be difficult to distinguish histologically. Both are commonly associated with pleural effusion. As in the case of pleural effusions, CT is extremely useful in identifying localized or diffuse pleural abnormalities, but is somewhat limited in determining their cause.

Pneumothorax In the conventional upright radiograph, air within the pleural cavity is best seen at the apices, where the thin line of visceral pleura surrounding the partially collapsed lung is easily identified. If doubt exists, a radiograph taken during expiration may make a pneumothorax more obvious. In supine patients, or in patients with pleural adhesions, pneumothorax may be

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seen only at the bases, medially or laterally. CT is useful in demonstrating small pneumothoraces, which may not be appreciated on conventional radiographs. Trauma, including that of iatrogenic origin, is the most common cause of pneumothorax. Spontaneous pneumothorax occurs in a variety of conditions. Most often the cause is unknown. On occasion, pneumothorax may be clearly attributed to a ruptured apical bleb. Diffuse lung disease, such as eosinophilic granuloma, is sometimes the cause of spontaneous pneumothorax. Chronic pneumothoraces are almost invariably associated with pleural effusions. The interface of air and fluid in the pleural space causes the fluid to assume a flat line (Fig. 30-71), rather than the usual curved line configuration (meniscus) seen when air is absent. A pneumothorax is ordinarily rapidly reabsorbed or replaced by fluid in the pleural space. A chronic pneumothorax strongly suggests a bronchopleural fistula.

PORTABLE CHEST EXAMINATION Use of portable radiographic studies in evaluation of seriously ill patients is routine. Interpretation of the portable radiograph is often difficult, since the film may be technically limited. Despite its problems, the portable radiograph usually provides useful information in postoperative patients, who may be difficult to examine clinically, and in mechanically ventilated, critically ill patients. Localized pulmonary consolidation seen in the postoperative radiograph generally indicates one of three possibilities: pulmonary contusion, pneumonia, or atelectasis (segmental or lobar). Pulmonary contusion, common after thoracic surgery, is generally noted immediately after the surgery; it resolves gradually. In contrast, pneumonia usually occurs after the second or third postoperative day. Radiographic findings may be diffuse or localized: when localized they are difficult to distinguish from atelectasis; when diffuse, pneumonia may mimic pulmonary edema. Patchy multifocal pneumonia is common and frequently due to aspiration. Atelectasis is a prevalent postoperative complication. It usually occurs in the lower lobes and is more common on the left. An increased density behind the cardiac shadow or obliteration of the diaphragmatic shadow behind the cardiac silhouette constitutes presumptive evidence of left lower lobe atelectasis. Frequently, distinction between atelectasis and pleural fluid based on a portable radiograph is difficult. Basilar atelectasis, also known as platelike atelectasis, Fleischnerâ&#x20AC;&#x2122;s lines, or discoid atelectasis, frequently occurs in very ill patients, particularly after abdominal surgery. Manifestations include linear densities at the bases that generally are oriented parallel to the diaphragmatic surface; the densities do not follow the usual patterns of lobar collapse. Basilar atelectasis is considered an indication of poor diaphragmatic

Figure 30-72 Platelike atelectasis. A linear density above the right hemidiaphragm in the postoperative patient represents platelike atelectasis. The configuration of this density does not correspond to that of a pulmonary subsegment, and it crosses segmental boundaries.

motion and often occurs with abdominal pain. Basilar atelectasis may be seen in patients who are obese or who have impaired diaphragm motion or diaphragm eventration (Fig. 30-72). Pleural effusions are often difficult to identify in a portable examination, since the patient is rarely upright in bed or optimally positioned; a lateral radiograph is generally not available. On occasion, a large pleural effusion mimics lower lobe atelectasis. Although difficult to perform, portable decubitus radiographs can be useful in distinguishing a pleural effusion from atelectasis. Using CT imaging, pleural effusions, both large and small, are frequently seen, even when not suspected on the portable film. In patients who have recently undergone thoracic surgery, fluid may accumulate in the extrapleural space in the area of the incision, simulating a loculated pleural effusion. With mediastinal incisions, mediastinal fluid accumulation is detected as diffuse widening of the mediastinal shadow. Comparison with earlier films is particularly useful in evaluating the process. Left ventricular failure or fluid overload is another common clinical problem that is often difficult to recognize on the portable radiograph. Distortions in heart size produced

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by inconsistent distances of the radiographic tube from the patient’s chest complicate study interpretation. Enlargement of the pulmonary vessels is the most reliable sign of leftsided heart failure or fluid overload. The finding must be interpreted with care, however, since portable radiographs are often made while the patient is supine, resulting in redistribution of blood flow toward the apices. Pulmonary interstitial edema and alveolar edema are additional signs of left-sided heart failure that are generally recognizable in the portable radiograph. The presence of diffuse alveolar consolidation generally signifies pulmonary edema. In the critically ill patient, however, pulmonary edema is often noncardiac in origin (see Chapters 144 and 145). Massive aspiration or diffuse community-acquired or nosocomial pneumonia may also produce the radiographic picture of diffuse alveolar consolidation. CT has become an indispensable tool in evaluating critically ill patients. Although significant challenges exist in transporting mechanically ventilated or hemodynamically unstable patients to the radiology department, the information gleaned may be critical to proper management. For example, CT imaging may elucidate an unexplained finding, or disclose a process not evident on the portable film. An unsuspected pneumonia or pleural effusion (perhaps, even a large effusion) may be demonstrated, or details, such as cavitation, may be appreciated. CT may be useful in helping elucidate the cause of diffuse alveolar consolidation by suggesting the presence of cardiogenic pulmonary edema, ARDS, or pneumonia, including that due to aspiration. Finally, many institutions have incorporated into their routine critical care practices a daily multidisciplinary conference in which radiologists review current studies with clinicians managing the patients. The resultant clinicalradiographic correlation provides invaluable insight into the cause of the radiographic findings.

SUGGESTED READING Albelda SM, Epstein DM, Gefter WB, et al: Pleural thickening: Its significance and relationship to asbestos dust exposure. Am Rev Respir Dis 116:621–624, 1982. Choe YM, Im J, Park JH et al: The Anatomy of the Pericardial Spaces: A study in cadavers and patients. AJR 149:693–697, 1987. Colby TV, Swenson SJ: State of the art: Anatomic distribution and histopathologic patterns in diffuse lung disease. Correlation with HRCT. J Thorac Imaging 11:1–25, 1996. Felson B: Chest Roentgenology. Philadelphia, WB Saunders, 1973. Fraser RG, Pare JAP: Diagnosis of Diseases of the Chest, 4th ed. Philadelphia, WB Saunders, 1989.

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Freundlich IM, Bragg DG: A Radiologic Approach to Diseases of the Chest, 2d ed. Maryland, Williams & Wilkins, 1997. Henschke CL, Yankelevitz JF, Naidich JP et al: CT screening for lung cancer: Suspiciousness of nodules according to size on base line scans. Radiology 231:164–168, 2004. Hessen J: Roentgen examination of pleural fluid: A study of the localization of free effusions, the potentialities of diagnosing minimal quantities of fluid and its existence of physiological conditions. Acta Radiol 86(Suppl):1–80, 1951. Lavender JP, Doppman J, Shawdon HE, et al: Pulmonary veins in left ventricular failure and mitral stenosis. Br J Radiol 35:293–302, 1962. Leung AN, Miller RR, Muller NL: Parenchymal opacification in chronic infiltrative lung diseases: CT pathologic correlation. Radiology 188:209–214, 1993. Lee JKT, Sagel SS, Stanley RS: Computed Body Tomography with MRI Correlation, 3rd ed. New York, Raven, 1998. Lillington GA: The solitary pulmonary nodule—1974. Am Rev Respir Dis 110:699–707, 1974. Miller WT, Miller WT Jr.: Field Guide to the Chest X-ray. Philadelphia, Lippincott Williams & Wilkins, 1999. Milne EC: Correlation of physiologic findings with chest roentgenology. Radiol Clin North Am 11:17–44, 1973. Muller N (ed): High resolution CT of the chest. Semin Roentgenol 26:104–192, 1991. Musset D, Parent F, Meyer G, et al: Diagnostic strategy for patients with suspected pulmonary embolism: A prospective multicentre outcome study. Lancet 360:1914–1920, 2002. Naidich DP, Harkins TJ: Airways and lungs: Correlation of CT with fiberoptic bronchoscopy. Radiology 197:1–12, 1995. Naidich DP, Zerhouni E, Siegelman S: Computed Tomography and Magnetic Resonance of the Thorax, 2nd ed. New York, Raven, 1991. Nathan MH, Collins VP, Adams RA: Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology 79:221– 232, 1962. Remy-Jardin M, Remy J, Wattinne L, et al: Central pulmonary embolism; diagnosis with spiral volumetric CT—comparison with pulmonary angiography. Radiology 185:381–387, 1992. Thurlbeck WM: Chronic airflow obstruction in lung disease, in Bennington JL (ed), Major Problems in Pathology, vol 5: Chronic Airflow Obstruction in Lung Disease. Philadelphia, WB Saunders, 1976. West JB: Regional Differences in the Lung. New York, Academic, 1977. Worthy SA, Muller NL: Small airways diseases. Radiol Clin North Am 36:163–173, 1998. Zeman RK, Silverman JM, Vieco PT, et al: CT angiography. Am J Roentgenol 165:1079–1088, 1995. Zwirewich CV, Vidal S, Miller RR, et al: Solitary pulmonary nodule: High resolution CT and radiologic-pathologic correlation. Radiology 179:469–476, 1991.

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31 Pulmonary Cytopathology Prabodh K. Gupta

Zubair W. Baloch

I. THE CYTOPATHOLOGY REPORT II. PULMONARY SAMPLES Spontaneously Produced Sputum Induced Sputum Bronchial Washings Bronchoalveolar Lavage Bronchial Brushings Postbronchoscopy Sputum Transbronchial Aspiration Percutaneous Transthoracic Fine-Needle Aspiration Endobronchial and Endoscopic Ultrasound-Guided Fine-Needle Aspiration

Goblet Cells Alveolar Macrophages V. TOXIC ENVIRONMENTAL INHALATION EFFECTS Cigarette Smoke Asbestosis Berylliosis Crack Cocaine Inhalation VI. INFECTIONS Bacterial Infections Fungal Infections Viral Infections Parasitic Infections

III. SPECIMEN PROCESSING Direct Smears Saccamanno’s Fixative Cytospin Preparations Cellulosic (Millipore) Filters Cell Block Ancillary Laboratory Diagnostic Techniques

VII. OTHER NON-NEOPLASTIC CONDITIONS Aspiration Pneumonia Lipid Pneumonia Pulmonary Infarction and Intra-alveolar Hemorrhage Sarcoidosis Radiation and Chemotherapy Effects

IV. NORMAL BRONCHOPULMONARY CYTOLOGY Squamous Cells Ciliated Bronchial Columnar Cells

VIII. PULMONARY NEOPLASMS Early Lung Cancer Detection Established Lung Cancer Immunocytochemistry of Lung Tumors

In his Atlas of Exfoliative Cytology, George N. Papanicolaou described the success and utility of cytopathology in detection and diagnosis of malignant lesions of the respiratory tract. Over the past 40 years, development of flexible fiberoptic bronchoscopy, transthoracic and transbronchial needle aspiration, and ultrasound-guided transesophageal and transbronchial fine-needle aspiration have broadened the methods by which cytological materials are obtained. These advances, coupled with refinements in specimen collection, cytopreparation, and ancillary laboratory diagnostic techniques, have established pulmonary cytopathol-

ogy as an accurate, economical, safe, and rapid diagnostic procedure.

THE CYTOPATHOLOGY REPORT A number of neoplastic and nonneoplastic pulmonary lesions can be accurately diagnosed with cytological techniques. For a valid and reliable diagnosis, the specimen must be satisfactory—that is, representative of the lesion(s) under investigation, adequate in cellular quantity and preservation,

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and prepared and examined by experienced and qualified laboratory professionals. A cytopathology report should carry the same clinical and diagnostic significance as does a report from a representative histological study. The value of collaborative interaction between the clinician and laboratory personnel cannot be overemphasized. Relevant clinical information must be furnished to, and reviewed by, the cytopathologist. While cytological findings, at times, may be nonspecific, consultation between clinician and cytopathologist can help with patient management.

PULMONARY SAMPLES A wide variety of pulmonary specimens may be examined cytologically; the most commonly employed are described below.

Spontaneously Produced Sputum Spontaneously expectorated sputum has been a mainstay in the diagnosis of pulmonary lesions. While some patients readily produce a representative sputum sample, the collection procedure can be time consuming, uneconomical, and inefficient. Typically, three to five deep-cough specimens are obtained on consecutive days after the patient is instructed in the proper technique for providing a satisfactory specimen: after mouth rinsing and throat cleaning, the patient takes a deep breath, holds it for up to 20 seconds, and then coughs. With this method, material is forcefully expectorated from the airways. The procedure should be repeated for up to 30 min to produce a sufficient quantity of a representative specimen. In addition to mucus and mature and immature squamous cells exfoliated from the oral cavity, the specimen may contain lymphoid cells from the tonsils and adenoids. A satisfactory specimen is one that is representative of the bronchial mucosa and pulmonary parenchyma and contains macrophages (generally, carbon-bearing) derived from the alveolar spaces. Inspissated mucus from the terminal airways (Curschmann’s spirals) and columnar cells from the bronchial tree and nasopharynx can also be seen (Fig. 31-1). The presence of only squamous cells indicates an unsatisfactory sample. However, exfoliated cells from upper airway epithelial lesions may be seen in such samples.

Induced Sputum Many patients, particularly those who are asymptomatic, generally are unable to spontaneously produce a satisfactory sputum specimen by deep coughing. These patients may be “induced” to produce a diagnostic sample representing the respiratory mucosal surface and associated lesions. Induction techniques vary, but generally they involve inhalation of a preheated (37◦ C) hypertonic saline solution or mucolytic agent (Mucomyst) for 10 to 15 min. The patient is asked to cough for

Figure 31-1 A satisfactory pulmonary cytology specimen (bronchial washing). Note the presence of macrophages, a Curschmann’s spiral, and a few macrophages, indicative of a deep cough and pulmonary contents. Squamous cells most often indicate oral material. (Papanicolaou stain, ×105.)

up to an additional 20 min; a pooled sputum sample is then collected and submitted for examination. Following initial sample procurement, the patient is instructed to collect more specimens for 2 to 3 days. The additional specimens, which are valuable diagnostically, should be pooled and preserved in a polyethylene glycol-alcohol mixture according to Saccamanno’s technique (see below) or in commercially available preservatives following the vendor’s recommendations.

Bronchial Washings Cytological examination of bronchial washings has been in use for many years. While normal saline may be used to obtain bronchial washings, use of a physiological solution, such as Normosol or Plasmalyte, is preferable. Fresh specimens should be submitted to the laboratory. Fresh smears may be made on-site and fixed immediately in 95 percent ethyl alcohol for at least 20 min; alternatively, spray fixation (Surgipath cytology fixative) may be employed. Such preparations are diagnostically inferior to fresh specimens processed using cellulosic (Millipore) filters or other concentration techniques. Segmental sampling of the bronchial tree (while taking adequate precautions against contamination of the specimen) may be useful in lesion localization. When delays are expected in specimen submission and processing, the material may be fixed by mixing the specimen with an equal volume of 50 percent ethyl alcohol or liquid-based cytology preservative, as specified by the vendor (ThinPrep or SurePath).

Bronchoalveolar Lavage Bronchoalveolar lavage (BAL) consists of instillation of a physiological solution (normal saline, Normosol, or Plasmalyte) into a specified area of the pulmonary parenchyma, followed by aspiration (Chapter 36). The material obtained represents sampling of 1 to 3 million alveoli (about 1 percent of all alveoli).

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BAL samples are most useful in investigating diffuse alveolar processes, such as Pneumocystis carinii pneumonia, viral infections, chemotherapy- or radiation-related changes, or lesions with transalveolar spread, such as alveolar proteinosis and bronchoalveolar cell carcinoma. Additionally,BAL has been used in the study of various immunologic, inflammatory, and infectious processes occurring within the alveolar spaces, including lymphomas, posttransplant lymphoproliferative disorders (PTLD), interstitial lung diseases, and inhalation-related disorders. Notably, only rarely are interstitial lung diseases diagnosed using BAL. However, the specimens obtained may be useful for differential cell counts and special ancillary investigations, including flow cytometry or immunohistochemical studies. BAL specimens must be differentiated from bronchial washings, as the cellular contents and diagnostic yields of the two specimens are different; while the bronchial wash represents the mucosal surface, BAL contains material from alveolar spaces.

Bronchial Brushings Bronchial brushings represent material obtained though catheter-based brushing of airway mucosa or lesions under direct visualization or fluoroscopic guidance. The specimens are particularly useful because morphologic details are usually well preserved and representative of mucosal lesions. Fresh specimens should be submitted to the laboratory. Alternatively, the saline-immersed brush can be mixed with an equal volume of 50 percent ethanol or proprietary collection fluid for concentration methods when a delay in specimen delivery is expected. Direct smears are prepared by rolling the brush on a clean glass slide, followed by immediate fixation using 95 percent ethanol. Caution must be exercised in their evaluation, since poorly preserved cells may appear hyperchromatic, have altered nucleocytoplasmic (N:C) ratios, and mimic undifferentiated tumors. Bronchial reserve cells, often seen in such specimens, may be mistaken for small-cell neoplasms. In hypersensitivity and inflammatory processes, proliferative goblet cells and columnar cells are commonly seen and may be associated with eosinophils and Curschmannâ&#x20AC;&#x2122;s spirals. Ciliocytophthoria (CCP), another manifestation of hypersensitivity reactions or viral infections, also may be observed in bronchial specimens. Proliferative mucosal cells may appear as cohesive aggregates; the cilia, which can be located centrally, may be inconspicuous. These so-called â&#x20AC;&#x153;creola bodiesâ&#x20AC;? may be mistaken for well-differentiated adenocarcinoma.

Pulmonary Cytopathology

and bizarre bronchial cells may be seen. An adequate clinical history and communication between bronchoscopist and cytopathologist are necessary for proper interpretation of postbronchoscopy specimens. The technique may be of particular value in patients who are unwilling or unable to undergo additional diagnostic procedures. Specimens can be poolcollected in 50 percent ethanol or a proprietary preservative.

Transbronchial Aspiration Transbronchial aspiration of pulmonary masses and intrathoracic and mediastinal lymph nodes is generally used to evaluate peritracheal, peribronchial, and, occasionally, anterior mediastinal lesions. An aspirating needle is introduced through the bronchoscope and directed to the area of interest. Considerable experience is needed for specimen collection and interpretation. On-site evaluation of specimens improves diagnostic accuracy and reduces the number of passes necessary. In situations where on-site evaluation is not available, specimens can be submitted to the laboratory in 50 percent ethanol or a proprietary preservative.

Percutaneous Transthoracic Fine-Needle Aspiration Localized pulmonary parenchymal abnormalities are frequently evaluated using transthoracic fine-needle aspiration (FNA) under imaging guidance. The technique is extremely accurate, rapid, and cost-effective; results are comparable to those from tissue biopsies. Diagnostic sensitivity ranges from 75 to 95 percent and specificity from 95 to 100 percent. Complications include bleeding and pneumothorax. The incidence of tumor cells seeding along the needle track is extremely low. While on-site cytological evaluation is valuable and preferred, specimens may be submitted to the laboratory in appropriate transport media. Use of a large-bore needle during aspiration may result in excessive bleeding, rendering on-site specimen preparation and evaluation difficult.

Endobronchial and Endoscopic Ultrasound-Guided Fine-Needle Aspiration Ultrasound-guided transbronchial and transesophageal fineneedle aspiration (FNA) are useful procedures in the evaluation of peripheral lung and mediastinal lesions, respectively. Radiation exposure is diminished, and a high degree of diagnostic accuracy is provided.

Postbronchoscopy Sputum Cytological analysis of postbronchoscopy sputum specimens may be of diagnostic value. The patient is directed to collect morning sputum specimens for 2 to 3 days following bronchoscopy. These samples are more cellular and may be representative of the underlying pathology. Caution in interpretation is necessary, however, since extremely reactive

SPECIMEN PROCESSING A variety of techniques are employed in the cytopreparations of pulmonary specimens.

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Direct Smears

Cell Block

Direct smears, prepared by trained laboratory personnel using the “pick and choose” technique, are best made from fresh, unfixed specimens. A biologic hood and necessary infectious precautions are employed. Any thick, pink, or dark suspicious areas are transferred to clear, prelabeled slides for preparation of smears. At least four smears should be made from each sample and fixed immediately in 95 percent ethanol or spray-fixed for Papanicolaou stain. The remaining material may be processed as described below.

Slides prepared using the cell block technique may permit accurate diagnosis when specimens contain abundant abnormalities. However, when cells of interest are limited, cell block preparations are suboptimal for diagnosis. In symptomatic patients, cell blocks have been found to improve cancer diagnosis by at least 50 percent compared with direct-smear slides prepared from induced sputum. In addition, cell blocks can be used for a variety of histochemical and immunocytological studies.

Saccamanno’s Fixative Saccamanno’s fixative is used in a popular technique in which a mixture of 50 percent ethyl alcohol and polyethylene glycol (Carbowax 1540) is added to the specimen. The specimen is either smeared directly on glass slides or used to prepare a slurry after mixing in a blender and subsequent centrifugation. However, alcohol causes coagulation of proteinaceous material, making direct smearing of the specimen difficult. Furthermore, blending may result in fraying of the delicate cell cytoplasm and cilia. This technique is useful in detection of squamous carcinoma, other large-cell tumors, and certain infections; it is less valuable for the diagnosis of tumors with neuroendocrine differentiation.

Cytospin Preparations Cytospin preparations can be prepared from either fixed or fresh specimens. At least four slides should be examined from each specimen when the technique is used exclusively for specimen evaluation. Liquid-based preparations (ThinPrep or SurePath) are popular cell concentration techniques and are superior to cytospin slides. Pulmonary specimens are collected and preserved in a vendor-provided solution and are submitted to the laboratory. The preparation background is clean, and cytological examination is easier. In addition, slide preparations can be used for other special investigations, such as morphometry or immunocytochemistry. However, cells may clump together and appear hyperchromatic. In addition, delicate morphologic and background features, such as necrosis and inflammation, are often lost, limiting evaluation and diagnosis.

Cellulosic (Millipore) Filters Cellulosic (Millipore) filters are used in processing fresh pulmonary specimens. An 8-nm pore filter is employed in the collection of cells; fixation artifacts are minimal. Adequate sampling, maintenance of intercellular relationships, and background features are facilitated using this technique. In addition, morphologic details and cellular preservation are excellent. However, the procedure is expensive and timeconsuming, and it requires a special setup and experienced technicians.

Ancillary Laboratory Diagnostic Techniques Specialized investigations, such as immunocytochemistry, electron microscopy, flow cytology, or microbial cultures may be undertaken in evaluating selected cytology specimens. Based upon the on-site evaluation of fine-needle aspirates and cytological findings, specimens for these special studies can be appropriately collected and processed. The techniques are especially useful in differentiation of adenocarcinoma from mesothelioma, diagnosis of bronchoalveolar carcinoma, elucidation of specific microbial infections, and further characterization of poorly differentiated tumors and lymphomas. In addition, molecular diagnostic procedures may be applied in the diagnosis of pulmonary infections.

NORMAL BRONCHOPULMONARY CYTOLOGY A variety of cells representing tracheobronchial tree and pulmonary parenchyma are seen in a pulmonary specimen that has been obtained using the previously described techniques. Notably, heavy oropharyngeal contamination can occur in sputum specimens obtained spontaneously or following induction, and in bronchial washings.

Squamous Cells Squamous cells are seen commonly in expectorated specimens as uniform, flat cells with pyknotic nuclei; sometimes the nuclei are vesicular and enlarged. Most cells are large and keratinized and vary minimally in size. Atypical pleomorphic, small, hyperkeratinized cells with altered N:C ratios and hyperchromasia (dysplastic squamous cells) may be observed with oropharyngeal and laryngeal squamous lesions. The presence of abnormally shaped keratinized cells, with little inflammation and background necrosis, should prompt examination of the upper airway (Fig. 31-2). Mechanical irritation in the oral cavity, generally by ill-fitting dentures or other prosthetic devices, can cause exfoliation of bizarrely shaped keratinized cells noted in small tissue fragments. Small, dense, keratinized metaplastic cells may be seen in patients who are endotracheally intubated or who have undergone tracheostomy. Chronic pulmonary diseases can often lead to squamous metaplasia and atypical cell

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Pulmonary Cytopathology

Figure 31-2 Upper airway brush specimen showing squamous cell carcinoma of the larynx. Note the group of small abnormal, keratinized cells occurring in a necrotic background. The patient had a normal chest radiograph. (Papanicolaou stain, ×166.)

Figure 31-4 Bronchial washing showing Charcot-Leyden crystal in a patient with bronchial asthma. Note the numerous needleshaped crystals occurring in an acute inflammatory background. The crystals are organophilic with the Papanicolaou method. (Papanicolaou stain, × 166.)

morphology, causing concern about underlying malignancy. Finally, oropharyngeal contamination is extremely common in bronchial washings. The presence of fungal organisms (e.g., Candida) does not necessarily represent pulmonary infection. These observations must be interpreted in light of clinical features (Fig. 31-3).

the proper identification of cilia. Fragmented ciliated cells (CCP) may occur in hypersensitivity and reactive conditions, as well as viral infection of the respiratory tract (as discussed below).

Goblet Cells Ciliated Bronchial Columnar Cells Ciliated bronchial columnar cells may occur singly and in small tissue fragments. These columnar cells contain basally located, vesicular nuclei and pale cytoplasm. The cells have cilia of uniform length; they exhibit periodicity and attach at right angles to the terminal plates. The cilia must be accurately identified because, almost always, true cilia, which are visible by light microscopy, do not occur on malignant cells. Cellular degeneration and trapped mucus can be a source of error in

Figure 31-3 Bronchial wash specimen. Note intense, acute inflammatory exudate and filament of Candida organisms (arrow). The findings are common and represent oral contamination. (Papanicolaou stain, ×166.)

Goblet cells are recognized less commonly in normal pulmonary specimens. When present, they appear as swollen, pale cells. In general, goblet cells possess a single large vacuole or multiple small vacuoles that may contain mucus. Hyperplastic columnar and goblet cells may be seen in chronic pulmonary diseases, such as bronchitis or bronchial asthma, and in allergic conditions. In bronchial asthma, Curschmann’s spirals may also be observed in cytological specimens. These are composed of a mucus shroud with numerous neutrophils and some eosinophils. Occasionally, needle-shaped CharcotLeyden crystals, which appear orangophilic with Papanicolaou staining, may be seen (Fig. 31-4). Hyperplastic bronchial columnar cells may appear quite bizarrely. They occur in tight tissue fragments with overlapping, hyperchromatic and enlarged, reactive nuclei that contain prominent nucleoli. On careful examination, such structures, known as creola bodies, reveal cilia on the edge or cell surface (Fig. 31-5). Creola bodies are a common cause of a false-positive diagnosis of adenocarcinoma. Similar hyperplastic structures can be seen in postbronchoscopy sputum specimens. The occurrence of large numbers of mucus-producing columnar cells without discernable cilia in tissue fragments obtained by FNA may be indicative of well-differentiated, mucin-producing adenocarcinoma.

Alveolar Macrophages The presence of alveolar macrophages and type II pneumocytes in a pulmonary specimen are excellent criteria for specimen adequacy. These cells occur singly and are round or

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Pulmonary macrophages can be stained with CD68 immunochemical antibodies. Such immunocytochemical studies can be diagnostically useful in establishing the precise nature of atypical or other questionable cells.

TOXIC ENVIRONMENTAL INHALATION EFFECTS

Figure 31-5 Bronchial washing showing creola bodies. Note the numerous glandular structures. Cells have prominent nucleoli, hyperchromasia, and evidence of mucus production. Some cells reveal terminal plates and cilia. Cilia may be few, poorly stained, and difficult to recognize. (Papanicolaou stain, ×208.)

cuboidal; typically, they have a kidney-shaped, vesicular nucleus which may contain a single, prominent nucleolus. Cell cytoplasm is pale and demonstrates fine vacuolation. Occasionally, ingested foreign material (carbon) or blood products (e.g., hemosiderin) may be observed in the cytoplasm. Multinucleated forms may occur in bronchoalveolar specimens obtained from patients who have pulmonary alveolar proteinosis or granulomatous diseases, or who have been exposed to pollutants (Fig. 31-6). Alveolar macrophages must be examined in the context of the specimen background. Whereas evidence of old hemorrhage and necrosis may suggest a neoplasm, acute inflammation may signify an inflammatory process. Pulmonary infarcts, organizing pneumonia, prior chemotherapy, and other factors produce atypical cellular changes in macrophages and epithelial cells. The cytopathologist must be provided with proper clinical information in evaluating these specimens.

Figure 31-6 Bronchial washing showing multinucleated giant cell in pulmonary specimen from a cigarette smoker. Note the acute inflammatory background, mucus, and foreign body–type giant cell. (Papanicolaou stain, ×208.)

Respiratory squamous and columnar cells and alveolar macrophages react to various environmental pollutants. As examples, the cytological responses of these cells to cigarette smoke, asbestos, beryllium, and “crack” cocaine are described briefly below.

Cigarette Smoke Exposure of the respiratory system to cigarette smoke leads to accumulation of a golden-brown, refractile pigment within pulmonary macrophages. The pigment may be indistinguishable from carbon and hemosiderin particles. Alveolar macrophages may be ringed by material composed of α 1 -antitrypsin, which stains orange-red with Papanicolaou stain. This material has been further investigated using appropriate immunocytochemical procedures. Intracellular α 1 antitrypsin may be tapered at one or both ends of the macrophage, creating a “tailed” appearance. Affected cells have been termed “pink-tailed” macrophages (Fig. 31-7).

Asbestosis Asbestosis generally arises from exposure to dust containing mainly chrysolite and other forms of asbestos fibers. Elongated asbestos bodies, also referred to as ferruginous bodies, may be observed in pulmonary specimens from subjects exposed to asbestos. Ferruginous bodies vary in size from 4 to 5 nm to over 200 nm. They are commonly dumbbell-shaped; a central translucent fiber core is surrounded by layers of a material containing minerals (iron, calcium) and mucopolysaccharide. The color of ferruginous bodies is variable, from a pale golden yellow to dark brown or black. The outer coat tends to be segmented and oriented at right angle to the long axis of the fiber. Ferruginous bodies are generally accompanied by a tissue reaction comprised of macrophages and giant cells (Fig. 31-8). On rare occasions, needle-shaped asbestos fibers without any surrounding deposits are observed within the macrophages. Besides asbestos exposure, ferruginous bodies are also observed following inhalation of other minerals and fibers. No definitive correlation between the presence of ferruginous/asbestos bodies and occupational exposure to asbestos fibers has been observed. Although large numbers of ferruginous bodies may be seen after massive exposure to asbestos, occasional ferruginous bodies are observed as a nonspecific finding. Prussian blue staining for iron compounds helps further identify ferruginous bodies.

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Figure 31-7 A. Bronchial washing showing ‘‘pink-tailed” macrophages in pulmonary specimen from a patient with a 15 pack-years cigarette-smoking history. B. Even distribution of 1 -antitrypsin around macrophages. While 1 -antitrypsin is distributed in the ‘‘points” in A, it is seen in close apposition to the cell in B. (Papanicolaou stain, ×330.)

Pulmonary Cytopathology

Figure 31-8 Induced sputum showing ferruginous bodies in pulmonary specimens from a shipyard worker. A. Details of the central fiber core are visible. B. The surrounding core with segmented appearance is evident. (Papanicolaou stain, ×330.)

Berylliosis Chronic exposure to beryllium and certain other heavy metals may result in profound pneumocyte proliferation and giantcell formation. Multinucleated giant cells tend to be syncytial and often occur as large tissue fragments (Fig. 31-9). Variable numbers of lymphocytes may be present in the background. Clinical correlation is necessary before the cytopathologist can establish such a diagnosis.

Crack Cocaine Inhalation Repeated inhalation of recreational drugs may result in accumulation of large quantities of “black soot” within the alveoli and pulmonary macrophages (Fig. 31-10). The occurrence of large amounts of carbonaceous material within macrophages obtained by BAL appears to be unique to this patient population. The finding of similar pigmented macrophages within pleural fluid cells has been reported.

Figure 31-9 Bronchoalveolar lavage specimen showing multinucleated giant cell in beryllium exposure. Note the extremely large foreign body–type giant cell and alveolar macrophages (Diff-Quik stain, ×208.)

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Generally, a histochemical (modified acid-fast) stain is used for further identification.

Figure 31-10 Bronchoalveolar lavage specimen showing pulmonary macrophages in a crack cocaine user. Note the abundant pigmented material in the cytoplasm of the cells, some of which appear reactive. Occurrence of pigment, per se, is a nonspecific finding. (Papanicolaou stain, ×208.)

Mycobacteriosis Acid-fast organisms may be detected in a variety of pulmonary specimens from patients with mycobacterial infections. Both tuberculous and nontuberculous mycobacterial infections are seen in immunocompetent and immunosuppressed patients. In immunosuppressed patients (e.g., those with human immunodeficiency virus [HIV] infection), the sample background is variable and may not be diagnostically helpful; only foamy macrophages, neutrophils, and a few lymphocytes may be seen (Fig. 31-11). While infection with Mycobacterium tuberculosis may yield only a few organisms in respiratory samples, specimens obtained from patients with atypical mycobacterial infections may yield numerous organisms that are identified easily by histochemical stains. Appropriate cultures should be performed in all such cases for a specific microbiologic diagnosis.

INFECTIONS A variety of infections of the respiratory tract result in cytopathological changes seen in specimens obtained by the aforementioned methods. The following sections outline changes that may be observed in pulmonary specimens obtained from patients with common bacterial, fungal, viral, or parasitic respiratory infections.

Bacterial Infections Although bacterial infections of the respiratory tract are extremely common, cytopathology does not offer much help in their diagnosis or management. In selected cases, cytopathology may be useful. Actinomycosis In patients with infection caused by species of Actinomycetes, pulmonary specimens generally contain large aggregates of filamentous, branching, thin organisms seen as tight, “woolly” clumps in an acute inflammatory background. The organisms are easily recognized in routine preparations and are correctly identified using appropriate immunohistochemical techniques. Diagnostic interpretation is made in view of the clinical and radiographic features. The constellation of these findings is important, since occurrence of actinomycetes in the oral cavity is extremely common, and morphologic detection may not indicate pulmonary infection. Nocardiosis Nocardia may be associated with pneumonia and cavitary pulmonary lesions. The organisms are visualized as delicate, nonseptate, filamentous, branching structures. The diagnosis can be made on specimens obtained from FNA or bronchoscopy.

Figure 31-11 Fine-needle aspirate of the lung, atypical mycobacterial infection. A. Note the necrotic background, lack of inflammatory cells, and ‘‘ghost” forms of bacillary organisms. These can be seen in air-dried smears using Romanovsky’s stain (Diff-Quik stain, ×330). B. Induced sputum specimen showing acid-fast, intracellular, atypical mycobacterium organisms. (ZiehlNeelsen stain, ×330.)

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Pulmonary Cytopathology

Fungal Infections A number of fungal organisms can be easily recognized in pulmonary specimens using the Papanicolaou stain. These include both true pathogens and a number of contaminants. Appropriate mycobial cultures should be performed if clinicopathological correlation is lacking and a specific diagnosis of the fungal type is important. A

Candidiasis Candida albicans may be seen as budding yeast forms in many specimens that are not freshly prepared and that have been stored at room temperature before fixation. This finding is of little clinical significance and is generally not reported by the cytology laboratory. In contrast, the occurrence of filamentous Candida forms, especially in specimens obtained by FNA, may be clinically important and should be reported. Such findings are seen in patients who are immunocompromised or suffer from diabetes or other disabling conditions. A laboratory report of Candida organisms in pulmonary specimens such as spontaneous or induced sputum or bronchial washings should be correlated with clinical and radiographic observations. B

Aspergillosis Aspergillus-related pulmonary disorders are quite varied in their clinical presentation. While establishing the presence of true tissue invasion may be difficult, the presence of the organism in pneumonic or cavitary lesions can be diagnosed cytologically. Most parenchymal infections are caused by A. fumigatus, although infections with A. niger and A. flavus also occur. Sputum specimens, bronchial washings, bronchial brushings, and FNAs can be diagnostic. Since Aspergillus is an opportunistic airborne organism that sometimes contaminates pulmonary specimens, care should be exercised in reporting infection with Aspergillus if it is seen only on one slide or one set of slides. The presence of an acute inflammatory background and clinical and radiologic correlation are necessary for accurate diagnosis. The organisms are seen as broad, filamentous structures that branch at acute angles. In immunosuppressed patients with overwhelming infections, “fruiting bodies” (conidiospores) can be seen. Birefringent calcium oxalate crystals may occur in specimens containing Aspergillus; they are more commonly observed with A. niger (Fig. 31-12). Epithelial cells may show metaplastic and atypical morphologic features. Cryptococcosis Patients with cryptococcosis may be asymptomatic. Organisms can be visualized in sputum, bronchial washings, bronchial brushings, or FNA specimens. Most commonly, narrow-necked, budding yeast forms are observed; they demonstrate marked variation in size (5 to 40 nm) (Fig. 31-13). The organism has a surrounding mucopolysaccharide-rich capsule that can be stained with mucicarmine or other histochemical agents (Fig. 31-14). In fresh, unfixed specimens, an India-ink preparation outlines the organisms quite well.

Figure 31-12 A1. Bronchoalveolar lavage (BAL) specimen showing broad filamentous forms and acute angle branching of Aspergillus. A2. BAL specimen showing fruiting bodies (conidiospores). B. Bronchial washing specimen. Calcium oxalate crystals in association with Aspergillus infection seen with partially polarized light. (A1., Papanicolaou stain, ×260; A2., Papanicolaou stain ×160; B., Papanicolaou stain, ×208.)

Occasionally, broad filamentous forms are observed (Fig. 3115). Infection may present as noncaseating granulomas with multinucleated giant cells and macrophages. Histoplasmosis Pulmonary infection with Histoplasma capsulatum may be asymptomatic or associated with signs and symptoms that

Figure 31-13 Bronchial washing showing Cryptococcus. Note the numerous budding organisms. Budding is narrow, and organisms show variation in size. (Silver methenamine stain, ×260.)

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Figure 31-14 Bronchial washing showing Cryptococcus. Intracytoplasmic organisms show variation in size and a pale thick capsule. (Papanicolaou stain, ×330.)

mimic tuberculosis. The organisms are small, budding yeast forms, (2 to 4 nm) and are generally intracellular, occurring within the pulmonary macrophages, the bronchial epithelial cells, or neutrophils. Organisms are best identified using a silver-methenamine technique (Fig. 31-16). Blastomycosis Patients with respiratory infection caused by Blastomyces dermatididis may be asymptomatic or have signs and symptoms of chronic suppurative pulmonary disease. A clinical history demonstrating exposure in an endemic area (e.g., Ohio, Mississippi River Valley, or southeastern U.S.) is usually helpful. The organism is seen as a budding yeast, generally with single, broad-based refractile walls. The budding form has a short neck, and the daughter bud is found in close apposition to the mother bud. Coccidioidomycosis Patients with coccidioidomycosis generally present with features of a respiratory tract infection, including productive

Figure 31-15 Bronchoalveolar lavage showing Cryptococcus. Note the broad, filamentous forms. Budding organisms are seen at the tips of the filaments. (Mucicarmine stain, ×330.)

Figure 31-16 Fine-needle aspiration lung. Histoplasma capsulatum within the macrophages. Insert shows details and budding fungal forms. (Diff-Quik stain, ×260; insert, silver methenamine stain, ×330.)

cough; alternatively, the principal clinical finding may be a solitary pulmonary mass. Coccidioides immitis is found in dry, sandy areas of the southwestern U.S. (e.g., California, Arizona, New Mexico, and Texas). The organism is large (20 to 60 nm) and occurs as a nonbudding spherical structure. Spherules have a distinct thick wall and contain a variable number of endospores. The endospores are small (1 to 3 nm), round, and nonbudding. With most specimens, the background examination reveals a heavy acute inflammatory exudate that obscures the faintly stained organisms. Pulmonary fine-needle aspirates can be helpful in the diagnostic evaluation of solitary pulmonary nodules caused by coccidioidomycosis (Fig. 31-17). Pneumocystis Pneumonia (PCP) Pneumocystis carinii infection was originally described by Carlos Chagas in 1909 and confirmed a year later by Antonio

Figure 31-17 Fine-needle aspiration of lung. Coccidiodomycosis infection. Fungal spherule containing endospores (arrow). (Papanicolaou stain, ×330; case courtesy of Dr. Tunda Farkas.)

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Carinii. Recently, Pneumocystis jiroveci was proposed as the organism’s new name. Infection with P. carinii has been most commonly reported among patients with underlying neoplastic or immunodeficiency diseases, particularly the acquired immunodeficiency syndrome (AIDS). Systemic chemotherapy for neoplastic diseases and transplantation also may result in immunosupression and subsequent infection. Initially regarded as a parasite, P. carinii is now considered a fungus, based on ribosomal RNA studies. Attempts to culture the organism have been unsuccessful. P. carinii occurs in zygote or sporocyte forms, which are 1 to 5 nm in diameter and have a distinct nucleus. Up to eight spores may occur within the cyst, which measures 6 to 8 nm in diameter— roughly the size of a red blood cell. Organisms infect adjacent tissue after being liberated from the ruptured cysts. P. carinii infects alveolar macrophages; in rare instances, the organism may be seen in macrophages in pleural fluid, lymph nodes, or other reticuloendothelial cells. Although, historically, PCP was often diagnosed from examination of tissue obtained by surgical lung biopsy, carefully collected cytology specimens obtained by fiberoptic bronchoscopy give comparable or better results with minimal patient risk. The technique is sensitive, rapid, and economical. While early reports on the diagnostic yield from examination of induced sputum specimens were encouraging, the findings have not been uniformly confirmed. The best results are obtained using BAL. P. carinii infection may be suspected upon inspection of routine Papanicolaou stains, as well as hematoxylin-and-eosin–stained pulmonary specimens. For a definitive diagnosis, a variety of histochemical, immunologic techniques are routinely used. Recently, molecular procedures have been used in identification of PCP.Zygote forms can be visualized using selected stains (e.g., Romanovsky’s); basic dye (crystal violet, toluidine blue); and periodic acidSchiff (PAS), Papanicolaou, and Gram-Weigert’s stains. The most commonly used histochemical procedure, the silvermethenamine (Grocott) stain, outlines the cyst wall. Immunocytochemical and monoclonal antibody techniques can be used to identify the organisms, as well as the cyst walls.

Pulmonary Cytopathology

Figure 31-18 Bronchial washing specimen. Pneumocystis carinii occurring as intra-alveolar cast ‘‘coagulum”. (Papanicolaou stain, ×260, Millipore preparation.)

ter treatment, the cysts undergo lyses, with fragmentation of the walls, necrosis, and ingestion of the organisms by pulmonary macrophages (Fig. 31-20). Among commonly used histochemical stains, Gram-Weigert’s appears slightly more sensitive and specific than silver-methenamine; Giemsa’s stain is the least sensitive technique. Great care must be exercised in interpretation of silver and special stains for P. carinii. Yeast forms of Candida arising from oral contamination of sputum and other specimens may resemble P. carinii cysts. However, these yeast forms lack the soft, wrinkled, “poached egg” appearance. In addition, they occur in oral mucoid material, not in the proteinaceous, granular alveolar contents or coagulum. In situ hybridization and molecular techniques provide results similar to other diagnostic procedures; however, quantitative differences exist. Other fungi, including Paracoccidioides, Mucor, and Sporothrix, are seen occasionally in pulmonary specimens.

Cytomorphology

In air-dried specimens prepared using the Romanovsky’s, Papanicolaou, or hematoxylin-eosin methods, P. carinii appears within the alveolar material or foamy “coagulum” (Fig. 31-18). The fungal organisms occur in cyst forms that may contain sporocytes (see above). In silver-methenamine (Grocott) and Gram-Weigert’s stained preparations, the cysts frequently collapse, giving a crescent or “poached egg” appearance (Fig. 31-19). The sensitivity of the staining techniques varies according to the quality of preparation, content of pulmonary material, and duration of therapy before the diagnostic procedure is performed. Silver-methenamine and some of the immunologic techniques may give negative results in specimens collected from patients who have received prior therapy. Af-

Figure 31-19 Bronchoalveolar lavage showing Pneumocystis carinii. Note the cluster of organisms with collapsed cyst walls and central clearing. These forms should be distinguished from the yeast form of Candida, which is commonly seen in pulmonary specimens. (Gram-Weigert’s stain, ×260.)

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Figure 31-20 Bronchoalveolar lavage showing Pneumocystis carinii infection after therapy. Note the degenerated and ghost forms of the organisms in the alveolar cast material. (GramWeigert’s stain, ×330.)

Viral Infections Pulmonary specimens may reveal specific or nonspecific viral effects on cell components. When infected, bronchial epithelial cells may demonstrate CCP, noted previously. In CCP the cells degenerate when the cytoplasmic tip and attached cilia are exfoliated. The basal portion of the cell shows a pyknotic, degenerated nucleus (Fig. 31-21). Specimens generally have an acute inflammatory background and may contain numerous reactive bronchial cells that can be mistaken for neoplasm. CCP also may be observed in some pulmonary hypersensitivity states. Herpes Simplex Virus Herpes simplex virus (HSV) may infect the oral mucosa, tracheobronchial tree, or pulmonary parenchyma. The finding of HSV in a pulmonary cytological specimen is useful in localizing infection to the lower respiratory tract only when the specimen is “uncontaminated,” (i.e., is obtained by FNA, tracheal aspiration, bronchial washing, or BAL). Clinical-radiologic correlation is necessary in most cases. When pulmonary parenchymal infection is present, the specimen background is extremely inflammatory, showing numerous neutrophils, abundant mucus, and cellular degeneration. Unless adequate pulmonary material is carefully examined, pulmonary HSV infection can be easily overlooked. The infected cells may be small (10 to 15 nm) and round and contain intranuclear evidence of the virus as a “ground glass” appearance. This pattern is commonly seen with tracheobronchial infection or in specimens obtained from aspiration of material through a tracheotomy tube. In cases of severe pulmonary infection, multinucleated giant cells demonstrating internuclear molding, intranuclear acidophilic inclusions, or a gelatin chromatin pattern may be seen (Fig. 31-22). Care should be exercised in distinguishing HSV inclusions and prominent nucleoli within bronchial cells.

Figure 31-21 A. Bronchial washing specimen showing ciliocytophthoria (CCP) in a case with pulmonary viral infection. Note numerous fragmented, ciliated columnar cells and macrophages. B. Details of CCP. Note the cilia in a degenerated cell. (Papanicolaou stain: A., ×208; B., ×330.)

Figure 31-22 Bronchial washing showing herpes simplex virus (HSV). Note the large single cells with prominent intranuclear inclusions and gelatinous nuclear chromatin. (Papanicolaou stain, ×260.)

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Figure 31-23 Bronchial brush from a patient with lung transplant showing cytomegalovirus (CMV). Note the large, intranuclear acidophilic inclusions with radiating chromatin threads. (Papanicolaou stain, ×330; Millipore preparation.)

Cytomegalovirus A member of the herpes virus family, cytomegalovirus (CMV) may infect the bronchial epithelium and alveolar lining cells. Infection is common among immunocompromised patients. Infected cells show cytomegaly and large, generally distinct acidophilic intranuclear inclusions. Thin strands of nuclear chromatin bridge the space between the inclusion and the nuclear envelope (Fig. 31-23). Occasionally, the inclusions are basophilic and intracytoplasmic. In rare instances, CMVinfected cells may show multinucleation. Pulmonary HSV infection may occur concurrently with CMV. Viral infection may occur in a polymicrobial environment. CMV can occur with pneumocystis, HSV, and other pulmonary infections. Respiratory Syncytial Virus Respiratory syncytial virus (RSV) is often not recognized in routine cytological specimens. The virus produces two types of inclusions within bronchial and alveolar lining cells: (1) dense acidophilic inclusions with clear halos around them, and (2) “smudge” cells, which contain a basophilic nucleus with obliteration of chromatic details.

Pulmonary Cytopathology

Figure 31-24 Bronchial washing in para-influenza viral infection. Note organophilic cytoplasmic changes affecting columnar cells (arrow). Insert shows multiple cytoplasmic inclusions. (Papanicolaou stain, ×260; insert, ×330.)

may cause tracheal papillomatosis and produce fragments of squamous epithelium containing typical koilocytes, which are squamous cells with eccentric, vesicular nuclei and a distinct cytoplasmic halo or cavity. The cells contain intranuclear HPV antigens, which can be demonstrated by use of various tissue and molecular techniques. Most airway HPV infections are caused by viral types 6 and 11.

Parasitic Infections A number of parasitic infections may occur in the lung. They are seen almost exclusively in either endemic areas or among immunosuppressed patients. Strongyloidosis Pulmonary infection with Strongyloides stercoralis may be seen in patients with AIDS or those who are iatrogenically immunosuppressed (e.g., by prolonged corticosteroid

Para-influenza Virus Para-influenza infection in the upper respiratory tract produces a variable number of infected columnar cells, which demonstrate eosinophilic degeneration and cytoplasmic inclusions. The inclusions are considered degenerative, rather than viral, particles (Fig. 31-24). Adenovirus Although more common in children and infants, adenovirus infection can also occur in adults. Depending upon the duration of the disease, intranuclear inclusions can be seen in bronchial columnar cells (Fig. 31-25). Other Viruses Multinucleation and eosinophilic cellular inclusions may be observed in measles infection. Human papillomavirus (HPV)

Figure 31-25 Bronchial brush specimen in adenovirus infection. Numerous intranuclear eosinophilic inclusions (arrow) are seen infecting the bronchial cells. (Papanicolaou stain, ×330.)

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Figure 31-26 Spontaneously produced sputum specimen from a patient with AIDS. Strongyloides filariform larva present in a necrotic background. (Papanicolaou stain, ×110.)

Figure 31-27 Induced sputum specimen showing Paragonimus egg. (Papanicolaou stain, ×110.) B

administration). Filariform larvae, which are easily identifiable, may be seen in bloody sputum specimens. The larvae measure up to 500 nm in length and contain a gullet and notched tail. Ova may be observed in some sputum specimens (Fig. 31-26). Uncommonly, other parasites, including Echinococcus, Entamoeba, microfilaria, Toxoplasma and Paragonimus (Fig. 31-27), may infect pulmonary tissues and be diagnosed cytologically. Trichomonas infection also has been identified in pulmonary specimens obtained from immunosuppressed patients.

OTHER NON-NEOPLASTIC CONDITIONS Cytopathological findings may be observed in a number of other non-neoplastic conditions. Some of the common ones that can be detected in pulmonary specimens are described below.

Aspiration Pneumonia Generally, both severe acute inflammation and foreign-body giant-cell reactions may be observed in pulmonary specimens obtained from patients with aspiration pneumonia. The latter reaction is related to the duration of the disease. Often the aspirated material can be recognized in pulmonary specimens.

Figure 31-28 Fine-needle aspiration of lung showing organizing pneumonia. A. Note the hyperchromatic, atypical alveolar cells (Diff-Quik, ×260). B. Pulmonary core biopsy showing similar cells lining the alveolar spaces (H&E, ×166).

Organizing pneumonia can produce both radiographic and cytological changes affecting the alveolar lining cells that may mimic a neoplastic process (Fig. 31-28).

Lipid Pneumonia Lipids may enter the respiratory system through exogenous sources (e.g., by ingestion, aspiration, or use of nasal sprays containing emollient particles) or through endogenous routes (e.g., from the bone marrow after injury—fat embolism). Cytologically, large foamy cells with small vesicular nuclei may be seen, either singly or in small tissue fragments (Fig. 31-29). The presence of endogenous or exogenous fats can be confirmed by appropriate histochemical stains. Differentiation and diagnosis can be valuable for infants and children with pneumonia.

Pulmonary Infarction and Intra-alveolar Hemorrhage A radiographic lesion due to pulmonary infarction may be aspirated on clinical and/or radiographic suspicion

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Figure 31-29 Bronchial washing showing lipid pneumonia. Note the large vacuolated cells with hyperchromatic nuclei and prominent nucleoli. Such cells can be mistaken for adenocarcinoma. (Papanicolaou stain, ×260.)

of malignancy. These specimens often contain numerous macrophages containing ingested hemosiderin. The hemoglobin metabolite occurs as dark green or brown intracellular clumps that can be stained histochemically. Extremely bizarre, reactive bronchial cells may accompany such macrophages and pose a diagnostic challenge (Fig. 31-30). Bronchoalveolar lavage or bronchial washing performed following lung transplantation or in the setting of a number of autoimmune or other disorders may contain numerous alveolar macrophages which contain golden-brown, fine intracytoplasmic pigment (Fig. 31-31). Pigmented macrophages occur in a background of fresh hemorrhage and reactive bronchial epithelial cells in specimens obtained from patients with acute intra-alveolar hemorrhage, such as that which occurs in Goodpasture’s syndrome (Fig. 31-32).

Figure 31-30 Fine-needle aspiration. Pulmonary infarct. A. Note the numerous degenerated macrophages and alveolar cells which have lost morphologic features and contain ingested red blood cells. B. Corresponding lung core biopsy revealing similar changes. (A. Papanicolaou stain, ×260; B. H&E stain, ×260.)

Sarcoidosis Cytological diagnosis of sarcoidosis is considered accurate and cost-effective. Pulmonary specimens (especially BAL) obtained from patients with suspected parenchymal involvement with sarcoidosis, may reveal diagnostic cytological changes. Typical findings include a clean background, a few lymphocytes, Langhans’-type multinucleated giant cells, and syncytial forms of histiocytic cells. Giant cells often have a clear cytoplasm and vesicular or pyknotic nuclei (Fig. 31-33). These giant cells should be distinguished from the multinucleated cells associated with cigarette smoking, bronchial irritation, or pneumonia. The multinucleated giant cells from cigarette smokers often contain golden-brown pigment; numerous reactive columnar cells characterize the irritative processes; the pneumonic processes commonly include an inflammatory background. Concentrically laminated Schumann’s bodies or spiderlike asteroid bodies may be observed in pulmonary specimens. Important to note is that these findings are uncommon and not specific for sarcoidosis. Sarcoidosis is usually diagnosed by the finding of noncaseating granulomas within lung tissue or lymph nodes in

Figure 31-31 Bronchoalveolar lavage specimen from lung transplant patient showing intra-alveolar hemorrhage. A. Note golden-brown pigment (arrow) within the macrophages and acute inflammatory background. B. Hemosiderin pigment revealed by Prussian blue reaction (arrow). (A. Papanicolaou stain, ×260; B. Prussian blue reaction, ×260.)

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the absence of an alternative explanation for granulomatous inflammation (Fig. 31-33B). Additional studies for acid-fast and fungal organisms should be performed in all cases in which noncaseating granulomas are found.

Radiation and Chemotherapy Effects

Figure 31-32 Bronchoalveolar lavage specimen showing intraalveolar hemorrhage in Goodpasture’s syndrome. Note extensive fresh blood in the background and numerous blood-filled macrophages (arrow). (Papanicolaou stain, ×260.)

Some of the most bizarre and atypical cytological changes can be seen in pulmonary specimens obtained after radiation or chemotherapy. The value of obtaining a proper clinical history in this regard cannot be overemphasized. Radiation may affect squamous, bronchial, and alveolar lining cells. The effect is long-term and dose-dependent. General features include cytomegaly and karyomegaly; N:C ratios are unaltered. Irradiated nuclei are generally pale and have a finely divided, evenly distributed chromatin (Fig. 31-34). Cells reveal minimum pleomorphism and contain prominent acidophilic inclusions. The cytoplasm may be variable, dense, or vacuolated. Chemotherapeutic agents, including alkylating drugs (e.g., busulfan and cyclophosphamide) and antimetabolites

A A

Figure 31-33 Sarcoidosis. A. Bronchial brushing. Note numerous multinucleated giant cells and lymphocytes occurring in a non-necrotic background. B. Perihilar lymph node aspiration. Note noncaseating granulomas with lymphoid and epithelioid cells. (Papanicolaou stain: A., ×166; B., ×83.)

Figure 31-34 Bronchial washing. A. Radiation changes in bronchial epithelial cells. Note the extremely bizarre cells with marked variation in size. B. Prominent nucleoli are evident. Cells have thin and uniform nuclear membranes and pale chromatin. (Papanicolaou stain, ×260.)

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detected when the disease is localized, with an associated 5-year survival rate exceeding 60 percent. Regional and distant metastases are present in over 70 percent of cases at time of diagnosis; overall 5-year survival in this group is under 20 percent.

Early Lung Cancer Detection

Figure 31-35 Bronchial washing showing chemotherapy effect on bronchial epithelial cells. A. Note the bizarre cells with cytomegaly, nuclear atypia, hyperchromasia, and lack of nuclear details. (Papanicolaou stain, ×330.) B. Bronchoalveolar lavage specimen showing atypical alveolar cells that can be mistaken for malignancy. (Papanicolaou stain, ×260.)

(e.g., methotrexate and azathioprine), generally produce changes that affect bronchial epithelial cells and type II pneumocytes. These cells enlarge and become hyperchromatic, although the chromatin remains uniform and generally does not show abnormal clumping and clearing. Nucleoli are single or multiple and appear prominent. The nuclei may appear smudged, with loss of chromatin granularity and nuclear detail (Fig. 31-35). Great care should be exercised in diagnosing neoplasm in such cases. A proper history, comparison of cells with the original tumor, and familiarity of cytomorphologic changes are useful adjuncts to correct diagnosis. Similar cellular changes may be associated with amiodarone therapy.

PULMONARY NEOPLASMS In the United States in 2005, lung cancer will have accounted for approximately 163,000 deaths; 172,000 new cases will have been diagnosed. Only 16 percent of lung cancers are

In some lung cancers (e.g., squamous cell carcinoma), precursor lesions, including squamous dysplasia and in situ changes, precede development of invasive cancer. Early detection of this tumor type may improve survival. However, the multicentric origin of tumors, along with coexisting illnesses, contributes to mortality. Furthermore, moderate, atypical squamous metaplasia of the bronchial epithelium represents a lesion that, in a significant number of cases, may develop into squamous carcinoma. Application of molecular techniques to analysis of sputum specimens can detect moderately and markedly atypical metaplastic cells in patients at risk of subsequent lung cancer, a second primary tumor, or recurrent tumor. Attempts to identify the “at-risk” population using immunocytochemical techniques have been only partly successful. The labor and costs associated with sputum collection, sampling, and cell concentration have contributed to limited use of these techniques. Molecular methods are currently being evaluated for early lung cancer detection. Based on experience from an early Veterans Administration study, and using the evolution of cervical cancer as a model, a multi-institutional, early lung cancer detection project was launched by the National Cancer Institute in the early 1970s. Guidelines were outlined for early lung cancer detection using chest radiographs, sputum cytology, and, when indicated, fiberoptic bronchoscopy. In addition, treatment methods were delineated for “early” cancer, which was defined as an unsuspected, asymptomatic tumor detected by cytological or imaging techniques. Nearly 30,000 high-risk participants were screened using sputum cytology or chest radiographs (or both) at three participating centers. Cases were followed for up to 15 years. While sputum cytology and chest radiography detected a number of presymptomatic, early-stage lung cancers (especially squamous cell carcinomas), higher resectability and survival rates among the study group did not result in a lower overall mortality.

Established Lung Cancer Although pulmonary cytology in its present form has been used for detection and diagnosis of lung cancer for about 50 years, the earliest description of the technique dates back to 1767, when exfoliated respiratory cells were first described. In patients with suspected pulmonary malignancies, examination of a single, expectorated sputum has a low diagnostic yield of nearly 20 percent; when five early-morning, deep-cough specimens are examined, the yield is as high as 90 percent. The type of pulmonary specimen (random, earlymorning, induced, pooled, bronchial washing, bronchial brushing, transbronchial aspiration, or transthoracic needle

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Table 31-1 Histological Classification of Lung Tumors 1. Epithelial tumors a. Benign i. Papillomas ii. Adenomas 1. Alveolar and papillary adenoma 2. Adenoma of salivary gland type 3. Mucinous cystadenoma b. Preinvasive lesions (dysplasia, carcinoma in situ, atypical adenomatoid hyperplasia, diffuse idiopathic pulmonary neuroendocrine hyperplasia) c. Malignant i. Squamous cell carcinoma ii. Adenocarcinoma 1. Acinar adenocarcinoma 2. Papillary adenocarcinoma 3. Bronchioalveolar carcinoma 4. Adenocarcinoma with mixed subtype iii. Large cell carcinoma iv. Adenosquamous carcinoma v. Carcinoma with pleomorphic, sarcomatoid, or sarcomatous elements vi. Carcinoid tumor (typical and atypical) vii. Carcinoma with salivary-gland type 2. Soft-Tissue tumors 3. Mesothelial tumors 4. Miscellaneous tumors (hamartomas, sclerosing hemangioma, thymoma, clear cell tumor) 5. Hematopoietic and lymphoid lesions 6. Secondary tumors 7. Unclassified tumors 8. Tumorlike lesions (tumorlet, Langerhansâ&#x20AC;&#x2122; cell histiocytosis, inflammatory pseudotumor) Source: Modified from Travis WD, Colby TV, Corrin B, et al: Histologic Typing of Lung and Pleural Tumors, 3rd ed. World Health Organization. Berlin, Springer, 1999.

aspiration), technique of collection (fresh or fixed), quantity of specimen examined, and technique of specimen preparation have bearing on the value of pulmonary cytology in cancer detection. Additionally, the location of the lesion, associated pathology, and sampling techniques may contribute to the number of diagnostic tumor cells present in a specimen. The two most important issues addressed in the diagnosis of pulmonary neoplasm are whether the tumor is primary or metastatic and, if primary, whether the cell type is small cell or nonâ&#x20AC;&#x201C;small cell. The World Health Organization (WHO) classification of lung tumors is summarized in Table 31-1. Non--Small-Cell Lung Carcinoma Squamous Cell Carcinoma

Squamous cell carcinoma accounts for almost one-third of all primary pulmonary malignancies. The cytomorphologic diagnosis of squamous cell cancer is highly accurate and ap-

proaches 100 percent. Tumor cells detected in expectorated sputum or bronchial washings generally are more keratinized and poorly preserved than those obtained using bronchial brushing or FNA. From a cytology perspective, early squamous cell carcinoma is the best-studied lung tumor; definitive precursor (dysplastic) and early (in situ) lesions have been documented. In situ tumor cells are recognizable as single cells with a high N:C ratio, hyperchromatic nuclei with no nucleoli, and an even chromatin pattern with some chromatin clumping and clearing. Cytoplasm is frequently keratinized (Fig. 31-36). The dysplastic cells can occur in small tissue fragments, especially in bronchial brush specimens. The metaplastic bronchial lining cells associated with mechanical irritation (e.g., tracheal intubation), infections (e.g., bronchitis, bronchiectasis, abscess, viral infection), or prior radiation or chemotherapy can mimic dysplastic squamous cells. Invasive squamous cell carcinoma often leads to a mass or cavitary lesion with tumor necrosis and secondary

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Figure 31-37 Induced sputum showing invasive squamous cell carcinoma. Note an obvious malignant cell with necrotic background and numerous squamous cells. (Papanicolaou stain, ×208.)

Figure 31-36 Bronchial washing showing ‘‘early” lung cancer. The cells in (A) and (B) represent nuclear and cytoplasmic features that are indicative of early squamous cell carcinoma. (Papanicolaou stain: A., ×260; B., ×330.)

infection. The background of such specimens may display acute inflammation, necrotic debris with numerous infarcted, necrotic cells lacking nuclear detail, and malignant features. The well-preserved tumor cells are pleomorphic and may appear as “tadpole” or fiber forms. Bizarre, irregularly shaped cells with obvious malignant features (nuclear membrane irregularities, abnormal chromatin clearing and clumping, and prominent nucleoli) can occur. Squamous differentiation of the cytoplasm is variable (Fig. 31-37). Examination of cells for intercellular bridges or keratohyaline granules is necessary before a definitive diagnosis of squamous cell carcinoma can be established. However, these cytoplasmic features are almost always absent in cases of poorly differentiated squamous cell carcinoma. Adenocarcinoma Pulmonary adenocarcinoma can be diagnosed relatively easily in bronchial washings and brushings when the tumor is located within central airways; however, diagnosis is extremely difficult with peripheral tumors or scar-associated malignancies. The latter require direct sampling by FNA under radiologic guidance. The cells from adenocarcinoma generally occur in tissue fragments, which may appear as acinic and papillary

structures (Fig. 31-38). Cells have a soft cytoplasm that may contain evidence of mucin secretion. Tumor cells may exhibit bizarre, malignant nuclei with obvious nuclear membrane and chromatin abnormalities and prominent nucleoli. Nucleoli can be variable in number and are usually large and abnormally shaped. Shedded cells obtained from postbronchoscopy specimens, following viral infections, or during pulmonary infarction can be mistaken for tumor cells. Bronchoalveolar Cell Carcinoma The cytological diagnosis of bronchoalveolar cell carcinoma can be problematic due to lack of obvious malignant features. The key diagnostic features include presence of a monotonous tumor cell population arranged in papillary and acinic formations. The individual tumor cells show a prominent single

Figure 31-38 Bronchial washing showing adenocarcinoma of the lung. Note glandular features with nuclear chromatin and nucleolar variability. Evidence of mucus secretion is present in the cell in the center of the field. (Papanicolaou stain, ×330.)

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Figure 31-40 Bronchial washing showing large-cell undifferentiated carcinoma. Note that the malignant cells lack any obvious differentiation. (Papanicolaou stain, ×330.)

Figure 31-39 Bronchial washing showing bronchoalveolar carcinoma. A. Papillary formation. B. Prominent nucleoli and tenacious intercytoplasmic connection (TIC). (Papanicolaou stain: A., ×105; B., ×330.)

nucleolus and cuboidal or columnar cell forms, with or without intracytoplasmic mucus (Fig. 31-39). Occasionally, calcified psammoma bodies may be seen; tumor cells may display intranuclear grooves or inclusions. Under these circumstances, in patients with a history of papillary thyroid carcinoma, immunohistochemical stains for thyroglobulin are necessary to differentiate between a primary lung tumor and metastatic thyroid cancer. Tenacious intracytoplasmic connections, when present, are helpful diagnostically. Cytological diagnosis can be extremely accurate (60 to 80 percent). Bronchoalveolar tumor cells can often be confused with reactive bronchial cells, which may be seen with inflammation or after instrumentation or treatment. Large-Cell Undifferentiated Carcinoma Large-cell undifferentiated carcinoma represents a group of tumors that cannot be easily subclassified. Cells occur in tissue fragments. They show marked pleomorphism and classic malignant features (Fig. 31-40). These tumors can demonstrate features of both squamous cell and adenocarcinoma.

Small-Cell Undifferentiated Carcinoma Small-cell undifferentiated carcinoma is relatively easy to diagnose when the specimen is of good technical quality. Wellpreserved cells are an absolute requirement for cytological diagnosis of small-cell undifferentiated carcinoma. In fresh smears or monolayer preparations, tumor cells are seen in syncytial groups and as singly scattered cells. The cells have a high N:C ratio and uniformly distributed chromatin. Nuclei are absent or inconspicuous, intercellular molding is prominent, and cytoplasm is delicate and scant (Fig. 31-41). Individual tumor-cell necrosis or apoptosis is common. The background usually shows extensive tumor necrosis and strands of basophilic material representing DNA from fragmented fragile tumor nuclei. However, these cytological findings may not be prominent in the new monolayer cytological preparations. Subclassification of the tumors as oat cell or intermediate varieties may be possible, but this distinction is generally impossible on the basis of cytological preparations.

Figure 31-41 Bronchial washing showing small-cell undifferentiated carcinoma. Note the soft cells with uniformly granular chromatin, intercellular molding, and scant cytoplasm. (Papanicolaou stain, ×330.)

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Great care needs to be exercised in the proper diagnosis of small-cell undifferentiated tumors. Lymphoid cells from tonsils and adenoids, reserve cells, degenerated bronchial columnar cells, or lymphoma may resemble small-cell carcinoma of the lung. Diagnostic accuracy with this tumor type approaches 100 percent in certain laboratories; most centers report 70 to 80 percent predictability of cytological diagnosis. Not all small-cell tumors possess typical morphologic features. The tumors may contain a few prominent nucleoli, coarser chromatin, and a variable amount of cytoplasm. Such tumors are best classified as “undifferentiated tumors with neuroendocrine features.” Immunocytochemical stains for chromogranin and neuron-specific enolase and ultrastructural studies are helpful in diagnosis. Other Neuroendocrine Tumors Carcinoid

A majority of pulmonary carcinoid tumors occur submucosally and do not exfoliate diagnostic cells. Diagnostic cells can, however, be obtained by bronchial brush and FNA techniques. When present, the cells are small and round or oval; they possess scant, delicate cytoplasm and contain one or two nucleoli. The cells exist in microacinic formations or in trabecular and papillary structures. Intercellular molding, pleomorphism, or necrosis are usually not observed. Atypical Carcinoid

Atypical carcinoid tumors are classified morphologically as midway along the pathological spectrum between carcinoids and small-cell undifferentiated carcinomas. These tumors show neuroendocrine differentiation on the basis of morphology and immunohistochemistry. Although cells may not have the nuclear features typical of a small-cell carcinoma or the microacinic and trabecular pattern of a carcinoid, they can reveal occasional mitoses and focal necrosis. Lymphoma

A diagnosis of lymphoma may be made from pulmonary specimens. A proper clinical history and use of marker studies are necessary for accurate diagnosis. Hodgkin’s disease can be diagnosed by recognition of typical Reed-Sternberg cells in a variety of pulmonary specimens. Metastatic Tumors Malignant melanoma and breast, prostate, kidney, and gastrointestinal tumors commonly metastasize to the lungs. Knowledge of the patient’s history, coupled with typical morphologic changes and immunohistochemical studies, is often helpful. Patients with an extrapulmonary primary tumor may develop a primary pulmonary malignancy; concurrent or sequential development of malignancies is common in cigarette smokers, particularly laryngeal and pulmonary squamous cell tumors.

Pulmonary Cytopathology

Immunocytochemistry of Lung Tumors Immunocytochemistry can often be used as an adjunct in the morphologic diagnosis of lung tumors. The technique is often needed to differentiate between primary and metastatic tumors and between and small-cell and non–small-cell carcinoma. Primary pulmonary tumors, including small-cell cancers and adenocarcinomas, express thyroid transcription factor (TTF-1) and cytokeratin-7; rarely, they are positive for cytokeratin-20. TTF-1 can also be seen in primary thyroid tumors, although primary lung tumors do not express thyroglobulin. Carcinoembryonic antigen (CEA) is seen in lung adenocarcinoma; however, it can also be seen in adenocarcinoma of pancreas, colon, breast, or other organs. Pulmonary neuroendocrine tumors, both benign and malignant, express neuroendocrine markers, chromgraninA, synaptophysin, neuron-specific enolase, and CD56. These tumors also express cytokeratin-7 and TTF-1. Interestingly, small-cell carcinomas may also express calcitonin.

CONCLUSIONS Cytology is an accurate, economical, rapid technique that can be useful in diagnosing a large number of nonneoplastic and neoplastic pulmonary lesions. Proper sampling, procurement of high-quality specimens, adequate specimen preparation, careful examination of material, and correlation with clinical and radiographic features are essential for accurate diagnosis.

SUGGESTED READING Annema JT, Versteegh MI, Veselie M, et al: Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer. JAMA 294:931–936, 2005. Bender BL, Cherock M, Sotos SN: Effective use of bronchoscopy and sputa in the diagnosis of lung cancer. Diagn Cytopathol 1:183–187, 1985. Centers for Disease Control: Pneumocystis pneumonia—Los Angeles. MMWR 30:250–252, 1981. Cushion M: Pneumocystis carinii, in Collier L, Baslow A, Sussman M (eds), Topley and Wilson’s Microbiology and Microbial Infections, vol 4, Medical Mycology, 9th ed. New York, Arnold Publishing, 1998, p 764. Duboucher C, Gerbod D, Noel C, et al: Frequency of trichomonas as infecting agents in pneumocystis pneumonia. Acta Cytol 49:273–277, 2005. Edman JC, Kovacs JA, Masor H, et al: Ribosomal RNA sequence shows Pneumocystis carinii to be a member of the Fungi. Nature 334:519–522, 1988. Frost JK, Ball WC Jr., Levin ML, et al: The National Cancer Institute cooperative early lung cancer detection program results of initial screen (prevalence). Early lung cancer

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detection: Summary and conclusions. Am Rev Respir Dis 130:656–670, 1984. Frost JK, Gupta PK, Erozan YS, et al: Pulmonary cytologic alterations in toxic environmental inhalation. Hum Pathol 4:521–553, 1973. Greenbaum E, Copeland A, Grewal R: Blackened bronchoalveolar lavage fluid in crack smokers: A preliminary study. Am J Clin Pathol 100:481–487, 1993. Herth FJF, Ernst A, Becker HD: Endobronchial ultrasoundguided transbronchial lung biopsy in solitary pulmonary nodules and peripheral lesions. Eur Respir J 20:972–974, 2002. Johnson FL, Gill GW, Erozan YS, et al: Improved diagnostic sensitivity for lung cancer from cell block sections plus Cytospin and smear preparations of sputum specimens induced with INS316. Lung Cancer 41(Suppl 2):S196, 2003. Johnston WW: Cytopathology of the lung, diagnostic applications of sputum, bronchial brushings and fine needle aspiration specimens, in Wied GL, Keebler CM, Koss LG, et al (eds), Compendium on Diagnostic Cytology, 7th ed. Chicago, Tutorials of Cytology, 1992, pp 225–238. Johnston WW: Pulmonary cytopathology in the compromised host, in Greenberg SD (ed), Lung Pathology for Clinicians. New York, Thieme-Stratton, 1982. Larsen SS, Vilmann P, Krasnik M, et al: Endoscopic ultrasound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging. Lung Cancer 48(1):85–92, 2005.

Linder J, Rennard S: Bronchoalveolar Lavage. Chicago, American Society of Clinical Pathologists, 1988. Miller YE: Pathogenesis of lung cancer: 100 year report. Am J Respir Cell Mol Biol 33:216–223, 2005. Mulshine JL, Sullivan DC: Lung cancer screening. N Engl J Med 352:2714–2720, 2005. National Cancer Institute, National Institutes of Health, US Department of Health and Human Services: Atlas of Early Lung Cancer. New York, Igaku-Shoin, 1983. Naylor B, Railey C: A pitfall in the cytodiagnosis of sputum in asthmatics. J Clin Pathol 17:84–89, 1964. Papanicolaou GN: Atlas of Exfoliative Cytology. Cambridge, MA, Commonwealth Fund, Harvard University Press, 1954. Rajwanshi A, Bhambhani S, Das DK: Fine-needle aspiration cytology diagnosis of tuberculosis. Diagn Cytopathol 3:13– 16, 1987. Smith RA, Cokkinides V, Eyre HJ: American Cancer Society guidelines for the early detection of cancer: CA Cancer J Clin 55:31–44, 2005. Tochman MS, Erozan YS, Gupta P, et al: The early detection of second lung cancers by sputum immunostaining. Chest 106:385s–390s, 1994. Wang KP, Terry PB: Transbronchial needle aspiration in the diagnosis and staging of bronchogenic carcinoma. Am Rev Respir Dis 127:344–347, 1983. Wardwell NR, Massion PP: Novel strategies for the early detection and prevention of lung cancer. Semin Oncol 32:259– 268, 2005.

32 Interventional Radiology in the Thorax: Nonvascular and Vascular Applications Aalpen A. Patel Scott O. Trerotola

I. IMAGE-GUIDED NEEDLE PROCEDURES IN THE THORAX Application of Diagnostic Methods Tools and Techniques Results Complications Postprocedural Care II. DRAINAGE OF THORACIC COLLECTIONS Empyema and Other Pleural Collections Lung Abscess Lung Cancer Aspergilloma

Over the last few decades, medicine has seen the birth and growth of the field of interventional radiology (IR). IR complements various diagnostic and therapeutic surgeries or replaces them entirely. IR techniques are image-guided, minimally invasive methods that usually carry less morbidity compared to their surgical counterparts. From a historical perspective, the first percutaneous needle biopsy of the lung was performed (without image guidance) in 1882. Thereafter, lung biopsy was used mainly for determining the microbial agent(s) causing lobar pneumonia. Due to high complication rates with early techniques, percutaneous biopsies fell out of favor until fine needles were developed. When computed tomography became available, image-guided transthoracic lung, pleural, and mediastinal diagnostic interventions became more widely adopted, especially for percutaneous drainage of pleural, lung, and mediastinal collections. Additional radiography-based interventions were developed through application of vascular approaches in the 1960s, including bronchial arteriography. Subsequently, em-

III. BRONCHIAL ARTERY EMBOLIZATION IV. EMBOLIZATION OF PULMONARY ARTERIOVENOUS MALFORMATIONS V. VENOUS PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY AND STENTING VI. INTRAVASCULAR FOREIGN BODY RETRIEVAL VII. THORACIC DUCT EMBOLIZATION VIII. PULMONARY ARTERY THROMBECTOMY

bolotherapy of the bronchial arteries for hemoptysis was described in the 1970s. Thereafter, refinements in catheter technology and techniques established bronchial artery embolization as an accepted component of the management of patients with hemoptysis. Embolotherapy has also been used in the pulmonary arterial circulation to treat pulmonary arteriovenous fistulae. Endovascular techniques have also proved useful in foreign body retrieval from the heart and pulmonary arteries. With the advent of intravascular stents, surgical conditions, such as superior vena cava syndrome, can be treated using endovascular techniques. Modification of prior designs and introduction of new vena cava filters that have small introduction sheaths have also made percutaneous caval interruption routine for interventional radiologists. As IR develops into an evidence-based practice, its techniques will become more widely accepted and adopted by other specialties as their own. IR has now become a fullfledged clinical specialty, providing outpatient and inpatient consultation and follow-up.

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This chapter focuses on the most common and pertinent techniques and presents them as either nonvascular or vascular interventions. Adjunctive imaging modalities employed include ultrasound (percutaneous or intraluminal), fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI). Each modality has its advantages and disadvantages; the first three modalities are most commonly used; MRI holds much promise. Although some interventional radiologists are actively involved in procedures such as thoracic aortic endograft placement for aneurysmal disease, these procedures will not be discussed in this chapter. Likewise, treatment of peripheral vascular disease of the thoracic vessels using balloon angioplasty or stents is commonplace in IR, but is beyond the scope of this chapter. Bronchial and esophageal stent placement is often performed by interventional radiologists, but these topics are covered in Chapter 36.

IMAGE-GUIDED NEEDLE PROCEDURES IN THE THORAX Appropriate use of image-guided, needle-based procedures in diagnosing chest lesions entails consideration of indications for the procedure, expected results, recognized complications, and post-procedure management.

obviously increased in the presence of baseline lung function abnormalities or coagulation defects. Furthermore, patients who plan air travel within 6 weeks of the procedure (possibly increased risk of delayed pneumothorax), prior pneumonectomy, presence of pulmonary arterial or venous hypertension (possibly increased bleeding risk), and lack of patient cooperation (despite administration of conscious sedation) increase the risk. Finally, one absolute contraindication to needle biopsy is a vascular lesion, such as aneurysm or arteriovenous malformationâ&#x20AC;&#x201D;entities that are usually recognized by careful review of preprocedural imaging studies.

Tools and Techniques Patient evaluation prior to the biopsy is essential. Published recommendations include that the INR be less than 1.4, platelets greater than 100,000, and recent FEV1 greater than 35 percent predicted. At our institution, less stringent guidelines for coagulation parameters are used: INR less than 1.5 and platelets greater than 50,000. The biopsy may be performed using a fine needle (cytopathological evaluation) and/or a cutting needle, the choice of which is based upon operator expertise, availability and expertise of a cytopathologist, and suspicion as to whether the mass is malignant or benign (requiring a confirmatory diagnosis). Coaxial techniques traverse the pleura fewer times than non-coaxial techniques; they may be faster and may carry less risk of pneumothorax.

Application of Diagnostic Methods As with any procedure or test, image-guided sampling of thoracic structures is performed when a clinical or therapeutic decision rests upon it (e.g., when the histology of a lung nodule needs to be established prior to treatment), or when pleural fluid requires sampling for determining whether infection, malignancy, or other processes are present. CT and ultrasound are the most commonly used adjunctive imaging modalities employed for this procedure, especially when collections are too small to be reliably accessed using bedside techniques. Ultrasound is useful when a pleural fluid collection requires aspiration or when a tissue mass is in contact with the parietal pleura and intervening air is absent. Needle aspiration or biopsy may be used to evaluate any lesion in the lung, pleura, or mediastinum, especially if it is not visible bronchoscopically and if it is safely accessible using a needle. Clinical circumstances in which needle aspiration or biopsy is commonly used include: (1) a new or enlarging lung nodule seen on chest radiograph or CT scan; (2) multiple nodules noted in a patient with known prior or current malignancy; (3) persistent pulmonary infiltrates or consolidation of unknown cause; (4) a hilar mass with nondiagnostic results on bronchoscopy; and (5) a suspected, but unconfirmed empyema or malignant pleural effusion. Several relative contraindications to lung biopsy or aspiration are recognized. As with any procedure, risks must be weighed in relation to benefits. The risk of complications is

Results Fine-needle biopsy has a diagnostic accuracy of 64 to 97 percent. Accuracy is a function of the size of the lesion and on-site availability of a cytopathologist. Sensitivity of a cutting needle biopsy ranges from 74 to 95 percent, and accuracy of a benign diagnosis is improved with use of a cutting, rather than fine, needle. For suspected, but unproved, infections in immunocompromised patients, the diagnostic yield ranges from 73 to 79 percent.

Complications The most common complications of needle biopsy of thoracic lesions are pneumothorax and hemoptysis. The pneumothorax rate is a function of chest wall thickness, lesion size, and depth of the lesion below the chest wall surface, among other factors. Whether obstructive lung disease affects the risk of pneumothorax is controversial. In one study, patients whose lesions were â&#x2030;¤2 cm in diameter had a rate of pneumothorax that was eleven times greater than those whose lesions were >4 cm. Patients with subpleural lesions had four times the rate of pneumothorax as those whose lesions were deeper than 2 cm. The incidence of pneumothorax ranges from 0 to 60 percent for a fine-needle biopsy (average, 20 percent), with 1.6 to 18 percent (average, 5 percent) requiring a chest tube; the

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incidence of pneumothorax is 26 to 54 percent for a cutting needle biopsy, with 3.3 to 15 percent requiring chest tube insertion. Hemorrhage, with or without hemoptysis, occurs in fewer than 10 percent of patients. The risk of bleeding may be ten times higher for lesions deeper than 2 cm from the pleura compared to more superficial abnormalities. Most biopsy-related complications do not have secondary adverse consequences. The death rate from needle biopsy is very low (estimated at 0.02 percent).

Postprocedural Care The patient should be placed such that the biopsy entry site is in a dependent position for 2 hours, thereby decreasing air leakage as the weight of the lung helps to appose the two pleural layers. A chest radiograph with the patient in an erect position is obtained immediately and 2 hours after the procedure. If no pneumothorax is present, the patient is discharged. If after 2 hours a pneumothorax is present, the chest radiograph is repeated at 4 hours; if the pneumothorax is resolved, or is small and stable, the patient is discharged and asked to return the next day for repeat chest radiography. If the patient is symptomatic, or the pneumothorax is moderate or large or enlarging, a small catheter with a one-way (Heimlich) valve is inserted. The patient may be discharged to return the next day for a chest radiograph and clinical evaluation in which the catheter is clamped for 2 hours. If the pneumothorax has resolved and does not recur after the clamping, the chest tube may be removed.

DRAINAGE OF THORACIC COLLECTIONS Since the advent of CT, image-guided drainage or aspiration of air or fluid collections in the thorax (lung parenchyma or pleural space) has become increasingly popular. The documented safety and effectiveness of this intervention have made it an alternative to surgical options in many patients. Image-guided aspiration or drainage may be performed for virtually any collection in the thorax.

Empyema and Other Pleural Collections Annually, approximately 65,000 patients in the United States and United Kingdom (combined) develop empyemas or complicated parapneumonic effusions. Twenty percent of these patients die; the associated health care costs are estimated to approach $500 million. The early stage of an evolving empyema (stage I), the socalled exudative phase, can usually be treated using medical therapy. The intermediate stage (stage II), or fibrinopurulent phase, requires catheter drainage. The late stage (stage III), or organizing phase, responds less favorably to catheter drainage alone and usually requires lung decortication. In fact, some

thoracic surgeons recommend early decortication as initial therapy for stage III empyema. A comprehensive description of drainage technique is beyond the scope of this chapter, but an initial aggressive approach is recommended. Some investigators recommend early aggressive management of complex empyema with multiple catheter placements (if needed for multiple loculations) and use of fibrinolytic agents (to allow complete drainage of locules and partial debridement of the pleural surface). Technical success is virtually 100 percent. Clinical success is 70 to 89 percent in previously unviolated empyemas, and 80 percent in those who have had a prior surgically placed chest tube. Most failures occur in stage III empyema (range of success, 11 to 30 percent). Formation of an extensive pleural peel may prevent catheter insertion or cavity collapse. Instillation of fibrinolytics into the pleural cavity may help prevent fibrin deposits and loculations. Clinical success rate ranges from 62 to 100 percent. In one recent, randomized, placebocontrolled trial, the clinical success rate was 82 percent for streptokinase-treated patients (250,000 IU daily) vs. 48 percent for those receiving placebo ( p = 0.01). In addition, fewer referrals for surgery (9 percent vs. 45 percent; p = 0.02) were noted in the treatment group. Although allergic reactions (nonanaphylactic) to streptokinase have been reported, and concern exists over a potential systemic thrombolytic effect, up to 1.5 million units of streptokinase have been used safely. In addition, urokinase is also effective when compared to saline alone for intrapleural treatment of loculated parapneumonic effusions. Compared with placebo, intrapleural instillation of urokinase is effective in improving chest-tube drainage and the radiographic appearance of the chest; early use of urokinase may be more effective than late use when catheter drainage alone has failed. Comparison of urokinase with streptokinase shows no difference in effectiveness. Since urokinase is no longer available in the United States, alternative agents have been sought. Tissue plasminogen activator (t-PA) has been shown to be effective in reducing the duration of required chest tube placement in children with complicated parapneumonic effusions (using 4 mg of t-PA in 30 to 50 ml of saline instilled through the chest tube, which is clamped for 1 hour before applying suction to the tube). No adverse events have been noted. One retrospective study suggests that t-PA may be even more effective than urokinase in improving the early radiographic appearance of the chest. In our practice, 10 mg of t-PA in 50 ml of saline is instilled through the chest catheter, followed by 20 ml of a saline â&#x20AC;&#x153;flush.â&#x20AC;? If possible, the patientâ&#x20AC;&#x2122;s position is rotated every 10 min for 1 h before the catheter is connected to suction. Some theoretical and observed complications of intrapleural fibrinolysis include hemorrhage, allergic reactions, transient chest pain, and promotion of bronchopleural fistula formation. Although, in theory, intrapleural instillation of thrombolytic agents may alter systemic coagulation parameters, many studies have shown that this effect does not

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occur. Furthermore, although hemorrhage is also possible, it is rarely observed.

Lung Abscess Most lung abscesses are successfully treated using medical therapy. However, the mortality rate associated with lung abscess remains high, and ranges from 15 to 20 percent. In 10 to 20 percent of pyogenic lung abscesses, a conservative approach fails, and surgical management (e.g., lobectomy) may be considered. Less invasive approaches, including endoscopic or percutaneous drainage, have been used successfully. Percutaneous management of lung abscess remains somewhat controversial. In one comprehensive review, the success rate was about 85 percent. The causes for failure included multi-loculation and presence of a thick abscess wall. The procedure complication rate was just under 10 percent. Overall mortality rate related to the abscess was about 5 percent. Additional studies are needed to establish percutaneous catheter drainage as the standard of care in patients who fail medical therapy. However, the technique is appealing because it results in immediate external drainage of pus without the need for thoracotomy, and it reduces the risk of aspiration of purulent material into the airways. For patients who fail medical therapy (e.g., after 10 to 14 days of treatment) or who have abscesses greater than 4 cm in diameter, and who are not fit for surgical intervention, percutaneous catheter drainage should be considered. Complications of the procedure include empyema, bronchopleural fistula, pneumothorax, hemothorax, intrabronchial hemorrhage, and catheter occlusion.

Lung Cancer Since the introduction in 1990 of ultrasound-guided thermal ablation of malignant hepatic lesions using radiofrequency electrode needles, open radiofrequency ablation (RFA) and percutaneous RFA under imaging guidance have been increasingly employed. Use of RFA in treatment of renal cell carcinoma and bone and lung tumors has been described more recently, and results are promising. Other thermal ablation methods, including cryoablation and microwave ablation, may also have a future role in management of lung tumors. Adjunctive use of radiotherapy or chemotherapy with RFA is also being explored. As pulmonary RFA is still considered investigational, delineation of indications for its use is difficult. An “ideal” candidate for RFA is a patient without underlying lung disease whose pulmonary lesion is small (2 to 3 cm), peripheral, and distant from vital intrathoracic structures. However, until evidence supports use of RFA as a primary treatment modality, its value currently lies in treatment of patients who are inoperable because of severe underlying lung disease. As with many IR-based procedures, application of RFA in treating lung tumors is performed with the patient under moderate sedation. When the patient’s cardiopulmonary sta-

tus is questionable, an anesthesiologist may be consulted to provide a greater level of anesthesia oversight. Many RFA probes of differing size and design are available (e.g., water-cooled, monopolar, bipolar, or expandable [umbrella-like]) (Fig. 32-1). Each delivers an alternating current, which agitates tissue ions and generates frictional heat, leading to cell death. Any cross-sectional imaging modality may be used in conjunction with RFA; however, due to limitations of ultrasound in imaging air-filled structures, CT is the preferred modality in treatment of lung tumors; MRI may have a niche role. Depending on the tumor size and its proximity to vascular structures, more than one probe or more than one treatment (after probe repositioning) may be needed to achieve complete tumor ablation. The end point for a treatment session may be impedance-based or temperature-based. Although few data about ablation size in human lung cancer are available, some guidance may be derived from extrapolation of findings from a study in which a mean tumor size of 2.2 ± 0.6 cm was associated with a mean RFA time of 12 min, 9 sec. According to a recent review of prior studies using RFA in treating primary and secondary lung tumors ranging in size from 0.7 to 12 cm (mean range, 2.7 to 5.2 cm), complete ablation was achieved in 38 to 91 percent. The highest rates of complete ablation were achieved in treatment of small tumors (mean size, 2.0 cm). In a study of 30 patients, most of whom had primary bronchogenic carcinoma, complete ablation was achieved using RFA in all tumors that were less than 3 cm in diameter; mean survival in this group was 19.7 months, more than twice that for tumors greater than 3 cm in diameter, in whom mean survival was 8.7 months. The complication rate for RFA is similar to that for percutaneous lung biopsy. The rate of pneumothorax is 20 to 40 percent; 10 to 15 percent of patients sustaining a pneumothorax require a chest tube. Other complications include pleurisy, pleural effusion, pulmonary hemorrhage, and productive cough; death has been reported. In patients with large tumors, tumor cavitation and formation of a bronchopulmonary fistula have been reported.

Aspergilloma Although surgical resection of a symptomatic aspergilloma is definitive, not all affected patients are surgical candidates. Indeed, aspergilloma formation is frequently associated with underlying lung disease, such as chronic obstructive pulmonary disease (COPD), sarcoidosis, lung abscess, tuberculosis, or pulmonary complications related to chronic immunosuppression. In this context, embolization of bronchial arteries has been used as a temporizing measure to control massive hemoptysis (see below). Unfortunately, in the absence of definitive treatment of the aspergilloma, recurrent bleeding is likely. Furthermore, systemic antifungal agents have a limited role in the primary treatment, as they are unable to penetrate the fungal mass. Consequently, intracavitary instillation of antifungal agents has been performed.

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Figure 32-1 Nonoperable patient with nonâ&#x20AC;&#x201C;small-cell lung cancer and multiple co-morbidities. A & B. Right lung lesion. C & D. Radiofrequency ablation probe (with umbrella-like tines) deployed through the tumor. E. Successful treatment of the tumor, with surrounding edema and hemorrhage. Images are courtesy of Jeffrey Solomon, M.D.

Typically, the cavity is accessed under imaging guidance (usually CT imaging), and the antifungal agent (e.g., amphotericin B) is instilled. Liquid-, gelatin-, and paste-based formulations of the agent have been employed. A relative contraindication to performing the technique is endotracheal intubation and limited ability to reposition the patientâ&#x20AC;&#x201D;

circumstances that put the patient at risk for spillage of the therapeutic agent into the airways and related complications. In one study of 40 patients with aspergillomas who were treated using amphotericin paste to completely fill the cavities, hemoptysis stopped in all; however, adjunctive bronchial artery embolization was required in six. The aspergillomas

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resolved and serum tests for Aspergillus became negative in 65 percent, although complete disappearance of both the aspergillomas and cavities was observed in only 7.5 percent. In a smaller series, which used a liquid mixture of amphotericin and gelatin that solidified rapidly at body temperature when injected into the cavities, resolution of the aspergillomas was observed in 3 out of 4 patients. In the fourth patient, the aspergilloma decreased in size, but pneumonectomy was required for recurrent hemoptysis.

BRONCHIAL ARTERY EMBOLIZATION Massive hemoptysis (300 to 600 ml or greater per 24 h) may be due to a wide variety of causes (among the more common are tuberculosis, aspergilloma, bronchiectasis, lung cancer, and a variety of chronic infectious or inflammatory processes) and carries a significant mortality rate (50 to 85 percent) when treated conservatively. Even when pulmonary resectional surgery is undertaken emergently, the mortality rate is 35 to 40 percent. Although definitive therapy is surgical resection of the bleeding source, not all patients are surgical candidates, due to severe underlying lung disease. In these patients, therapeutic arterial embolization plays an important role in mitigating the hemoptysis. The two major indications for bronchial artery embolization include: (1) palliative therapy for patients who have acute, massive hemoptysis and who are not surgical candidates; and (2) preoperative intervention to stop active bleeding, thereby allowing definitive surgical therapy to be performed electively. A less common, and more controversial, indication is recurrent, moderate hemoptysis for which conservative management in the nonsurgical candidate has clearly failed. A preoperative chest CT and bronchoscopic evaluation help with lateralization and further localization of the source, which has obvious therapeutic implications. An initial descending thoracic aortogram may also provide useful information. Knowledge of whether nonbronchial arteries supply the region is helpful, particularly in the setting of hemoptysis due to inflammatory processes. In this regard, CT arteriography has recently been shown to be helpful in planning bronchial artery embolization. Failure to embolize these additional vessels may be responsible for early treatment failure. The embolic agent of choice is polyvinyl alcohol particles (usually, 350 to 500 microns in diameter). Use of other microembolic agents has also been described. Although true contrast extravasation at the bleeding site is frequently not observed, detection of abnormal vascularity in an area localized by direct visualization or by imaging should prompt embolization of the branch (Fig. 32-2). Since the anterior and posterior spinal arteries receive branches from bronchial arteries and some nonbronchial arteries (e.g., intercostals and cervical and thyrocervical trunks), care must be taken to avoid embolization of these branches.

An absolute contraindication to performance of the procedure is inability to avoid embolization of these branches, as this may lead to transverse myelitis (see below). Bronchial artery embolization is initially effective (i.e., during the first month following the procedure) in controlling massive hemoptysis in over 75 percent of patients. However, the long-term success rate is less favorable: 10 to 50 percent of patients experience a recurrence months to years later. If the underlying disease process is not addressed, recurrence of bleeding is not unexpected. Recruitment of additional vessels, recanalization of occluded vessels, incomplete therapeutic embolization, and new bleeding from pulmonary arterial sources (5 percent) contribute to the recurrences. The most feared complication of bronchial artery embolization is transverse myelitis due to nontarget occlusion of radiculomedullary branches. Transverse myelitis occurs in 1.4 to 6.5 percent of patients undergoing the procedure. Other complications include chest pain (24 to 91 percent), transient dysphagia (0.7 to 18.2 percent), and, rarely, bronchial necrosis, nontarget embolization of abdominal viscera leading to ischemia, pulmonary infarction, and transient cortical blindness due to occipital cortex embolization.

EMBOLIZATION OF PULMONARY ARTERIOVENOUS MALFORMATIONS Pulmonary arteriovenous malformations (PAVM) are dilated vascular shunts that connect directly the pulmonary artery and pulmonary vein. PAVM occur most often in patients with hereditary hemorrhagic telangiectasia (HHT), a genetic disorder with an autosomal-dominant pattern of inheritance. While the effects of the resultant right-to-left shunt may be transparent and well compensated, paradoxical embolization and vascular rupture are possible. Hence, accurate diagnosis and appropriate treatment are warranted. Patients who have PAVM identified serendipitously (e.g., during whole-body CT screening or imaging performed for other reasons) should proceed directly to embolization. In addition, they should also be evaluated for HHT, ideally in a center with expertise in the disorder. Patients with HHT and their first-order family members should be screened using contrast (bubble) echocardiography. Those with a positive study should proceed to CT scanning. We prefer highresolution pulmonary CT angiography with intravenous contrast; however, care must be taken with any intravenous injection in these patients, because of the potential risk of paradoxical embolization of an air bubble through these right-toleft shunts. All patients with identified PAVM should proceed to treatment to prevent the risk of paradoxical emboli, which can result in brain abscess and cerebrovascular events, as well as less common complications, such as hemoptysis. Ideally, PAVM embolization should be performed in centers that regularly perform large numbers of the procedure. Centers devoted to the diagnosis and management of HHT are located

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Figure 32-2 Patient with tetralogy of Fallot and previous surgical repair who presented with bronchoscopically documented bleeding from the left upper lobe. A & B. Bronchial arteries supplying left upper lobe are hypertrophied and originate from the concave surface of the aortic arch (rare anatomic variant). C. Selective catheterization of bronchial artery. D. Disappearance of flow to abnormal area.

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throughout the world; 10 such centers are located in North America. A long-standing recommendation has been to treat only those PAVM with feeding arteries 3 mm and larger in diameter. However, improvements in catheter and imaging technology, coupled with emerging evidence that paradoxical emboli can occur in patients with feeding arteries much smaller than 3 mm, have prompted us to undertake treatment of any readily accessible vessel, including those as small as 1.5 mm in diameter (Fig. 32-3). Although some interventional radiologists perform the procedure on an inpatient basis, we treat patients on an outpatient basis. Bilateral pulmonary arteriography using digital subtraction technique is performed to create a “roadmap” and to identify PAVM undetected by CT. However, in the era of multislice CT scanning, use of digital subtraction is becoming far less important. After identifying the vessel(s) supplying the PAVM, each lesion is treated by embolization of the feeding artery, usually using stainless steel or platinum coils, although many other devices have been described, including detachable balloons and nitinol plugs (Fig. 32-4). The technical success rate for the procedure is 88 to 100 percent. Although shunt fraction remains abnormal in 60 to 100 percent of patients, improvement in dyspnea (in previously symptomatic patients) or hypoxia is frequently noted. Small lesions have a potential for growth and should be evaluated by CT scanning every 5 years. Despite embolization of visible PAVM in patients with HHT, other subclinical lesions account for persistent right-to-left shunting; the contrast echocardiogram remains positive in most patients following PAVM embolization. Thus, patients should receive prophylaxis for endocarditis for life. In patients without HHT who have a solitary PAVM, follow-up CT scanning and endocarditis prophylaxis may not be necessary. Although bronchial artery embolization is safe, complications can arise, including pleurisy (with fever and occasional pulmonary infarction), nontarget embolization, and stroke. Pleurisy is noted in 3 to 16 percent of patients within the first few days following the procedure. Delayed pleurisy is noted in up to 5 percent of patients; it responds well to nonsteroidal anti-inflammatory agents. If a superimposed infection is suspected, a course of antibiotics may be needed. The most feared complications of PAVM embolization are nontarget embolization and stroke; fortunately, these are rare (less than 1 percent) when the procedure is performed by experienced interventional radiologists.

VENOUS PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY AND STENTING Obstruction of the superior vena cava (SVC), brachiocephalic vein, or subclavian vein may be caused by benign or malignant conditions. Inflammatory lesions, radiation, and trauma

sometimes result in scarring, causing venous obstruction. Chronic central venous access devices also may lead to thrombosis or occlusion. Tumors may cause obstruction via direct invasion or external compression. Since the surgery required for symptomatic central venous obstruction is very invasive and, at times, not possible, endovascular management using stent placement or percutaneous transluminal angioplasty (PTA) has become a standard mode of treatment. (The treatment of benign venous stenosis or occlusion is not discussed here.) In the case of malignant obstruction of the SVC and its tributaries, treatment using endovascular techniques, in particular stent placement coupled with balloon angioplasty, is commonly employed. In SVC or brachiocephalic vein occlusion due to primary or metastatic malignant tumors (e.g., primary lung cancer, lymphoma, or malignant adenopathy), the vessel should be stented primarily and angioplasty performed. Increasing evidence supports the use of early stenting in symptomatic malignant occlusion of the SVC as safe and effective in achieving rapid improvement in symptoms. Relative contraindications to performing the procedure are extensive peripheral thrombosis and low cardiopulmonary reserve. Patients must be able to lie flat, and in patients with SVC syndrome, this occasionally precludes percutaneous management or creates the need for general anesthesia. Preoperative imaging using magnetic resonance venography (MRV) or CT venography of the central veins may be used to plan the approach and technique. Ultrasound imaging is not adequate for evaluation of the central veins. The clinical success rate after recanalization of central veins is 68 to 100 percent. Most symptoms, including face, neck, and upper limb edema, resolve in 1 to 4 days—far faster than with radiation therapy. A small retrospective study in patients with non–small-cell lung cancer showed that stent placement achieved more rapid symptomatic relief and more frequent complete resolution of SVC obstruction than did radiation therapy. Compared to alternatives such as no treatment, radiation, or chemotherapy, complications of stent placement and PTA are relatively uncommon and minor. Major complications, such as stent misplacement or migration, transient cardiac arrhythmias, pulmonary embolization, venous rupture, hemomediastinum, and pulmonary edema, are uncommon.

INTRAVASCULAR FOREIGN BODY RETRIEVAL For decades, interventional radiologists have employed techniques for intravascular foreign body retrieval. A variety of instruments, including catheters, tip-deflecting wires, snares, baskets, and forceps, used alone or in combination, has been

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Suspected PAVM

Both Tests - Negative

Contrast Echocardiogram Supine and erect oximetry (especially in children)

STOP (If child, rescreen during adolescence)

Either Test - Positive CT scan of the Chest

No PAVMs visible on CT

Small PAVMs with feeding arteries < 1.5 mm

PAVMs with feeding arteries â&#x2030;Ľ 1.5 mm

Pulmonary arteriography and embolization 6-12 month - CT scan to assess adequacy of treatment

Lifelong Antibiotic Prophylaxis Follow-up CT scan Clinical evaluation Every 3-5 years to assess for PAVM growth Before pregnancy for women During adolescence Figure 32-3 Management algorithm for patients with suspected pulmonary arteriovenous malformations (PAVM). (Modified version of the algorithm from Pollack JS, White RI, Jr: Pulmonary arteriovenous malformation, in Baum S, Pentecost MJ (eds): Abrams Angiography, Interventional Radiology, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2006, p 935.)

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Figure 32-4 A. Pulmonary arteriovenous malformations (PAVM) in the right lung. At least three PAVM are visible. B. Embolization using soft platinum coils. Note that shunting through the PAVM is eliminated, but very little of the surrounding lung parenchyma has been sacrificed.

applied to percutaneous foreign body retrieval from the venous system and hollow organs. These procedures constitute the standard of care for most intravascular foreign body retrievals (Fig. 32-5).

THORACIC DUCT EMBOLIZATION Iatrogenic chylothorax (incidence, 0.1 to 0.4 percent), in which the daily output of chyle may exceed 1000 ml, is a serious complication of thoracic surgery. The problem can be controlled by direct ligation of the thoracic duct (TD). However, since surgical intervention carries a significant mortality rate (11.8 to 16 percent), application of percutaneous methods has been sought. TD ligation is commonly used to treat high-output chylothorax or chylous pleural effusions if there is no improvement after 1 to 2 weeks of conservative management, including implementation of a low-fat diet or total parenteral nutrition, administration of somatostatin, and chest tube drainage. As patients lose chyle over this time, the combined loss of fluid, proteins, lipids, electrolytes, and T lymphocytes leads to malnutrition, increased susceptibility to infection, and increased operative risk. Under these circumstances, TD embolization should be considered as an initial alternative to surgical TD ligation. Percutaneous transabdominal catheter-directed embolization or needle disruption of retroperitoneal lymphatics is effective and minimally invasive. In one series of 42 pa-

tients with chylothorax due to a variety of etiologies, treatment with percutaneous TD embolization using microcoils, particles, glue, or lymphatic collateral disruption resulted in a partial or complete response rate in 3 to 6 weeks of 74 percent. The procedure carries a minimal risk of serious complication or death; however, as the frequency with which the procedure is performed increases, the complication rate will likely grow (Fig. 32-6). The technique is not suitable for treating chylothorax resulting from malignancy.

PULMONARY ARTERY THROMBECTOMY Traditional therapies for pulmonary embolism include anticoagulation, systemic thrombolysis, and surgical thrombectomy. More recently, endovascular techniques, such as catheter-directed thrombolysis, mechanical thrombolysis (clot fragmentation), and embolectomy have been described. These may be used in conjunction with pulmonary artery stent placement. However, the precise role of these more aggressive approaches is very controversial. Use of a Greenfield thrombectomy device in major pulmonary embolism has been shown to improve cardiac output and carries a success rate of 91 percent. Although small, nonrandomized trials and case reports have described the utility of catheter-directed mechanical clot fragmentation or extraction, no randomized trials of systemic thrombolysis vs. surgical or catheter-based techniques for treatment of pulmonary embolism have been published.

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Figure 32-5 A. Surgically placed subclavian port on the left. Note the broken catheter fragment overlying the left pulmonary artery. B. Following selective catheterization using femoral approach, the pulmonary arteriogram shows patency of the artery. C. â&#x20AC;&#x2DC;â&#x20AC;&#x2DC;Gooseneckâ&#x20AC;? snare used to engage and capture the catheter. D. The catheter fragment has been removed through a common femoral vein sheath.

In a small, multicenter trial of 34 patients with pulmonary embolism who were given either intravenous or intrapulmonary t-PA infusions, neither approach demonstrated a clear advantage over the other. Frequently, comorbid conditions make open surgical thrombectomy or

thrombolytic therapy in these usually critically ill patients untenable. Under the circumstances, percutaneous thrombectomy and thrombolysis remain options. Treatment of pulmonary embolism is discussed in detail in Chapter 82.

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Figure 32-6 Gunshot wound to thorax resulting in thoracic duct injury and massive chylothorax. A. Lymphangiogram shows contrast leakage just above the left sternoclavicular joint. B. Cisterna chyli at L1 level shown in a patient different from the one shown in A. Lymphatic access achieved via one of the cisterna chyliâ&#x20AC;&#x2122;s tributaries. C. Successful embolization of thoracic duct using platinum microcoils and cyanoacrylate glue. Images are courtesy of Maxim Itkin, M.D. and Andrew Kwak, M.D.

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Interventional Radiology in the Thorax: Nonvascular and Vascular Applications

SUGGESTED READING Barth KH: Preintervention assessment, intraprocedure management, postintervention care, in Baum S, and Pentecost MJ, eds.: Abrams’ Angiography: Interventional Radiology, 2nd ed, Philadelphia, Lippincott Williams & Wilkins, 2006, pp. 1–18. Bessoud B, de Baere T, Kouch V, et al: Experience at a single institution with endovascular treatment of mechanical complications caused by implanted central venous access devices in pediatric and adult patients. AJR 180:527–532, 2003. Bierdrager E, Lampmann LE, Lohle PN, et al: Endovascular stenting in neoplastic superior vena cava syndrome prior to chemotherapy or radiotherapy. Neth J Med 63:20–23, 2005. Cope C, Kaiser LR: Management of unremitting chylothorax by percutaneous embolization and blockage of retroperitoneal lymphatic vessels in 42 patients. J Vasc Interv Radiol 13:1139–1148, 2002. Dupuy D, Zagoria RJ, Akerley W, et al: Percutaneous radio-frequency ablation of malignancies in the lung. AJR 174:57–59, 2000. Fernando HC, Stein M, Benfield JR, et al: Role of bronchial artery embolization in the management of hemoptysis. Arch Surg 133:862–865, 1998. Ghaye B, Dondelinger RF: Imaging guided thoracic interventions. Eur Respir J 17:507–528, 2001. Ghaye B, Dondelinger RF: Percutaneous imaging guided interventional procedures in the thorax, in Bolliger CT, Mathur PN (eds): Interventional Bronchoscopy, vol 30. Respiratory Research, Basel, Karger, 1999, pp 198–214. Giron J, Poey C, Fajadet P, et al: CT-guided percutaneous treatment of inoperable pulmonary aspergillomas: A study of 40 cases. Eur J Radiol 28:235–242, 1998. Greillier L, Barlesi F, Doddoli C, et al: Vascular stenting for palliation of superior vena cava obstruction in non–small-cell lung cancer patients: A future ‘standard’ procedure? Respiration 71:178–83, 2004. Hwang SS, Kim HH, Park SH, et al: The value of CT-guided percutaneous needle aspiration in immunocompromised patients with suspected pulmonary infection. AJR 175:235–238, 2000. Manhire A, Charig M, Clelland C, et al: Guidelines for radiologically guided lung biopsy. Thorax 58:920–936, 2003.

Moulton JS, Moore PT, Mencini RA: Treatment of loculated pleural effusions with transcatheter intracavitary urokinase. AJR 153:941–945, 1989. Nguyen CL, Scott WJ, Young NA, et al: Radiofrequency ablation of primary lung cancer: Results from an ablate and resect pilot study. Chest 128:3507–3511, 2005. Patel AA, Trerotola SO: Foreign body retrieval, in Sze D, Ferral H, eds.: SIR Syllabus: Venous Interventions, 2nd ed. The Society of Interventional Radiology, Fairfax VA; 2006, pp 89–96. Pollak JA, White RI: Pulmonary arteriovenous malformations, in Baum S, Pentecost MJ, eds.: Abrams’ Angiography: Interventional Radiology, 2nd ed. Philadelphia, Lippincott Williams & Wilkins, 2006, pp 928–945. Savader SJ, Misra S: Foreign body retrieval, in Savader SJ, Trerotola SO (eds): Venous Interventional Radiology with Clinical Perspectives, 2nd ed. New York, Thieme, 2000, pp 613–627. Silverman SG, Mueller PR, Saini S, et al: Thoracic empyema: management with image-guided catheter drainage. Radiology 169:5–9, 1988. Thanos L, Mylona S, Pomoni M, et al: Primary lung cancer: Treatment with radio-frequency thermal ablation. Eur Radiol 14:897–901, 2004. Vainrub D, Husher DM, Guinn GA, et al: Percutaneous drainage of lung abscess. Am Rev Respir Dis 117:153–157, 1978. Weinstein M, Restrepo R, Chait PG, et al.: Effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions. Pediatrics 113:182–185, 2004. White RI, Jr, Lynch-Nyhan A, Terryu P, et al: Pulmonary arteriovenous malformations: techniques and long term outcome of embolotherapy. Radiology 169:663–669, 1988. http://www.hht.org/content/hht-summary.html (last accessed August 9, 2007) Yeow, KM, Tsay, PK, Cheung, YC, et al: Factors affecting diagnostic accuracy of CT-guided coaxial cutting needle lung biopsy: Retrospective analysis of 631 procedures. J Vasc Interv Radiol 14:581–588, 2003. Yoon W, Kim JK, Kim YH, et al: Bronchial and nonbronchial systemic artery embolization for life-threatening hemoptysis: A comprehensive review. RadioGraphics 22:1395–1409, 2002.

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33 Scintigraphic Evaluation of Pulmonary Disease Abass Alavi

Daniel Worsley Ghassan El-Haddad

I. RADIOPHARMACEUTICALS AND TECHNIQUES IN VENTILATION-PERFUSION LUNG SCANNING

VI. SCINTIGRAPHIC ASSESSMENT OF ALVEOLARCAPILLARY MEMBRANE PERMEABILITY

II. LUNG SCANNING IN THE DIAGNOSIS OF ACUTE PULMONARY EMBOLISM Prospective Investigation of Pulmonary Embolism Diagnosis Study Interpretation Criteria and Amendments to Original PIOPED Criteria CT Angiography in the Diagnosis of Pulmonary Embolism Recommendations Regarding Use of VentilationPerfusion Lung Scans and CT Angiography in Evaluating Suspected Pulmonary Embolism

VII. EVALUATION OF MUCOCILIARY CLEARANCE

III. EVALUATION OF PULMONARY HYPERTENSION IV. QUANTITATIVE VENTILATION-PERFUSION LUNG SCANNING

VIII. POSITRON EMISSION TOMOGRAPHY AND ASSESSMENT OF SOLITARY PULMONARY NODULES AND LUNG CANCER Use of Positron Emission Tomography in Lung Cancer Staging Mesothelioma Integrated Positron Emission Tomography and Computed Tomography IX. OTHER APPLICATIONS Pneumoconioses Sarcoidosis Chronic Obstructive Pulmonary Disease and Accessory Muscles of Respiration

V. ASSESSMENT OF INFLAMMATORY AND GRANULOMATOUS LUNG DISEASE Gallium-67 Citrate Imaging of the Thorax in the Immunocomprised Host Noninfectious Inflammatory Lung Disease

Use of radiopharmaceuticals has made it possible to assess regional pulmonary function in a variety of pulmonary disorders. In 1955, 133 Xe was introduced for the study of regional ventilation. Shortly thereafter, it became possible to evaluate regional pulmonary blood flow using 15 CO2 by inspiration or 135 Xe by injection. In 1964, intravenous injection of 133 I-macroaggregated albumin made it feasible to obtain perfusion scans of the lungs. Although these techniques rapidly gained wide acceptance as tests of regional abnor-

malities in ventilation and pulmonary blood flow, the main practical application has been in the diagnostic evaluation of patients with suspected pulmonary embolism. Increasingly, the role of nuclear medicine in respiratory medicine has been expanded to include disorders such as preoperative assessment of lung function, inflammatory lung disease, and lung cancer. The more widespread availability of positron emission tomography (PET) and integrated PET/CT (computed tomography) has provided powerful tools to aid in the

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diagnosis, staging, and management of patients with lung cancer.

RADIOPHARMACEUTICALS AND TECHNIQUES IN VENTILATION-PERFUSION LUNG SCANNING Clinical application of perfusion lung scanning was first described in 1964, when iodine 131–labeled macroaggregates of albumin was utilized in the evaluation of pulmonary perfusion. Currently, the agents of choice for pulmonary perfusion imaging are technetium 99m–labeled human albumin microspheres (99m Tc HAM) and macroaggregated albumin (99m Tc MAA). 99m Tc MAA particles range in size from 10 to 150 µm; however, more than 90 percent of injected particles measure between 10 and 90 µm. 99m Tc HAM particles are relatively uniform in size and range between 35 and 60 µm. However, 99m Tc MAA is considered the agent of choice for routine perfusion lung scanning because of its availability, short residence time in the lungs, and relatively low cost. Radiolabeled particles are injected intravenously while the patient is in the supine position, thereby limiting the effect of gravity on regional pulmonary arterial blood flow. Following the administration of 99m Tc MAA, particles are mixed uniformly with the blood that is flowing to the heart; the particles then lodge in precapillary arterioles in the lungs. The usual administered dose of radioactivity is between 74 and 148 MBq (2 to 4 mCi).

The distribution of particles in the lungs is proportional to regional pulmonary blood flow at the time of injection. Approximately 200,000 to 500,000 particles are injected during a routine clinical perfusion lung scan. The normal adult human lung contains approximately 300 million precapillary arterioles and 300 billion capillaries. Therefore, only about 0.1 percent of precapillary arterioles are blocked following the procedure. In addition, the blockage of pulmonary precapillary arterioles by 99m Tc MAA is transient; the biologic half-life in the lung ranges between 2 and 6 h. In pediatric patients and patients with suspected or known right-to-left shunts, pulmonary hypertension, prior pneumonectomy, or a single lung transplant, the number of particles injected should be reduced. A minimum of 60,000 particles is required to obtain an even distribution of activity within the pulmonary arterial circulation and avoid potential false-positive interpretations. We routinely inject 100,000 and 200,000 particles of Tc-99m MAA when performing perfusion scintigraphy in patients with known pulmonary hypertension or in patients who have undergone single lung transplantation. Animal studies have demonstrated that perfusion imaging will detect greater than 95 percent of emboli that completely occlude pulmonary arterial vessels greater than 2 mm in diameter. A routine perfusion scan should include at least six views of the lungs; anterior, posterior, right and left lateral, and right and left posterior oblique views (Fig. 33-1). Right and left anterior oblique views may be helpful in selected cases. In spite of imaging in multiple projections, the perfusion scan may underestimate perfusion abnormalities. A solitary segmental perfusion defect within the medial basal segment of the

Figure 33-1 Normal perfusion scan using 99m Tc MAA. The distribution of particles is uniform, with a minimum gradient of activity from lung apex to base. The six views (left posterior oblique, posterior, right posterior oblique, right anterior oblique, anterior, left anterior oblique) shown correspond to those shown in subsequent figures.

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Figure 33-2 High-probability scan for pulmonary embolism. Ventilation scan utilizing 99m Tc DTPA aerosol is within normal limits. Perfusion scan shows large segmental defects in both lungs. This combination of findings is most consistent with pulmonary embolism.

right lower lobe is completely surrounded by normal lung. Consequently, a perfusion defect in this segment will not be detected on planar perfusion imaging. Perfusion lung scans are routinely utilized to examine patients with suspected pulmonary embolism. Unfortunately, perfusion imaging is sensitive, but not specific, for diagnosing pulmonary embolism. Virtually all lung diseases (including tumors, infections, asthma, and chronic obstructive pulmonary disease) may cause decreased pulmonary arterial blood flow in the affected lung zones. Therefore, combined use of perfusion and ventilation studies can improve the diagnostic specificity of lung scanning for pulmonary embolism. Pulmonary embolism almost always causes abnormal perfusion, while ventilation is preserved (mismatched defects) (Fig. 33-2). In contrast, in parenchymal pulmonary disorders, decreased ventilation and perfusion are noted in the same lung region (matched defects). Conditions in which the ventilation abnormality may appear larger than the perfusion abnormality (reverse mismatch) include airway obstruction, mucus plug, atelectasis, and pneumonia (Fig. 33-3). Patients with metabolic alkalosis or patients treated with inhaled albuterol fail to respond to hypoxic insults by vasoconstriction and may demonstrate reverse mismatch (perfusion of poorly ventilated sites) on ventilation-perfusion scans. 133 Xe has been widely used to determine regional ventilation in the lungs. However, other tracers, such as xenon 127, krypton 81m, and, recently, the technetium 99mâ&#x20AC;&#x201C;labeled aerosolsâ&#x20AC;&#x201D;Technegas and Pertechnegasâ&#x20AC;&#x201D;are utilized for this purpose. Studies that compare various ventilation agents are limited; however, based on the data available, there appear to

be no major differences with regard to diagnostic yield among various radiopharmaceuticals. Utilizing a closed breathing system and 133 Xe, the first inspiration image demonstrates regional ventilation in major airway systems (Fig. 33-4). Equilibrium images are obtained while the patient rebreathes the gas for several minutes. Regions of the lung that appear to ventilate poorly in the initial

Figure 33-3 Reverse ventilation-perfusion mismatch. Posterior and anterior perfusion scans appear within normal limits (upper row). Posterior and anterior aerosol ventilation scans show significantly reduced perfusion in the left lung.

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Figure 33-4 Normal ventilation scan using 133 Xe. The distribution of gas is uniform during the wash-in and equilibrium-phase images (left to right in upper row). During the washout phase, the radioisotope is rapidly cleared from both lungs (lower-row images). Ventilation images were obtained in the posterior projection.

image may fill in the equilibrium phase of the study because of collateral air drift. During the washout phase, while the patient inspires room air, areas of poor ventilation are detected as focal spots of gas retention on the image. Diagnostic yield from the ventilation-perfusion scan is significantly higher if studies are performed in the erect, rather than supine, position. Generally, for technical reasons (lower energy of gamma radiation of 133 Xe compared to 99m Tc), ventilation images with 133 Xe are obtained before perfusion imaging. The imaging technique for 127 Xe is similar to that for 133 Xe. However, because 127 Xe has a higher energy than 99m Tc, ventilation scanning with 127 Xe can be performed following perfusion imaging. The advantages of acquiring ventilation imaging following perfusion studies are that the patient can be positioned so ventilation to the areas of the lungs that reveal the greatest perfusion abnormality can be imaged with optimal detail and ventilation imaging may be avoided altogether in selected cases when the perfusion lung scan appears normal. However, 127 Xe scanning has several disadvantages. It is more costly than 133 Xe and requires medium energy collimation, which degrades image resolution. With either 133 Xe or 127 Xe, images can be obtained only in a limited number of viewsâ&#x20AC;&#x201D;in contrast to perfusion images, which are obtained in multiple projections.

Krypton 81m is a noble gas that can be used to evaluate regional ventilation. This radioactive gas has a very short physical half-life (13 s), and images acquired with this agent reveal ventilation to major airway systems only. However, the short physical half-life of 81m Kr allows generation of images of the lungs in multiple projections. 81m Kr is produced from a rubidium 81 generator. The parent radionuclide has a physical half-life of 4.7 h, which limits the useful lifetime of the generator to only 1 day. As with 127 Xe ventilation studies, imaging with 81m Kr is generally performed following the perfusion scan. Technetium-labeled aerosol studies can be performed following the inhalation of several preparations, including 99m Tc DTPA (diethylene triamine penta-acetic acid), 99m Tc sulfur colloid, 99m Tc pyrophosphate, 99m Tc MDP (methylene diphosphate), and 99m Tc glucoheptanate. The most popular is 99m Tc DTPA. However, this agent has a relatively short residence time within the lung, especially in smokers. In such patients, use of 99m Tc-labeled sulfur colloid or pyrophosphate may be more appropriate. 99m Tc-labeled radioaerosols have particles between 0.5 and 3 Âľm in size and are produced by utilizing commercially available nebulizers. The patient generally breathes from the nebulizer for 3 to 5 min or until 37 MBq (1 mCi) of radioactivity is deposited in the lungs. The regional distribution of radioactivity in the lungs is

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proportional to local ventilation. 99m Tc-labeled radioaerosol studies are generally performed before perfusion imaging. The lungs are imaged in multiple projections, which correspond to those obtained during the subsequent perfusion study. Ventilation studies using 99m Tc-labeled radioaerosols require minimal patient cooperation and can be performed at the bedside and on patients who are on ventilators. Disadvantages of 99m Tc-labeled radioaerosols include the central deposition of radioactivity in patients with chronic obstructive pulmonary disease (COPD) or airway obstruction and the need to dispose of the substantial unused amount of radioactivity that is deposited in the nebulizer. Central deposition of 99m Tc-labeled radioaerosol in patients with COPD is a major drawback to the use of aerosol agents, and newer agents have been developed to overcome this deficiency, including 99m Tc Technegas and 99m Tc Pertechnegas. These agents are generated by burning 99m Tc pertechnetate in a carbon crucible at very high temperatures, which produces an ultrafine radiolabeled aerosol (particle size, 0.02 to 0.2 Âľm). Pertechnegas is purged with 5 percent oxygen and 95 percent argon; Technegas is purged with 100 percent argon. This relatively minor change in production of the final preparation causes profound differences in the biologic behavior of particles generated. When inhaled, both agents distribute homogeneously in the lung in proportion to regional ventilation and with very minimal central deposition, even in patients with COPD. Pertechnegas readily penetrates the alveolar epithelial membrane; therefore, its biologic half-life in the lungs is quite short (approximately 6 to 10 min). On the other hand, very little transalveolar or mucociliary clearance is seen with Technegas; thus, residence time in the lung is approximately equal to the physical half-life of 99m Tc (6 h). Both agents require minimal patient cooperation, and only two or three breaths are required to obtain sufficient deposition in the lungs for optimal ventilation imaging. In general, ventilation imaging with both Technegas and Pertechnegas is performed before perfusion imaging. As with 99m Tc-radiolabeled aerosols, multiple views of the lungs corresponding to those acquired during perfusion imaging can be generated with these preparations. More recently, considerable interest has arisen in imaging based upon antibody fragments and radiolabeled peptides directed against GP IIb/IIIa receptors on the surface of activated platelets. Tc-99m Acutetec, a labeled synthetic peptide which binds to the GP IIb/IIIa receptors, has been used for evaluation of patients with suspected deep venous thrombosis (DVT). The main advantage of the agent is its ability to distinguish between acute and chronic DVT. Several 99m Tc labeled peptides directed against activated platelets are currently under investigation in evaluation of patients with suspected pulmonary embolism. Radiolabeled peptide imaging has the potential to serve as a single, comprehensive modality in the evaluation of patients with venous thromboembolism. However, at the current time, further studies and development of newer radiopharmaceuticals are required to fully realize this potential.

Scintigraphic Evaluation of Pulmonary Disease

LUNG SCANNING IN THE DIAGNOSIS OF ACUTE PULMONARY EMBOLISM Pulmonary embolism (PE) is a common and potentially fatal disorder for which treatment is highly effective in decreasing mortality and morbidity if initiated soon after the event. The accurate and expeditious diagnosis of acute PE can be difficult because of the nonspecificity of clinical, laboratory, and radiographic findings.Approximately 10 percent of patients with PE die within 1 h of the event. For patients who survive beyond the first hour, anticoagulation with heparin or thrombolysis with thrombolytic agents is effective therapy. The mortality in patients with PE who are not treated is as high as 30 percent. In contrast, correct diagnosis and appropriate therapy significantly lower mortality to between 1 and 10 percent. Although anticoagulant therapy is effective in treating PE and reducing mortality, it is not without risks. The prevalence of major hemorrhagic complications among patients receiving anticoagulant therapy has been reported to be as high as 10 to 15 percent. Therefore, accurate diagnosis of PE is essential, not only to prevent death from recurrent embolism, but also to avoid complications related to unnecessary anticoagulant therapy. Ventilation-perfusion lung imaging has been shown to be a safe, noninvasive technique in evaluating regional pulmonary function undertaken for a variety of purposes. The technique has been widely used in the assessment of patients with suspected PE. In spite of its proven value in the management of patients with PE and availability of studies suggesting the underdiagnosis of PE, critics have suggested that this powerful method has been overutilized and that it has had a minimal impact on patient outcome. The first major study that utilized perfusion lung scanning as a screening test for the diagnosis of PE was the Urokinase Pulmonary Embolism Trial (UPET). In more than 90 percent of patients enrolled in the trial, perfusion lung scanning was performed following intravenous administration of 131 I-labeled MAA. Since lung imaging was carried out using rectilinear scanners, ventilation studies were not performed during the study. Despite utilizing a suboptimal radiopharmaceutical and imaging equipment, the UPET study established perfusion lung scanning as an effective technique in both screening for PE and assessing restoration of pulmonary blood flow following an embolic event. Most patients with acute PE either completely lyse the thrombi or partly recanalize the pulmonary artery clots. In UPET, approximately 75 to 80 percent of perfusion defects resolved by 3 months, and those that did not remained largely persistent when followed for 1 year. The degree of clot resolution observed in UPET may represent an underestimate, since ventilation scanning was not performed, and many of the unresolved perfusion defects might have been due to preexisting chronic obstructive pulmonary disease. The defect size at 7 to 10 days following the initiation of therapy was a good predictor of defect size at 6 months. In an American College

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of Chest Physicians consensus statement, the recommendation is performance of a follow-up ventilation-perfusion lung scan at 3 months following the initial diagnosis to evaluate clot resolution and serve as a baseline for future comparisons. If patients are unable to return in 3 months, a scan at discharge or 7 days following initiation of anticoagulant therapy may also be useful. Data from multiple prospective and large, outcomebased studies have reported on the efficacy of ventilationperfusion scanning in patients suspected of having acute PE and have been recently reviewed. One prospective study, designed to determine if anticoagulation could be safely withheld in patients with adequate cardiorespiratory reserve who did not have high probability ventilation-perfusion scans or proximal venous thrombosis (as determined by serial impedance plethysmography [IPG]), underscored the pathophysiological concept that venous thromboembolism is a systemic disease, and that pulmonary embolism is merely the respiratory manifestation of the disorder. A total of 874 patients suspected of having PE were enrolled. Ventilation-perfusion lung scan interpretations were classified as normal (36 percent), nonâ&#x20AC;&#x201C; high probability (56 percent), or high probability (8 percent) studies. Forty-seven percent had nonâ&#x20AC;&#x201C;high probability scans and adequate cardiorespiratory reserve, while nine percent had nonâ&#x20AC;&#x201C;high probability scans and inadequate cardiorespiratory reserve (pulmonary edema, right ventricular failure, systolic blood pressure less than 90 mmHg, syncope, acute tachyarrhythmia, or severely abnormal spirometry or arterial blood gases). During a 3-month follow-up period in which patients with non-high probability lung scans, adequate cardiorespiratory reserve, and negative serial IPG studies had anticoagulants withheld, only 2.7 percent had evidence of venous thromboembolism. The conclusion was that selected patients could be managed safely without anticoagulation, confirming findings from previous studies suggesting that the incidence of recurrent PE is very low in the absence of proximal lower extremity venous thrombus. Unfortunately, the criteria used to categorize the probability of PE (normal, nondiagnostic, or high) were different than those used in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, and direct comparison of the two studies is not possible. In another prospective study of over 1500 consecutive patients with suspected pulmonary embolism who underwent ventilation-perfusion scanning and IPG of the lower extremities, 40 percent had nondiagnostic scans and negative serial IPG studies. All had adequate cardiorespiratory reserve and were managed without anticoagulation. Only 1.9 percent had evidence of DVT or PE on follow-up. The findings suggest that a combination of ventilation-perfusion scanning and IPG can be useful in supporting a decision to withhold anticoagulation in patients who have not had clinically significant PE and who do not have evidence for proximal, lower extremity DVT. Similarly, in another prospective study of over 1200 patients categorized as having a pretest probability of PE as low,

moderate, or high, ventilation-perfusion lung scanning and bilateral lower extremity ultrasound revealed that only 0.5 percent (3 of 665) with low or moderate pretest probability and a non-high probability scan had PE or DVT during the 90-day follow-up period. The authors concluded that patients with clinically suspected pulmonary embolism could be managed safely based on pretest probability and results of a ventilation-perfusion scan. The findings are similar to those from another study of over 1000 patients with suspected PE, 22 percent of whom had a low clinical probability of PE, nondiagnostic lung scan, and negative venous study of the legs. These patients were not treated with anticoagulants, and in follow-up, the prevalence of DVT or PE was only 1.7 percent. Finally, in the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISAPED), which utilized perfusion scanning alone in conjunction with the chest radiograph, the sensitivity and specificity of scintigraphy were 92 percent and 87 percent, respectively. The prevalence of PE was high (39 percent). When considered in conjunction with clinical assessment of the likelihood of PE (very likely, possible, or unlikely), the positive predictive value (PPV) of a perfusion scan was 99 percent; the combination of a near-normal or abnormal perfusion scan without segmental defects and low clinical likelihood of PE had a negative predictive value (NPV) of 97 percent. Using standardized clinical assessment and perfusion lung scanning, the authors were able to accurately diagnose or exclude PE (PPV, 96 percent; NPV, 98 percent). CT angiography was required in only a minority of cases having discordant clinical and scintigraphic findings (see below).

Prospective Investigation of Pulmonary Embolism Diagnosis Study To date, the most comprehensive prospective investigation addressing the role of ventilation-perfusion scanning in the diagnosis of PE has been the PIOPED study. This multiinstitutional study was designed to evaluate the efficacy of various conventional methods for diagnosing acute PE. In particular, PIOPED focused on the sensitivity and specificity of lung scans in the diagnosis of acute PE. Although the clinical diagnosis of PE is not definitive, results from PIOPED emphasize the importance of incorporating clinical assessment in evaluating patients suspected of having acute PE. As expected, combining clinical assessment with lung scan interpretation improves diagnostic accuracy of the imaging technique. Similarly, although chest radiographic findings alone are not sensitive or specific for PE, they are essential for diagnosing conditions that can mimic PE clinically. Furthermore, chest radiographic findings heavily influence the criteria utilized for estimating the probability of PE based on lung scan patterns. The sensitivity, specificity, and positive predictive value of ventilation-perfusion lung scans in detecting acute PE are presented in Table 33-1. One of the limitations of ventilation-perfusion scanning is interobserver variability in scan interpretation. While

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Table 33-1 Sensitivity, Specificity, and Positive Predictive Value of Lung Scans in Detecting Pulmonary Embolism in Patients Enrolled in PIOPED Lung Scan Interpretation (Probability)

Sensitivity

Specificity

Positive Predictive Value

High

40%

98%

87%

High, intermediate

82%

64%

49%

High, intermediate, low

98%

12%

32%

there is generally excellent agreement in categorizing scans as normal or consistent with very low or high probability of PE, interobserver agreement on low-probability and intermediate-probability lung scans is not as good. Use of anatomic lung segment reference charts has been shown to reduce interobserver disagreement when interpreting scans. Other interpretative pitfalls include false-negative and -positive readings. False-negative interpretations (i.e., low probability read with PE present) do occur, and patients who have a recent history of immobilization (bed rest for 3 days), recent surgery, trauma to the lower extremities, or central venous instrumentation are particularly at risk. In patients with low or very low probability scans who have none of the aforementioned risk factors, the prevalence of PE is only 4.5 percent. Conversely, in patients with low or very low probability scans and one or more of the risk factors, the prevalence of PE is 12 percent and 21 percent, respectively (Table 33-2). Patients with false-negative lung scans tend to have nonocclusive subsegmental thrombi and a low pulmonary clot burden. In recent years, concern has arisen that a low probability scan may be misleading, resulting in unnecessary mortality in patients who have PE and are not anticoagulated.

The prognostic value of a low probability scan is excellent, particularly in patients with a low clinical pretest likelihood of disease or negative lower leg ultrasound. In a series of 536 consecutive patients with these findings, evidence that PE caused or contributed to death within 6 months of imaging was absent. The most common cause of ventilation-perfusion mismatch in patients who do not have acute PE is chronic or unresolved PE. Other causes include compression of the pulmonary vasculature (e.g., from mass lesions, lymphadenopathy, or mediastinal fibrosis), vessel wall abnormalities (e.g., pulmonary artery tumors or vasculitis), nonthrombembolic intraluminal obstruction (e.g., tumor emboli or foreign body emboli), and congenital vascular abnormalities (e.g., pulmonary artery agenesis or hypoplasia). In patients who have unilateral ventilation-perfusion mismatch (hypoperfusion or absent perfusion) within an entire lung or in multiple contiguous segments and normal perfusion in the contralateral lung, extrinsic compression of the pulmonary vasculature, congenital abnormalities, or proximal PE should be considered. Patients with a suspected false-positive scan or unilateral ventilation-perfusion mismatch often require further imaging using CT angiography.

Table 33-2 Risk Factors and Prevalence of Pulmonary Embolism in Patients with Low Probability and Very Low Probability Lung Scans Enrolled in PIOPED Patients with 0 Risk Factors (%)∗

Patients with 1 Risk Factor (%)∗

Patients with ≥2 Risk Factors (%)∗

PE positive

14 (2.2%)

19 (2.9%)

37 (5.7%)

PE negative

301 (46.4%)

136 (21.0%)

142 (21.9%)

Prevalence of PE ∗ Risk

4.5%

12.2%

20.7%

factors include immobilization, trauma to lower extremities, surgery, and central venous instrumentation within 3 months of enrollment.

Total 70 579 10.8%

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Table 33-3 Revised PIOPED Criteria for Interpretation of Lung Scans∗ High probability ≥2 Large segmental perfusion defects (>75% of a segment) without corresponding ventilation or radiographic abnormalities 1 Large segmental perfusion defect and ≥2 moderate segmental perfusion defects (25%–75% of a segment) without corresponding ventilation or radiographic abnormalities ≥4 Moderate segmental perfusion defects without corresponding ventilation or radiographic abnormalities Intermediate probability 1 Moderate to <2 large segmental perfusion defects without corresponding ventilation or radiographic abnormalities Corresponding ventilation-perfusion defects and radiographic parenchymal opacity in lower lung zone Single, moderate, matched ventilation-perfusion defects with normal radiographic findings Corresponding ventilation-perfusion defects and small pleural effusion Difficult to categorize as normal, low, or high probability Low probability Multiple matched ventilation-perfusion defects, regardless of size, with normal radiographic findings Corresponding ventilation-perfusion defects and radiographic parenchymal opacity in upper or middle lung zone Corresponding ventilation-perfusion defects and large pleural effusion Any perfusion defects with substantially larger radiographic abnormality Defects surrounded by normally perfused lung (stripe sign) >3 Small segmental perfusion defects (<25% of a segment) with a normal radiograph Nonsegmental perfusion defects (cardiomegaly, aortic impression, enlarged hila) Very low probability ≤3 Small segmental perfusion defects (<25% of a segment) with a normal radiograph Normal probability No perfusion defects; perfusion outlines the shape of the lung seen on the radiograph ∗ Criteria

generated after completion of prospective study.

Interpretation Criteria and Amendments to Original PIOPED Criteria Several diagnostic schemes have been suggested for interpretation of ventilation-perfusion scans. The original PIOPED criteria were developed to interpret the scans generated from the study based upon experience gathered over the preceding decade. However, several revisions of the original PIOPED criteria have been made since its original introduction (Table 33-3). It is now possible to decrease the number of intermediate scan readings and correctly interpret the scans as low probability. Use of revised PIOPED criteria has already been shown to provide a more accurate assessment of angiographically proven PE than the original criteria. Another now-recognized interpretation nuance is based upon the so-called stripe sign, defined as a rim of perfused lung tissue between the perfusion defect and the adjacent pleural surface (Fig. 33-5). In the PIOPED study, the presence of the sign excluded the diagnosis of PE within the affected zone in 93 percent of cases. Therefore, perfusion defects that demonstrate a stripe sign are unlikely to be due to PE, and in the absence of perfusion defects elsewhere, such

findings should be interpreted as representing a low probability of PE. The nuclear medicine physician’s subjective estimate of the likelihood of PE (without using specific interpretation criteria) correlated well with the fraction of patients with angiographic evidence of PE in the PIOPED study. When interpreting lung scans, experienced nuclear medicine physicians often rely on a complex interaction between information derived from clinical presentation, chest radiographic findings, published criteria, and ancillary findings. Thus, experienced readers (such as the PIOPED investigators) can provide an accurate estimate of the probability of PE based on clinical, radiographic, and scintigraphic findings.

CT Angiography in the Diagnosis of Pulmonary Embolism More recently, clinicians have employed spiral or helical CT angiography and electron beam computed tomography as an alternative to scintigraphy in the diagnosis of PE. With CT angiography, acute PE appears as an intraluminal filling defect, which partially or completely occludes

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Figure 33-5 Stripe sign. Both left posterior and right posterior oblique views (lower row) demonstrate a defect surrounded by perfused lung. This pattern is very rarely seen in pulmonary embolism.

the pulmonary artery, or as an abrupt vessel cut-off. Commonly, mild vascular distension at the site of the thrombus is present within the affected vessel. Other indirect signs that suggest PE include a dilated central pulmonary artery, dilated right ventricle, or wedge-shaped parenchymal consolidation. In animal models, CT angiography has been shown to detect thrombi in vessels as distal as the fourth division (segmental) pulmonary arteries. The performance of CT angiography for detection of PE is technically demanding. The sensitivity and specificity of CT angiography for detecting PE range from 53 percent to 100 percent and 75 percent to 100 percent, respectively. The diagnostic performance of CT angiography for detecting subsegmental thrombi is lower than for central PE. In one prospective study comparing spiral CT angiography and ventilation-perfusion lung scanning, CT angiography had a higher sensitivity than a high-probability ventilation-perfusion scan. The specificity, PPV, and NPV were similar between the two modalities. A more recent study reported a higher sensitivity and specificity for CT angiography than ventilation-perfusion scanning. Spiral CT angiography also provides for higher interobserver agreement and the ability to elucidate an alternative diagnosis for patients with suspected PE. Limitations of CT angiography include technical failures and incomplete examinations. Patient-related factors which can result in incomplete or suboptimal examinations include orthopnea, poor intravenous access, and inability to breath-hold because of dyspnea. In patients who are unable to breath-hold, respiratory misregistration may occur, degrading image quality. A poor signal-to-noise ratio or vascular enhancement may occur in patients with right heart failure, large right-to-left shunts, or extravasated intravenous lines.

Scintigraphic Evaluation of Pulmonary Disease

Intravenous contrast must be used cautiously, particularly in patients with renal insufficiency. The prevalence of suboptimal CT angiography examinations depends on the technique used and the population examined. In selected patients, technically inadequate studies occur in about 2 to 4 percent . In spite of its technical demands, CT angiography can provide a prompt and accurate diagnosis of PE in most patients. Studies evaluating the safety of withholding anticoagulation in patients with a negative CT angiogram suggest that in selected patient populations, CT angiography has a high NPV and that anticoagulant therapy may be safely withheld. A meta-analysis of 3500 patients reported that CT angiography is equivalent to convential angiography in ruling-out clinically significant PE. In the authorsâ&#x20AC;&#x2122; opinion, use of spiral CT in the diagnosis of PE has not yet been adequately evaluated, and further prospective studies are required to determine the sensitivity, specificity, and safety of the technique. PIOPED II, a multicentered, prospective, outcomebased study supported by the National Heart, Lung, and Blood Institute, is designed to assess the accuracy of CT angiography in the evaluation of acute PE. Preliminary data indicate that the sensitivity, specificity, PPV, and NPV of the technique are 83, 96, 86, and 95 percent, respectively.

Recommendations Regarding Use of Ventilation-Perfusion Lung Scans and CT Angiography in Evaluating Suspected Pulmonary Embolism Proponents of CT angiography suggest that it should be used as the first-line study in patients with suspected PE. Others suggest that ventilation-perfusion lung scanning should remain the first-line test, with CT angiography used in those patients in whom the diagnosis remains uncertain. In patients with a normal chest radiograph, the ventilation-perfusion lung scan is an effective, noninvasive initial study. However, in patients with significant chest radiographic abnormalities, CT angiography is more likely to provide a definitive diagnosis of PE or an alternative diagnosis. Furthermore, the combination of CT angiography and CT venography has the potential to provide a single, comprehensive evaluation of patients with suspected venous thromboembolism. In summary, based upon results from prospective and outcome-based studies conducted over the last few years, the following conclusions can be drawn regarding use of radionuclide and CT imaging in evaluating patients with suspected PE: (a) A normal ventilation-perfusion scan excludes the diagnosis of clinically significant PE (Fig. 33-6). (b) Patients with very low or low probability scans and a low clinical likelihood of PE have a low (<5 percent) prevalence of PE and generally do not require pulmonary angiography or anticoagulation. (c) Patients with very low or low probability scan, intermediate or high clinical likelihood of PE, and negative serial noninvasive venous studies of the lower extremities generally do not require anticoagulation. In selected cases, CT angiography is helpful in excluding PE and providing an alternative diagnosis. (d) Clinically stable patients with an intermediate

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Figure 33-6 Outcome classification of patients enrolled in PIOPED. Data are from patients who completed ventilation-perfusion scans. See text for details. PE = pulmonary embolism; OCC = Outcome Classification Committee.

probability scan require noninvasive venous studies of the legs; if negative, CT angiography is required for definite diagnosis of PE. (e) A clinically stable patient with a high probability scan and high clinical likelihood of PE, or a patient suspected of having a false-positive scan requires treatment; no further diagnostic tests are required to confirm the diagnosis. (f) Clinically stable patients with a high probability scan and a low clinical likelihood of PE require noninvasive venous studies of the legs; if negative, CT angiography may be required for definitive diagnosis.

EVALUATION OF PULMONARY HYPERTENSION Pulmonary hypertension (PH) as a consequence of chronic pulmonary thromboembolism is a serious and potentially surgically treatable disease. Estimates are that between 0.5 and 4 percent of patients with acute pulmonary emboli eventually develop chronic thromboembolic PH. Unfortunately, the clinical features, laboratory studies, and other noninvasive assessments employed are often unreliable in distinguishing chronic thromboembolic PH from primary and nonthromboembolic secondary PH. Pulmonary angiography is usually required to confirm the diagnosis and determine whether surgical intervention is indicated. Although there have been reports that pulmonary angiography may be performed safely in patients with severe PH, others have documented a high frequency of complications, including death. Ventilation-perfusion lung scanning is a safe, noninvasive technique that facilitates selection of patients with PH for pulmonary angiography to confirm the diagnosis of chronic PE. In order to prevent potential adverse hemodynamic effects when performing ventilation-perfusion lung scans in patients with PH, the number of 99m Tc MAA particles administered should be reduced. Both ventilation-perfusion lung scanning and pulmonary angiography may produce underestimations

of the magnitude of vascular occlusion by chronic emboli, as determined at thromboendarterectomy. In one study of 25 patients with chronic thromboembolic PH, 96 percent of ventilation-perfusion lung scans were interpreted as high probability for PE; in one patient, the scan was interpreted as intermediate probability. The findings suggest that in chronic PH, CT angiography or pulmonary angiography should be performed in those patients with intermediate or high-probability ventilation-perfusion scans in order to confirm the diagnosis of chronic PE. Most patients with primary PH or secondary, nonthromboembolic PH have low-probability scans. The distribution of 99m Tc MAA particles within the lungs is diffuse and nonhomogeneous. Patients with PH rarely, if ever, have normal or very-low-probability scans. Thus, a lowprobability ventilation-perfusion scan effectively excludes chronic thromboembolism as the cause of PH.

QUANTITATIVE VENTILATION-PERFUSION LUNG SCANNING In patients undergoing pulmonary resection or lung transplantation, quantitative ventilation-perfusion lung scanning is a useful method for determining regional lung function. The major use of the technique is prediction of postoperative pulmonary function following lung volume reduction for chronic obstructive pulmonary disease or pneumonectomy for other reasons. Peripheral lung carcinomas are associated with ventilation and perfusion defects that correspond to abnormalities noted on the chest radiograph. In patients with central bronchogenic carcinomas, mismatches between ventilation and perfusion patterns may be noted. In these cases, either the primary lung tumor or adenopathy may compress the main pulmonary artery or vein, which, in turn, may result in decreased perfusion to affected areas. When the airway is

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Figure 33-7 Quantitative ventilation-perfusion lung scan. Regional ventilation and perfusion can be quantified by outlining regular or irregular regions of interest and generating ratios that correspond to percent of total pulmonary function. Images shown were analyzed by dividing each lung into two equal rectangles.

partly or totally occluded by cancer, a matching ventilationperfusion pattern is seen in affected lung zones. In patients with central tumors, regional perfusion values correlate well with regional lung physiology and can be utilized to predict postoperative pulmonary function. The postoperative FEV1 is calculated by multiplying the preoperative value by the ratio of the counts in the remaining lung to total lung activity (Fig. 33-7).

ASSESSMENT OF INFLAMMATORY AND GRANULOMATOUS LUNG DISEASE Gallium-67 citrate and labeled white blood cells are the radiopharmaceuticals of choice for imaging pulmonary infection and inflammation. Gallium-67, which has a physical half-life of 78 h, is an iron analog. Following intravenous administration, approximately 90 percent of the dose injected is bound to transferrin. The kidneys excrete only 25 percent of the administered preparation during the first 24 h after injection. Another 10 percent of the injected activity is excreted in stool over the next several days. The remaining 65 percent is distributed within the body. Typically, gallium is taken up in the liver, skeleton, bone marrow, spleen, nasopharynx, lacrimal and salivary glands, and external genitalia. The precise mechanism of gallium localization at sites of inflammation or infection is not completely understood. Increased vascular permeability, direct bacterial uptake (binding to siderophores), binding to lactoferrin (which is secreted by activated leukocytes), and direct binding to circulating leukocytes have been postulated. The optimal time for imaging the thorax is at least 48 to 72 h following the administration of gallium. Increased gallium activity in the lungs is a sensitive, but relatively nonspecific, indicator of pulmonary infection or inflammation.

A variety of conditions, including acute respiratory distress syndrome, pneumonia, drug reactions (e.g., those due to busulfan, cyclophosphamide, amiodarone, or contrast agent following lymphangiography), pneumoconiosis, idiopathic pulmonary fibrosis, and sarcoidosis may cause increased radiogallium accumulation in the lungs. The intensity and distribution of the pulmonary accumulation can be quantified to determine the degree of parenchymal inflammation. Malignant processes, such as lymphoma, leukemia, mesothelioma, and lung metastases may also result in increased radiogallium uptake when there is focal disease activity.

Gallium-67 Citrate Imaging of the Thorax in the Immunocompromised Host Diffuse gallium uptake in the lungs of HIV-infected patients who have normal chest radiographs is highly suggestive of Pneumocystis carinii pneumonia (PCP) (Fig. 33-8). The sensitivity of gallium scanning for detecting PCP is approximately 95 percent, and when gallium uptake in the lungs is intense (greater than the liver), the specificity also approaches 95 percent. Other conditions associated with diffuse lung uptake in immunocompromised patients are cytomegalovirus pneumonitis, cryptococcal infections, and lymphoma. Although localized lung uptake may be associated with PCP, particularly in patients treated with prophylactic aerosolized pentamidine, focal accumulation is often secondary to bacterial pneumonia or immunoblastic lymphoma. Focal activity in the lung and corresponding regional lymph nodes is typical for infection with M. avium-intracellulare or M. tuberculosis. Kaposiâ&#x20AC;&#x2122;s sarcoma does not accumulate radiogallium, but the lesions are clearly visualized following the administration of thallium-201 chloride. Combined imaging with gallium-67 citrate and thallium-201 chloride has been suggested as a way to distinguish Kaposiâ&#x20AC;&#x2122;s sarcoma from PCP and lymphoma in HIV-infected patients.

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Figure 33-8 Pneumocystis carinii pneumonia with diffuse parenchymal lung uptake. Anterior and posterior gallium scans of the chest and abdomen reveal intense uptake of radiogallium, indicating a diffuse inflammatory process in both lungs.

Noninfectious Inflammatory Lung Disease Gallium-67 citrate lung imaging has been used to quantify the degree of alveolitis in various interstitial lung diseases, particularly sarcoidosis and idiopathic pulmonary fibrosis. In patients with idiopathic pulmonary fibrosis, the intensity of radiogallium uptake has been shown to correlate with the degree of alveolitis assessed by open lung biopsy and the percentage of neutrophils present in bronchoalveolar lavage fluid. However, pulmonary uptake of gallium-67 citrate may be normal in patients with low-grade alveolitis. Unfortunately, pulmonary accumulation of radiogallium in idopathic pulmonary fibrosis is not reliable in predicting the response to treatment with corticosteroids or prognosis. Patients who have normal thoracic gallium scans may eventually develop pulmonary fibrosis, while patients showing a marked increased uptake may remain stable or improve. Therefore, the routine use of gallium-67 scintigraphy in patients with idiopathic pulmonary fibrosis is not recommended. Scintigraphy with gallium-67 citrate has been advocated for assessment of disease activity in pulmonary sarcoidosis. In patients with sarcoidosis, radiogallium activity in the lung correlates well with the presence of alveolitis detected by lung biopsy and the percentage of T lymphocytes detected by bronchoalveolar lavage. Although it is not specific for sarcoidosis, this disorder is characterized by bilateral, perihilar, or peritracheal uptake of gallium-67 citrate (Fig. 33-9). This appearance, combined with increased uptake in the parotid glands, is virtually pathognomonic for sarcoidosis. Parenchymal activity can also be seen, with or without hilar activity. Parenchymal uptake is usually in the midlung, with relative

sparing of the upper and lower lung zones. Gallium-67 citrate imaging in sarcoidosis is useful in selecting the site for lung biopsy and distinguishing fibrotic changes from active inflammatory disease. Several studies have also shown a correlation between the degree of uptake of radiogallium and response to therapy with corticosteroids. Gallium-67 citrate scintigraphy is also useful in assessing extrapulmonary manifestations of sarcoidosis.

SCINTIGRAPHIC ASSESSMENT OF ALVEOLAR-CAPILLARY MEMBRANE PERMEABILITY Assessment of alveolar-capillary membrane permeability requires the inhalation of 99m Tc-labeled radioaerosols. The rate of aerosol clearance from the lung is measured using a counting probe or gamma camera. Several factors influence the rate at which inhaled aerosols “wash out” from the lungs. The most important determinant is the site of aerosol deposition. Aerosols of relatively small aerodynamic diameter (e.g., 99m Tc DTPA) are deposited largely within the small airways and alveoli, whereas larger particles (e.g., 99m Tc MAA or 99m Tc sulfur colloid) are deposited within the proximal airways. The normal half-time of 99m Tc DTPA washout from the lungs is 86 ± 26 min. In the presence of epithelial alveolar damage, the clearance of 99m Tc DTPA is accelerated. A variety of acute or chronic pulmonary conditions may cause increased clearance of 99m Tc DTPA from the lungs,

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Figure 33-9 Bilateral hilar lymphadenopathy in sarcoidosis. Anterior and posterior whole-body images demonstrate intense uptake of radiogallium in both hilar regions. These areas are clearly defined on tomographic (SPECT) images in coronal planes. Similar patterns are seen in patients with lymphoma.

including pneumoconiosis, idiopathic pulmonary fibrosis, collagen vascular diseases, sarcoidosis, acute respiratory distress syndrome, and pneumocystis pneumonia. Cigarette smoking or physiological factors, such as posture and exercise, also influence epithelial lung clearance. Since increased alveolar-capillary membrane permeability is relatively nonspecific, 99m Tc DTPA clearance studies have been utilized only to assess the effects of therapy in patients with known pulmonary diseases. Comparison of serial studies is of value only if a consistent pattern of distribution of radiopharmaceutical activity is demonstrated on repeated studies. Otherwise, results from such studies are of little help in determining the course of the disease.

EVALUATION OF MUCOCILIARY CLEARANCE Determination of mucociliary clearance may be obtained after the inhalation of relatively large aerosolized particles, followed by measurement of the rate of clearance with a gamma camera. The rate of mucociliary clearance depends on several factors, including ciliary activity and mucus production. Inhaled particles, such as 99m Tc MAA or 99m Tc sulfur colloid, tend to be deposited within the proximal airways. The normal mucociliary clearance half-time is approximately 24 h. Delayed mucociliary clearance is seen in patients with airway inflammation (e.g., due to COPD, asthma, or viral respiratory tract infections), following bronchial surgery, or after irradiation. Physiological factors, such as aging and sleep, can also delay mucociliary clearance.

POSITRON EMISSION TOMOGRAPHY AND ASSESSMENT OF SOLITARY PULMONARY NODULES AND LUNG CANCER PET is a nuclear medicine technique that provides images of metabolic or physiologic processes. Application of PET in respiratory medicine has primarily focused on the evaluation of solitary pulmonary nodules and lung cancer. The most commonly used radiopharmaceutical in clinical PET is F-18-fluorodeoxy-d-glucose (FDG). Metabolic differences between benign and malignant tissue can be accurately characterized using FDG-PET. The mechanism of cellular uptake and initial phosphorylation of FDG is similar to that of glucose. However, once FDG is phosphorylated (to FDG-6-phosphate), it is trapped within the cell and can be imaged using PET (Fig. 33-10). The amount of intracellular FDG is proportional to glucose uptake and, therefore, to the metabolic activity of the tissue. Cells that have undergone malignant transformation have increased glucose transport and metabolism due to accelerated cell proliferation and increased hexokinase activity. Current indications for PET-FDG imaging in patients with proven or suspected lung cancer include distinction of benign from malignant pulmonary nodules, mediastinal staging of nonâ&#x20AC;&#x201C;small-cell lung cancer, detection of distant metastasis, and diagnosis of recurrent disease. A solitary pulmonary nodule (SPN), defined as an opacity in the lung parenchyma that measures up to 3 cm and that has no associated mediastinal adenopathy or atelectasis, is commonly indentified on chest radiographs and CT scans and often poses a diagnostic challenge. Thirty to 50 percent of SPNâ&#x20AC;&#x2122;s are malignant and may represent a potentially

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Figure 33-10 Schematic representation of FDG metabolism in metabolically active cell. FDG is preferentially transported through the cell membrane. Following phosphorylation to FDG-6-phosphate by the hexokinase system, FDG remains trapped in the cell for a while, facilitating imaging of the abnormal tissue with PET.

curable stage of bronchogenic carcinoma; however, many represent benign processes. While a number of benign etiologies for SPN’s have a characteristic appearance on CT, many can not be characterized accurately using CT and often require further invasive assessment. Increased patient age, a history of smoking, large nodule size, and absence of nodule calcification are features associated with an increased probability of malignancy. FDG-PET provides an accurate, noninvasive diagnostic assessment of SPNs, without the morbidity and costs associated with invasive tissue sampling (Fig. 33-11). Sensitivity and specificity of FDG-PET in detecting benign and malignant pulmonary nodules range from 92 to 98 percent and 79 to 100 percent, respectively (Table 33-4).

Figure 33-11 Transaxial FDG-PET and CT. Non–small-cell lung cancer in left upper lobe demonstrating increased activity (hypermetabolic) on coregistered FDG-PET/CT images.

In one meta-analysis of 40 studies that included over 1400 focal pulmonary lesions studied with FDG-PET, the technique had an average sensitivity of 97 percent and specificity of 78 percent. No differences were noted between results using a semiquantiative analysis of FDG uptake and those based on qualitative visual assessment. False-positive studies are seen with active inflammation due to aspergillosis, tuberculosis, or sarcoidosis. False-negative results are seen with malignancies which have a low metabolic activity (e.g., bronchoaveolar carcinoma or carcinoid tumors) or are less than 8 mm in diameter. Nodules having a “ground-glass” or “mixed” appearance on CT scanning are associated with a higher incidence of malignancy than are solid-appearing nodules. Further investigation is necessary to evaluate the role of FDG-PET in evaluating ground-glass lesions. The low accuracy of PET in assessing these abnormalities is likely related to their small size and the cell types that predominate, including pure bronchioalveolar cell cancer or adenocarcinomas with bronchioalveolar features. As noted, the sensitivity of FDG-PET is a function of lesion size. In one study addressing this issue, the technique’s sensitivity in detecting malignancy was 69 percent for nodules ranging from 5 to 10 mm in diameter and 95 percent for nodules greater than 10 mm in diameter. The lower limit of spatial resolution of PET, which is about 5 to 6 mm, is lower than that of CT or MRI. One method aimed at compensating for this limitation is based on using lesion size measured on CT imaging to correct the so-called “standardized uptake value” (SUV), a semiquantitative expression of the intensity of lesion FDG accumulation determined on the PET scan. The SUV of an area in the image is calculated as the amount of tracer in the tissue (microcuries per gram) divided by the amount of radiotracer injected (millicuries) divided by the patient’s weight (kilograms). Lung cancers have a wide range of FDG uptake. Furthermore, while most infectious or inflammatory pulmonary disorders generally have a lower FDG uptake than malignancies, overlap exists. An SUV threshold of 2.5, measured at a single point in time, has been proposed to separate malignant (higher SUV) from benign (lower SUV) disorders.

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Table 33-4 FDG-PET in Evaluation of Solitary Pulmonary Nodules Sensitivity

Specificity

Nodule Size (cm)

Type of Analysis

95% Confidence Interval

Accuracy (%)

≤1.5

SUV Visual

80 100

60–100 100–100

95 74

85–100 55–93

>1.5

SUV Visual

96 98

90–100 94–100

80 60

55–100 45–74

93 91

≤3

SUV Visual

90 98

82–98 94–100

92 69

85–99 56–82

91 88

All sizes

SUV Visual

92 98

82–100 82–100

90 69

79–100 57–81

91 89

the single-time point method, and 100 and 89 percent, respectively, for the dual-time point technique.

Based on the observation in animal and human studies that FDG uptake by malignant tumors increases over time, while that of inflammatory tissue decreases (Fig. 33-12), dualtime point FDG-PET scanning has emerged as a potentially useful way of enhancing discrimination between benign and malignant diseases. Using this approach, images are obtained 1 and 2 h after administration of FDG. In one study in which an SUV cut-off value of 2.5 and a 10 percent increase in SUV was used to indicate malignancy, the sensitivity and specificity of FDG-PET were 80 and 94 percent, respectively, for

Use of Positron Emission Tomography in Lung Cancer Staging An additional advantage of FDG-PET in evaluating solitary pulmonary nodules is that the technique can be used in staging mediastinal lymph nodes in patients with non–small-cell

Figure 33-12 Transaxial FDG-PET images showing a focus of increased activity in the right upper lobe, corresponding to the patient’s non–small-cell lung cancer. Maximum SUV was 8.1 on the first time image (A) and increased to 9.7 on the second time image (B). Findings are consistent with malignancy.

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Table 33-5 Accuracy of FDG-PET in Mediastinal Staging in Lung Cancer Study

Number of Patients

Sensitivity

Specificity

PPV

NPV

Dunagan et al., 2001

0.52

0.88

0.61

0.84

Farrell et al., 2000

0.93

0.40

Liewold et al., 2000

0.93

0.78

0.69

0.95

Pieterman et al., 2000

102

0.91

0.86

0.74

0.95

Roberts et al., 2000

100

0.88

0.91

0.75

0.96

Magnani et al., 1999

0.67

0.84

0.67

0.84

Marom et al., 1999

0.73

0.94

0.85

0.88

Saunders et al., 1999

0.71

0.97

0.86

0.93

Vansteenkiste et al., 1998

0.93

0.95

0.93

0.95

Vansteenkiste et al., 1998

0.86

0.43

0.60

0.75

Bury et al., 1997

0.86

0.96

Guhlmann et al., 1997

0.87

0.89

Steinert et al., 1997

0.92

0.97

0.92

0.97

Bury et al., 1996

0.88

0.86

0.88

0.86

Sazon et al., 1996

1.00

Scott et al., 1996

1.00

Chin et al., 1995

0.78

0.81

0.64

0.89

Wahl et al., 1994

0.82

0.75

0.82

1045

0.84

0.89

0.79

0.93

Summary

Notes: Abbreviations: PPV = positive predictive value; NPV = negative predictive value.

lung cancer. The role of FDG-PET in staging of small-cell lung carcinoma remains controversial. Patients with stage I or II nonâ&#x20AC;&#x201C;small-cell lung cancer are typically referred for surgery, while those with stage IIIb (contralateral mediastinal disease) or stage IV (distant metastases) disease generally are not surgical candidates. Mediastinal staging using CT scanning is based primarily on assessment of lymph node size; nodes less than 1 cm in their short axis are considered benign, while those greater than 1 cm are considered potentially malignant. Using this anatomic approach, mediastinal staging based on

CT scanning has a sensitivity of 57 percent and specificity of 82 percent. In comparison with CT scanning, FDG-PET has a higher sensitivity and specificity for determining node status in patients with nonâ&#x20AC;&#x201C;small-cell lung cancer. The average sensitivity and specificity for FDG-PET are 84 and 89 percent, respectively (Table 33-5). However, a comparison of PET and mediastinoscopy in a study of over 200 patients revealed a PPV for PET of only 45 percent. Therefore, mediastinoscopy is still necessary in the staging of PET-positive mediastinal lymph nodes. PET can also be useful in identifying the optimal site

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Figure 33-14 PET/CT images (lower row) demonstrate abnormal FDG uptake in the body of multiple lower thoracic and lumbar vertebral bodies, consistent with bone marrow metastases. No clear abnormalities in the CT bone windows (upper row) are evident to suggest bone destruction. Osseous abnormalities are secondary to bone marrow involvement and can be visualized in the later stages of the disease.

Figure 33-13 Transaxial, sagittal, and coronal composite FDGPET/CT images (top row) of a patient being considered for pulmonary resection. A hypermetabolic nodule is seen within the left upper lobe, corresponding to the patientâ&#x20AC;&#x2122;s known lung cancer. Composite FDG-PET/CT images (bottom row) demonstrate a small, previously unknown, hypermetabolic focus in the left adrenal gland, which was confirmed as an adrenal metastasis.

for mediastinal lymph node biopsy and aiding selection of additional invasive methods for sampling lymph nodes inaccessible by mediastinoscopy. In addition to mediastinal evaluation, whole-body FDG-PET imaging may aid in detecting unsuspected distant metastases (Fig. 33-13). In one mutlicenter trial, adddition of PET to the conventional workup prevented unnecessary surgery in one out of five patients with suspected nonâ&#x20AC;&#x201C;smallcell lung cancer. Two common examples of extrapulmonary sites (stage IV disease) of lung metastases are worth considering in this regard: the adrenal glands and bone marrow. Although benign adrenal adenomas may be abnormal on PET, FDG-PET has a sensitivity of 100 percent and specificity of 80 to 94 percent in detecting adrenal metastases. In detecting bone metastases, compared with bone scintigraphy, FDG-PET has a similar sensitivity but a higher specificity. FDG-PET can detect bone marrow metastases before reactive bone formation takes place or prior to development of gross anatomic abnormalities (Fig. 33-14). In patients with residual parenchymal abnormalities following radiotherapy for lung cancer, PET-FDG scanning can be used to distinguish between persistent or recurrent cancer and radiation fibrosis. In a study of 35 patients who

had recurrent or persistent parenchymal abnormalities following radiotherapy, the sensitivity and specificity of FDGPET in detecting recurrent tumor were 97 and 100 percent, respectively. Only one patient, who had a very thin pleural tumor rind, had a false-negative study. In patients treated for lung cancer, FDG-PET offers prognostic value that correlates strongly with survival rate. Patients with positive FDG-PET results have a significantly worse prognosis than those with negative results.

Mesothelioma Benign fibrous mesothelioma is a rare, nonmalignant, localized tumor of the pleura that is unrelated to asbestos exposure. The tumor can be cured by excisional surgery. In contradistinction, the median survival for patients with malignant mesothelioma is 12 to 18 months. Thus, it is important to differentiate between benign lesions and malignant mesothelioma. Distinction based on histopathological criteria is difficult even for pathologists who specialize in this area. The radiologic appearances of benign and malignant pleural diseases are very similar. More than 50 percent of patients have a pleural effusion at the time of diagnosis; however, pleural fluid cytology is positive in only approximately 25 percent. Currently, definitive diagnosis is based on thoracoscopic biopsy, which, for malignant mesothelioma, carries the risk of tumor seeding along the operative tract. CT scanning and MRI can not always differentiate between benign and malignant pleural processes. Findings from CT and MRI studies can be used in tandem with those from FDG-PET in managing these difficult patients. Several studies have shown that FDG-PET can

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Figure 33-15 Transaxial, sagittal, and coronal views of FDG-PET scan demonstrating diffusely increased FDG activity throughout the diaphragmatic, mediastinal, and lateral right pleura, consistent with malignant mesothelioma.

accurately assess malignant transformation of reactive pleural disease, and in this regard, FDG-PET is clearly superior to CT scanning. Using an SUV cutoff of 2 to differentiate between benign and malignant mesothelioma, FDG-PET has a sensitivity of 91 percent and specificity of 100 percent and provides excellent correlation with thoracoscopic findings. FDG-PET is also useful in identifying the extent of disease locally and in the mediastinum, evaluating abnormal findings in the contralateral lung, and detecting occult extrathoracic metastases (Fig. 33-15). High levels of FDG uptake correlate with a poor prognosis and shorter survival. FDGPET also provides a semiquantitative index of disease activity that may be used to monitor the response to conventional or experimental therapies.

Integrated Positron Emission Tomography and Computed Tomography In recent years, dual-modality integrated PET/CT scanners have been introduced. They hold the promise of improving the overall yield of diagnostic imaging by combining morphological and functional modalities. In a prospective study of 50 patients with nonâ&#x20AC;&#x201C;smallcell lung cancer, integrated PET/CT provided additional diagnostic information in 41 percent and was significantly more accurate in disease staging than either PET or CT alone. Integrated PET/CT provides important clinical information by virtue of accurate localization of known disease and identi-

fication of lesions that do not consistently accumulate FDG, such as carcinoid tumors and bronchioloalveolar carcinoma. One of the advantages of the combined modality over PET alone in tumor staging is that PET is limited for T (tumor) staging, since the technique does not anatomically define tumor limits. In addition, PET/CT is particularly helpful in planning radiation therapy for patients with lung cancer associated with atelectasis. Currently, radiation therapy planning is based on CT imaging because of the close proximity of important structures to the radiation portals. A number of studies have demonstrated the added benefit of PET in defining and refining radiation treatment volumes, thereby reducing the radiation portal and allowing an increase in dose delivery to target tissues. PET/CT without CT enhancement is unable to distinguish confined, centrally located tumors from those producing direct invasion of mediastinal structures. Therefore, clinicians still must rely on contrast-enhanced CT scans to help define mediastinal vascular invasion. Furthermore, in patients with extensive mediastinal disease or multiple areas of nodal involvement, N (nodal) staging can be readily accomplished. Exact localization of a solitary metastatic lymph node in the hilum (and, hence, classification as N1 or N2 disease) is somewhat difficult with PET alone; anatomic information provided by CT scanning as part of combined imaging is important for this purpose. CT information is also essential for precise localization of lymph node metastases in patients with mediastinal shift due to atelectasis or anatomic variants. PET/CT offers the

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trast agents or indwelling metallic structures, leading to falsepositive results on corrected images (Fig. 33-16). Motion and misregistration between PET and CT images can also result in major artifacts in regions adjacent to the heart and diaphragm.

OTHER APPLICATIONS B

Radionuclide-based techniques have been applied to investigation of other pulmonary entities, albeit on a much less frequent basis than those described previously.

Pneumonconioses

Figure 33-16 An attenuation artifact is seen in the left upper thorax as an area of increased activity on the coronal attenuationcorrected PET images (A: arrow). This is caused by an implantable cardioverter defibrillator (B: arrow), and corresponds in reality to a photopenic defect on the nonattenuation-corrected images (C: arrow).

advantage of determining the exact location of a focal abnormality noted on PET. PET/CT also enables exact localization of FDG in sites altered by radiation. Assessment of multiple pulmonary nodules using FDG-PET is limited because of false-positive findings in instances of active granulomatous disease, such as tuberculosis, fungal disease, or sarcoidosis, or rheumatoid lesions. In this setting, pattern recognition on CT, in combination with FDGPET, may improve characterization of the lesions. PET/CT increases the accuracy of malignant pleural mesothelioma staging and is important in determining appropriate therapy in patients being considered for extrapleural pneumonectomy. Finally, PET/CT also has some limitations related to attenuation artifacts arising from use of high-density con-

Pneumoconioses may be progressive, even after dust exposure has ceased. The inhaled particles activate pulmonary macrophages that secrete cytokines that mediate an inflammatory reaction, inducing fibroblast proliferation and collagen deposition. The intensity of pulmonary FDG uptake in pneumoconioses depends on whether active inflammation (increased uptake) or end-stage fibrosis (reduced uptake) predominates at the time of the scan. FDG is taken up by both fibroblasts and alveolar inflammatory cells. In addition, progressive massive fibrosis has been shown to be associated with increased FDG accumulation. The findings from FDG-PET have direct clinical implications; therefore, they are ineffective as therapeutic interventions in end-stage fibrosis. PET imaging using 18F-fluoroproline, which accumulates in lung scar tissue, holds promise for providing early assessment of this category of lung diseases.

Sarcoidosis Hilar and mediastinal lymph nodes harboring active granulomas due to sarcoidosis accumulate FDG. Although FDG-PET

Figure 33-17 Sagittal (A) and coronal (B) FDGPET images showing increased FDG uptake by intercostal muscles in a patient with severe COPD.

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can not distinguish sarcoidosis from other diseases, such as Hodgkin’s or non-Hodgkin’s lymphomas, the technique is quite effective in assessing the extent of disease after an initial diagnosis is made. FDG-PET can also provide a means of assessing response to treatment.

Chronic Obstructive Pulmonary Disease and Accessory Muscles of Respiration Physiologic FDG uptake is noted in strenuously contracting respiratory muscles in patients with COPD. In particular, uptake in intercostal, cervical, and abdominal muscles can be readily identified (Fig. 33-17). Muscular uptake may also be evident in the trapezi, scalenes, sternocleidomastoids, and paraspinal muscles.

SUGGESTED READINGS Alavi A, Gupta N, Alberini JL, et al: Positron emission tomography imaging in nonmalignant thoracic disorders. Semin Nucl Med 32:293–321, 2002. Bastarrika G, Garcia-Velloso MJ, Lozano MD, et al: Early lung cancer detection using spiral computed tomography and positron emission tomography. Am J Respir Crit Care Med 171:1378–1383, 2005. Benard F, Sterman D, Smith RJ, et al: Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography. Chest 114:713–722, 1998. Blachere H, Latrabe V, Montaudon M, et al: Pulmonary embolism revealed on helical CT angiography: Comparison with ventilation-perfusion radionuclide lung scanning. AJR Am J Roentgenol 174:1041–1047, 2000. Bunyaviroch T, Coleman RE: PET evaluation of lung cancer. J Nucl Med 47:451–469, 2006. Gonzalez-Stawinski GV, Lemaire A, Merchant F, et al: A comparative analysis of positron emission tomography and mediastinoscopy in staging non-small cell lung cancer. J Thorac Cardiovasc Surg 126:1900–1905, 2003. Gould MK, Maclean CC, Kuschner WG, et al: Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: A meta-analysis. JAMA 285:914–924, 2001. Hickeson M, Yun M, Matthies A, et al: Use of a corrected standardized uptake value based on the lesion size on CT permits accurate characterization of lung nodules on FDGPET. Eur J Nucl Med Mol Imaging 29:1639–1647, 2002. Lardinois D, Weder W, Hany TF, et al: Staging of non-smallcell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 348:2500– 2507, 2003. Lee VW, Fuller JD, O’Brien MJ, et al: Pulmonary Kaposi sarcoma in patients with AIDS: Scintigraphic diagnosis with sequential thallium and gallium scanning. Radiology 180:409–412, 1991.

Lowe VJ, Fletcher JW, Gobar L, et al: Prospective investigation of positron emission tomography in lung nodules. J Clin Oncol 16:1075–1084, 1998. Matthies A, Hickeson M, Cuchiara A, et al: Dual time point 18F-FDG PET for the evaluation of pulmonary nodules. J Nucl Med 43:871–875, 2002. Mayo JR, Remy-Jardin M, Muller NL, et al: Pulmonary embolism: Prospective comparison of spiral CT with ventilation-perfusion scintigraphy. Radiology 205:447– 452, 1997. Miniati M, Pistolesi M, Marini C, et al: Value of perfusion lung scan in the diagnosis of pulmonary embolism: Results of the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis (PISA-PED). Am J Respir Crit Care Med 154:1387–1393, 1996. Patz EF Jr, Lowe VJ, Hoffman JM, et al: Persistent or recurrent bronchogenic carcinoma: Detection with PET and 2-[F-18]-2-deoxy-D-glucose. Radiology 191:379–382, 1994. Perrier A, Miron MJ, Desmarais S, et al: Using clinical evaluation and lung scan to rule out suspected pulmonary embolism: Is it a valid option in patients with normal results of lower-limb venous compression ultrasonography? Arch Intern Med 160:512–516, 2000. PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 263:2753– 2759, 1990. Quiroz R, Kucher N, Zou KH, et al: Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: A systematic review. JAMA 293:2012–2017, 2005. Rajendran JG, Jacobson AF: Review of 6-month mortality following low-probability lung scans. Arch Intern Med 159:349–352, 1999. Sostman HD, Coleman RE, DeLong DM, et al: Evaluation of revised criteria for ventilation-perfusion scintigraphy in patients with suspected pulmonary embolism. Radiology 193:103–107, 1994. UPET Investigators: The urokinase pulmonary embolism trial. A national cooperative study. Circulation 47:II1–108, 1973. Van Tinteren H, Hoekstra OS, Smit EF, et al: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: The PLUS multicentre randomised trial. Lancet 359:1388–1393, 2002. Wells PS, Ginsberg JS, Anderson DR, et al: Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 129:997–1005, 1998. Worsley DF, Alavi A: Radionuclide imaging of acute pulmonary embolism. Semin Nucl Med 33:259–278, 2003. Worsley DF, Palevsky HI, Alavi A: Ventilation-perfusion lung scanning in the evaluation of pulmonary hypertension. J Nucl Med 35:793–796, 1994.

34 Pulmonary Function Testing Michael A. Grippi

Gregory Tino

I. LUNG VOLUMES AND SUBDIVISIONS Definitions and Assessment The Vital Capacity and Its Subdivisions Functional Residual Capacity and Residual Volume Temperature Correction Factors Radiographic Assessment of Lung Volume II. STATIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM Static Compliance of the Lungs Static Compliance of the Chest Wall Elastic Properties of the Respiratory System as a Whole Elastic Properties of the Respiratory System in Health and Disease Respiratory Muscle Strength III. DYNAMIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM Forced Vital Capacity Flow-Volume Relationships Maximal Voluntary Ventilation Respiratory Resistance Measurement of Exhaled Nitric Oxide IV. AIRWAY REACTIVITY Background Indications for Bronchoprovocation Testing Methods of Bronchoprovocation Testing Precautions and Contraindications in Bronchoprovocation Testing V. SMALL-AIRWAY FUNCTION Dynamic Compliance Closing Volume Helium-Oxygen Flow-Volume Curves VI. GAS EXCHANGE FUNCTIONS Ventilation, Oxygen Uptake, and Carbon Dioxide Elimination

Dead Space Alveolar Gas Composition Diffusing Capacity Arterial Blood Gas Composition Testing for Air Travel-Related Hypoxemia VII. CONTROL OF BREATHING Ventilatory Response to CO2 Ventilatory Response to Hypoxia Nonventilatory Measures of Ventilatory Drive VIII. ASSESSMENT OF INTEGRATED FUNCTIONS: 6-MINUTE WALK TEST Technical Aspects Interpretation IX. QUALITY CONTROL IN THE PULMONARY FUNCTION LABORATORY Nonanalytical Factors in Quality Control Analytical Factors in Quality Control Quality Control of Test Results Responsibility and Cost in Quality Control Infection Control X. APPROACH TO INTERPRETING COMMONLY PERFORMED PULMONARY FUNCTION TESTS Interpretation Scheme and Classification of Abnormal Patterns Assessing Respiratory Muscle Strength and Effort Additional Details of Pulmonary Function Test Results in an Obstructive Pattern Additional Details of Pulmonary Function Test Results in a Restrictive Pattern Additional Details of Pulmonary Function Test Results in a Mixed Obstructive- Restrictive Pattern Isolated Decrease in the Efficiency of Gas Transfer Summary of Approach to Interpretation

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The assessment of human pulmonary function dates back to the seventeenth century, when the earliest measurements of tidal volume were noted. In 1700, Humphrey Davy employed a hydrogen dilution technique to measure his own residual volume. Subsequently, John Hutchinson, in his treatise, On the Capacity of the Lungs and on Respiratory Functions, defined the functional subdivisions of lung volume and reported the results of vital-capacity measurements performed in more than 1800 subjects. He related these measurements to the subjects’ height, age, and weight, thereby establishing a basis for determining normal values. Progress in development of techniques for pulmonary function testing progressed slowly over the next century. However, in the 1950s, pulmonary physiologists made use of the tools provided by the evolving fields of electronics and computer science. Currently, many techniques exist for assessing both the integrated performance of the cardiovascular and respiratory systems and their individual components. This chapter focuses on commonly used tests of pulmonary function. Detailed assessment of integrated pulmonary and cardiovascular function is described in Chapter 35.

LUNG VOLUMES AND SUBDIVISIONS Important quantitative aspects of respiratory function are the changes in lung volume with inspiration and expiration and the absolute volume of air that the lungs hold at various times during the respiratory cycle. These volumes and changes in volume are described below.

Definitions and Assessment For purposes of quantification and comparison, the total volume of gas in the lungs is conventionally subdivided into compartments (volumes) and combinations of two or more volumes (capacities). For many of these subdivisions, the endexpiratory volume—the volume of gas remaining in the lungs at the end of normal expiration—is the point of reference. Lung volumes and capacities are defined in Table 34-1 and are depicted schematically in the tracing shown in Fig. 34-1, which was obtained using a device called a spirometer. The relationships between the volumes recorded directly by the spirometer and the other lung volumes and capacities— including total lung capacity (TLC), functional residual

Table 34-1 Glossary for Static Lung Volumes and Capacities Term

Symbol

Definition

Volumes Residual volume

Volume of air remaining in the lungs after maximal expiration Maximal volume of air expired from the resting end-expiratory level Volume of air inspired or expired with each breath during quiet breathing Maximal volume of air inspired from the resting end-inspiratory level

Expiratory reserve volume

ERV

Tidal volume

TV∗

Inspiratory reserve volume

IRV

Capacities Inspiratory capacity

Vital capacity

Inspiratory vital capacity

IVC

Functional residual capacity

FRC

Total lung capacity

TLC

∗ The

Maximal volume of air inspired from the end-expiratory level (the sum of IRV and TV) Maximal volume of air expired form the maximal inspiratory level Maximal volume of air inspired form the maximal expiratory level Volume of air remaining in the lungs at the end-expiratory level (the sum of RV and ERV) Volume of air in the lungs after maximal inspiration (the sum of all volume compartments)

symbol TV is traditionally used for tidal volume to indicate a subdivision of static lung volumes. However, the symbol Vt is used for tidal volume in formulas for gas exchange.

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Figure 34-1 The subdivisions of lung volume as recorded by a spirometer. The record is generated on paper calibrated for volume in the vertical direction and time in the horizontal. The term capacity is applied to a subdivision composed of two or more volumes. The definitions of these subdivisions are found in Table 34-1. B

capacity (FRC), residual volume (RV), and inspiratory capacity (IC)â&#x20AC;&#x201D;are highlighted in the figure. Spirometers that measure volume or change in volume vs. time have been used extensively in pulmonary function laboratories. Through manual calculations or use of computers, the relationship among volume, flow, and time could be generated to provide a measure of the respiratory systemâ&#x20AC;&#x2122;s ability to move air. Two examples of these volume-type spirometers are shown in Fig. 34-2. In the water-sealed spirometer (Fig. 34-2A), a mouthpiece is attached to the tube through which air passes into a lightweight bell that is inverted over a water bath. Air movement through the mouthpiece into the bell during expiration causes the bell to rise; conversely, as air is withdrawn from the system during inspiration, the bell falls. The change in volume with time can be recorded on a calibrated rotating drum or digitally noted by a computer and displayed on a screen in both graphic and numeric formats. In the dry, rolling-seal spirometer (Fig. 34-2B), a cylinder with a rolling plastic seal is substituted for the spirometer bell and its water seal. Movement of air through the mouthpiece effects a change in the position of the piston, which is attached to a variable resistor. The resistor, in turn, generates voltage signals proportional to volume changes reflected in displacement of the piston. These signals are processed by a computer to generate graphic and numeric outputs similar to those of the water-sealed spirometer. Currently, most pulmonary function laboratories utilize flow-type spirometers using pneumotachographs or rotating turbines to determine airflow. Two types of pneumotachographs are in general use: hot-wire and flow-resistive. In the hot-wire type, air flowing past a heated wire cools the wire, thereby altering its resistance in proportion to changes

Figure 34-2 Two types of spirometers: water-sealed (A) and dry rolling-seal (B). Movement of air through the breathing tube results in movement of the bell (A) or piston (B). The output signal is either mechanical (pen on rotating drum) or electrical (flow and volume as voltage changes). The primary design criteria for these instruments are that inertia and resistance to airflow must be held to negligible levels, and the calibration must be accurate and stable.

in airflow. Flow-resistive pneumotachographs contain a resistive element composed of parallel tubes (Fig. 34-3), a wire mesh, or a fibrous, paperlike element. Airflow through the resistive element results in a pressure gradient across the

Figure 34-3 Principle of pneumotachography. During unidirectional airflow, a pressure drop is created across a resistive element made up of an array of parallel capillary tubes. The magnitude of the pressure drop is related to airflow, as described by Poiseuilleâ&#x20AC;&#x2122;s law for a laminar flow system. The pressure drop is transduced to a proportional voltage output, which can be recorded. A heating element (not shown) maintains the temperature of the expired gas near body temperature.

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device, which can be measured by a very sensitive differential pressure gauge. In the model depicted in Fig. 34-3, the array of parallel small-bore tubes maintains a laminar gas flow pattern through the pneumotachograph. As a result, the pressure-flow characteristics of the system can be described by Poiseuille’s law:

Hence, under laminar flow conditions, the flow of gas in each tube is proportional to the pressure drop across the tube. The calculation for the overall pressure drop across the entire resistive element is based on the parallel arrangement of the array of tubes. The pressure drop across the resistive element is sensed by a pressure transducer and converted to a voltage output that is proportional to flow. The flow signal can be integrated electronically to yield volume. The output signals for flow and volume are displayed on a monitor and recorded. Minimal standards have been established by the American Thoracic Society and the European Respiratory Society (Table 34-2) for spirometers used either for diagnostic purposes or patient monitoring. In a diagnostic setting, spirometers are used to: (1) evaluate symptoms, signs, or abnormal laboratory tests; (2) measure the effect of disease on pulmonary function;

8ηl !P = V˙ 4 πr where !P = pressure drop across the resistive element, dyn/cm2 ˙V = gas flow, cm3 /s η = viscosity of gas, dyn · s/cm2 l = length of resistive element, cm r = radius of resistive element, cm

Table 34-2 Minimal Recommendations for Diagnostic Spirometry Flow Resistance and Range (L/s) Time(s) Back Pressure

Test Signal

0.5–8 L ± 3% of reading or ± 0.050 L, whichever is greater

0–14

3-L cal syringe

FVC

0.5–8 L ± 3% of reading or ± 0.050 L, whichever is greater

0–14

<1.5 cm H2 O/L/s

24 standard waveforms 3-L cal syringe

FEV1

0.5–8 L ± 3% of reading or ± 0.050 L, whichever is greater

0–14

<1.5 cm H2 O/L/s

24 standard waveforms

Time zero

The time point from which all FEVt measurements are taken

Back extrapolation

PEF

Accuracy: ± 10% of reading or ± 0.30 L/s, 0–14 whichever is greater

Mean resistance at 200, 400, 600 L/s must be <2.5 cm H2 O/L/s

26 flow standard waveforms

Same as FEV1

24 standard waveforms

<1.5 cm H2 O/L/s

Proof from manufacturer

<1.5 cm H2 O/L/s

Sine wave pump

Test

Range/Accuracy (BTPS)

Precision: ± 5% of reading or ± 0.15 L/s, whichever is greater FEF25−75%

7.0 L/s ± 5% of reading or ± 0.200 L/s, whichever is even greater

±14

Instantaneous ±5% of reading or 0.200 L/s, whichever is 0–14 flows greater MVV

250 L/min at TV of 2 L within ± 10% of reading or ± 15 L/min, whichever is greater

±14 ± 3%

12–15

Note: BTPS = bady temperature and pressure, saturated with water vapor; VC = vital capacity; FVC = forced expiratory vital capacity; FEV1 = forced expiratory volume in 1 s; PEF = peak expiratory flow; FEF25−75% = forced expiratory flow, 25–75%; MVV = maximal voluntary ventilation; TV = tidal volume. Source: ATS/ERS Task Force: Standardization of lung function testing. Eur Resp J 26:319–338, 2005.

571 Chapter 34

(3) screen persons at risk of having pulmonary disease; (4) assess preoperative risk; (5) assess prognosis; and (6) assess health status before enrollment in strenuous physical activity programs. On the other hand, spirometers used for patient monitoring are used to: (1) assess therapeutic interventions, including bronchodilator therapy, management of congestive heart failure, etc.; (2) characterize the course of diseases affecting lung function (e.g., obstructive or interstitial lung diseases, congestive heart failure, or neuromuscular diseases); (3) track pulmonary function in persons working in occupations or receiving medications known to affect the lung; (4) evaluate large numbers of people in disability assessments; and (5) provide data as part of epidemiologic surveys. In general, the diagnostic spirometer is used to assess a patient’s lung function for purposes of comparison with values expected in a normal population. The monitoring spirometer, which is less expensive and more portable, is used to study a patient’s performance over time and to study large numbers of people for epidemiologic or other purposes.

The Vital Capacity and Its Subdivisions Two methods of performing a vital-capacity maneuver can be used: closed-circuit and open-circuit methods. In the closedcircuit method, the seated patient, with nose clip in place, breathes quietly into the apparatus. After several breaths to establish the resting end-expiratory level, which serves as a point of reference for all subsequent measurements, the patient is urged to inspire fully and then, after reaching a plateau at maximal inspiration, to expire maximally. This expiration must be performed slowly and evenly; attempts by the patient with obstructive pulmonary disease to maximize flow often reduce expiratory volumes because of dynamic compression of the airways caused by high positive pleural pressures (see Chapter 9). Figure 34-1 illustrates schematically this relaxed, or as previously known, slow vital capacity maneuver. From this record, tidal volume, inspiratory reserve volume, expiratory reserve volume, vital capacity, and inspiratory capacity are calculated. A similar maneuver in which the subject breathes out as rapidly and forcefully as possible after a maximal inspiration provides a measure of the forced vital capacity. Other timed measurements of expiratory airflow (e.g., the forced expiratory volume in 1 second, or FEV1 ) are also determined from this type of record (see “Dynamic Mechanical Properties of the Respiratory System,” below). In the open-circuit method of determining vital capacity, the patient inspires maximally, inserts the mouthpiece, and then exhales with a slow, constant effort to the point of maximal expiration. With this technique, the resting endexpiratory position is not recorded. Thus, only the vital capacity, not its component volumes, can be measured. The opencircuit technique offers some advantages. Since the patient inspires from room air before expiring into the apparatus, concern over acquisition of infection from contaminated inspired air is minimized. In addition, the open-circuit method is generally completed in a shorter time, providing a major

Pulmonary Function Testing

advantage when epidemiologic studies are being performed on large numbers of subjects.

Functional Residual Capacity and Residual Volume One compartment of the TLC that cannot be measured by spirometry is residual volume (RV), the volume of air remaining in the lungs at the end of a maximal expiration. RV is determined indirectly in three steps: (1) Functional residual capacity (FRC) is typically measured using one of three techniques: closed-circuit helium, open-circuit nitrogen, or total-body plethysmograph. (2) Expiratory reserve volume (ERV) is determined spirometrically. (3) RV is calculated as the difference between FRC and ERV. In principle, it is possible to determine the RV using a dilution technique or body plethysmography after maximal expiration. In practice, however, the resting end-expiratory level is a more reproducible starting point for determining FRC than is the maximal endexpiratory level for determining RV. Closed-Circuit Helium Method The closed-circuit helium dilution method for determining FRC is a variation of the hydrogen dilution method first used in the early nineteenth century. Both methods take advantage of the virtual insolubility of the test gas in body tissues and the law of conservation of mass. The development and simplification of this test were accomplished over a 20-year span in the mid-twentieth century. Schematic depictions of the principle upon which the technique is based and the apparatus used are shown in Fig. 34-4. When a fully manual device is used for measuring FRC, the system is prepared by the addition of about 2 L of air and sufficient helium to achieve an initial helium concentration of approximately 10 percent in the apparatus. The patient, with nose clip in place, then breathes room air through the mouthpiece (Fig. 34-4A). After a preliminary period of quiet breathing to familiarize the patient with the mouthpiece, apparatus, and environment, and after the baseline resting endexpiratory level is established, the test begins. At the end of a normal expiration, the valve at the mouthpiece is turned to connect the patient to the spirometer system (Fig. 34-4B). As the patient rebreathes from the closed circuit, the blower circulates the gas mixture. The CO2 is absorbed by soda lime (CO2 absorber), while O2 is added through a valve and flowmeter at a rate corresponding to the subject’s O2 consumption. As the helium, which was at first contained entirely within the apparatus, mixes with air contained in the lungs, its concentration, as monitored by the helium analyzer, falls. Stabilization of the helium concentration, indicated by a rate of change in concentration of less than 0.02 percent over a 30-s interval, signals the point at which the helium concentration has equilibrated throughout the lung-breathing circuit system; equilibration, the end point of the test, occurs within 7 min in normal persons. However, in patients in whom the distribution of ventilation is abnormal (e.g., those with chronic obstructive pulmonary

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described here is based on a manually operated device, the same principles hold when all the mechanical and computational steps are accomplished with a computer-controlled system. Nitrogen Washout Method Conceptually, the nitrogen washout method is similar to the helium dilution method described previously; however, it relies on an open circuit rather than the closed circuit used in the helium dilution method. The open-circuit nitrogen washout method for determining FRC requires that the subject breathe 100 percent O2 for 7 min; during this period, the concentration of N2 in expired gas is monitored. When the expired N2 concentration falls to zero, all the N2 present in the lungs at the start of O2 breathing has been “washed out.” The total volume of gas expired and the concentration of N2 in the expired gas are measured. The calculation of FRC is based on the reasonable assumption that the volume of N2 in the lungs at the start of the test (i.e., the product of lung volume and the concentration of N2 in the lungs) is the same as the total volume of N2 expired and collected during the period of the test (i.e., the product of the total volume of gas expired and the concentration of N2 in the expired gas):

F0N2 × V0 = FEN2 × V E B

where

Figure 34-4 Closed-circuit helium dilution method for measurement of functional residual capacity (FRC). A. Spirometer and tubing system with helium before subject begins breathing through the circuit. At the end of an expiration the mouthpiece valve is turned and the patient rebreathes through the circuit. Expired CO2 is ‘‘scrubbed” out of the system, and O2 is added to compensate for continued O2 uptake in the lungs. B. During equilibration, the measured helium concentration falls, reflecting a dilutional effect of the additional volume (FRC) on the spirometer circuit.

disease) equilibration may take much longer. Upon equilibration, the following equation, based on the law of conservation of mass, is applied: F0He × V0 = FfHe × Vf where F0He V0 FfHe Vf

= = = =

initial concentration of helium initial volume of system, L final concentration of helium final volume of system, L

The initial volume of the system is the volume of the spirometer and circuit tubing, whereas the final volume consists of the initial volume plus FRC. The latter value is the only unknown in the preceding equation. Corrections are usually made for the small amount of helium dissolved in body tissues during the test and for slight volume changes caused by a respiratory exchange ratio that is not equal to 1.0. Although the method

F0N2 V0 FeN2 VE

= concentration of N2 in the lungs = volume of gas in the lungs, L = concentration of N2 in the expired gas = volume of expired gas, L

Since the test is started at the end of a quiet expiration, the volume of gas in the lungs is FRC. This volume is calculated by substituting into the above equation the initial concentration of N2 in the lungs, estimated at 0.81 in fasting and 0.79 to 0.80 in nonfasting subjects, and the measured values for volume and N2 concentration of expired gas. Body Plethysmography The word plethysmography is derived form the Greek plethysmos, meaning “enlargement.” Although the concept of measuring FRC by recording changes in the volume of the body during “enlargement” of the chest was described in the late nineteenth century, it was not until 1956 that DuBois and coworkers introduced a practical plethysmographic technique, based on Boyle’s law, for determining thoracic gas volume. Any of three types of body plethysmographs can be used: (1) the pressure plethysmograph, in which pressure during breathing varies while volume remains constant; (2) the volume plethysmograph, in which volume varies during breathing while pressure remains constant; and (3) the pressure-corrected flow plethysmograph, which couples the pressure plethysmograph’s fidelity of response to high-speed

573 Chapter 34

Figure 34-5 Constant-volume, variable-pressure plethysmograph used for measuring functional residual capacity and airway resistance. The device has a fixed volume. Thoracic gas volume changes associated with changes in alveolar pressure are reflected as changes in pressure within the plethysmograph.

events with the volume plethysmograph’s ability to follow large changes in volume. Since the conceptual basis for all three devices is about the same, only the most popular one— the pressure plethysmograph—will be described. The pressure plethysmograph (Fig. 34-5) contains a pneumotachograph and transducer for measuring flow and volume and two strain-gauge transducers, one for sensing pressure at the mouth (Pm) and the other for sensing pressure in the box (Pbx). A solenoid-operated shutter mechanism is situated between the mouthpiece and the pneumotachograph. The three transducers are connected to an amplifying and monitoring system so that box pressure (or lung volume) and mouth pressure are displayed simultaneously on the X and Y axes, respectively, of an oscilloscope (Fig. 34-6). In order to determine FRC, the patient, seated comfortably within the box with nose clip in place, is asked to breathe quietly through the mouthpiece. At the end of a quiet expiration, the shutter is closed and the patient is instructed to pant gently against it. The panting movements cause both mouth pressure and box pressure to change. With each inspiratory effort, as mouth pressure falls and gas in the lungs is rarefied, lung volume increases. Because the plethysmograph is a closed box, the increase in lung volume produces a corresponding increase in box pressure. With each expiratory effort, as lung volume decreases, box pressure falls. Because the shutter is closed while the measurements are made, mouth pressure equals alveolar pressure (Pa). These oscillations in mouth pressure and box pressure or lung volume appear on the oscilloscope as a closed loop (Fig. 34-6). Measurement of the slope of this loop is used to determine the volume of gas in the lungs at the time of shutter closure—i.e., thoracic gas volume (TGV or VTG ). When the occlusion occurs at resting end-expiratory lung volume, the measurement yields FRC (see below).

Pulmonary Function Testing

Figure 34-6 Pressure-volume loop obtained from a person seated in a body plethysmograph. Pressure at the mouth represents alveolar pressure; pressure in the box represents thoracic gas volume. After the shutter has closed at end-expiration (Pm, V), the subject attempts to inspire. Pm falls, and the pressure in the box increases. This increase in box pressure is calibrated in terms of an equivalent volume change. The new position of the trace at the end of the inspiratory effort is (Pm + ! Pm, V + !V). The slope of the loop depends on the volume of gas in the lungs when the shutter is closed (FRC).

Applying Boyle’s law to the plethysmographic determination of lung volume, PV = (P + !P)(V + !V) where P = pressure in the lungs at end expiration (atmospheric pressure), cm H2 O ! P = change in pulmonary pressure produced by respiratory efforts, cm H2 O V = volume of gas in the lungs at end expiration (FRC), L !V = change in gas volume in the lungs produced by compression (during expiration) and rarefaction (during inspiration) secondary to respiratory efforts, L In the pressure plethysmograph, !V is sensed as a change in pressure within the box, and !P is determined from the change in mouth pressure during breathing efforts against the closed shutter. Rearranging the above equation and solving for V yield: !V (P + !P) !P However, since !P is small compared to P (atmospheric pressure), it may be disregarded. The equation then becomes: V=

V=P×

!V !P

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where V = functional residual capacity, L P = atmospheric pressure, cm H2 O !V/!P = inverse of slope of the loop on the oscilloscope Therefore, the only unknown in this equation is V, which can be calculated by incorporating values for barometric pressure and the inverse of the slope of the plot of mouth pressure vs. box pressure (!P/!V). Comparison of Methods Compared to the dilution and washout techniques, body plethysmography is, by far, the fastest method available for determining FRC. Indeed, it enables several determinations to be made per minute. Although the equipment required for body plethysmography is more expensive than that required for the other methods, in a busy laboratory this technique generally proves to be more economical because of the time saved and the additional uses to which the equipment can be put (e.g., measurement of airway resistance; see “Airway Resistance,” below). Technically, the test is only slightly more difficult than the inert gas dilution method. Sources of error inherent in the use of body plethysmography and discrepancies between results obtained by body plethysmography and the inert gas techniques should be noted. In patients with chronic obstructive pulmonary disease (COPD) and asthma, values for FRC obtained by body plethysmography may be artifactually high because of pressure differences between the mouth and alveoli generated during panting across narrowed airways. Consequently, pressures recorded at the mouth during shutter occlusion of the airway underestimate changes in alveolar pressure. The inert gas dilution and washout methods are similar both in principle and in results. The values for FRC with these techniques match those from the body plethysmograph except in persons in whom considerable areas of the lungs are poorly ventilated, usually due to obstructive airway disease. In these individuals, complete mixing or washout of the indicator gas is very slow, at times requiring 45 min or longer. Because of the slow equilibration of gas concentrations in the poorly ventilated areas, the usual time allotted for the test is inadequate, resulting in a lower value for FRC by the washout methods than by body plethysmography. One strategy commonly used to deal with this problem is to prolong the washout time. The primary advantage of these techniques over body plethysmography is that they can be used in persons for whom the plethysmograph is impractical (e.g., those with marked obesity, skeletal abnormalities, or claustrophobia).

Table 34-3 Factors for Converting Volumes from ATPS to BTPS at Barometric Pressure of 760 mmHg∗ Ambient Temperature, ◦ C

Multiplier to Convert Volumes to BTPS†

1.101

1.096

1.091

1.085

1.080

1.074

1.069

1.062

∗ Based

on Boyle’s, Charles’s, and Dalton’s laws. at ATPS × multiplier = volume at BTPS. Note: ATPS = ambient temperature and pressure, saturated with water vapor; BTPS = body temperature and pressure, saturated with water vapor. † Volume

from laboratories operating at different ambient temperatures and altitudes. To convert the volume of gas collected in a volume-type spirometer under ambient conditions (i.e., ambient temperature and pressure, saturated with water vapor, or ATPS) to BTPS, a conversion factor is applied (Table 34-3). Previously, it was presupposed that ambient air entering a spirometer was cooled immediately to ambient temperature and remained saturated with water vapor (ATPS). Under this assumption, only ambient temperature was considered in determining the appropriate correction factor. However, studies have addressed the assumption that expired gas is immediately cooled, as well as the practical consequences of temperature correction errors. The American Thoracic Society recommends temperature correction of results from volumetype spirometers based on measured gas temperature at the time of testing.

Radiographic Assessment of Lung Volume Temperature Correction Factors By convention, all lung volumes described above and airflows (see below) are expressed in terms of body temperature and pressure, saturated with water vapor (BTPS). This practice enables direct comparison of pulmonary function data

Although initial reports describing use of radiographic techniques to measure lung volumes date back over 40 years, these methods have not found widespread use in adult populations. More sophisticated computed tomography (CT) applications have demonstrated good correlation with plethysmographic and gas dilution techniques in normal individuals, but

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significant differences can arise in patients with a wide variety of lung diseases.

STATIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM Exploration of the elastic properties of the respiratory system and their effect on lung volumes and work of breathing began in earnest during the earlier part of the twentieth century. Although the groundwork had been laid centuries before (by Robert Hooke’s The Theory of Springs in 1678), between 1923 and 1956 investigators provided a wealth of information about the elastic properties of the respiratory system and its components and the work done in overcoming these elastic forces during breathing.

Static Compliance of the Lungs The elastic properties of the lungs are determined by relating the change in the volume of air contained in the lungs to the corresponding change in the recoil force of the lungs. Change in lung volume is most easily measured by determining the volume of gas inspired or expired at the mouth. Although expedient, this approach to determining the elastic properties of the lungs can underestimate the change in lung volume when incorporated into techniques (see below) that require the subject to expire gently against a closed shutter, a maneuver that compresses thoracic gas. However, the problem can be circumvented by placing the subject in a volume plethysmograph that uses a spirometer attached to the plethysmograph to record changes in thoracic gas volume due to gas compression. The recoil force of the lungs, measured as the transpulmonary pressure (Fig. 34-7), is the difference between the alveolar and pleural pressures (Pa and Ppl, respectively). Alveolar pressure is determined as the pressure at the airway opening (Pao)—i.e., the mouth—when airflow is arrested and the glottis is open. The pleural pressure is determined indirectly by measuring the pressure in the esophagus using an esophageal balloon catheter. This technique, first introduced in 1949, has been improved over the years and provides acPressure at the airway opening (Pawo) Pressure at the body surface (Pbs)

Transthoracic pressure (PA-Pbs)

Pleural pressure (Ppl)

Transpulmonary pressure (PA-Ppl)

Alveolar pressure (PA) Esophageal pressure (Pes)

Pressure difference across the chest wall (Ppl-Pbs)

Figure 34-7 Schematic representation of the chest depicting pressure terms and gradients used in analysis of the mechanics of breathing. The expressions for individual pressure measurements on the left are relative to atmospheric pressure. Pleural pressure (Ppl) is not routinely measured directly but is approximated by esophageal pressure (Pes) measured with a balloon catheter.

Pulmonary Function Testing

curate reflections of changes in pleural pressure at all lung volumes except those below FRC. A thin rubber balloon, about 10-cm long, is placed over a small-diameter polyethylene catheter. Several holes in the terminal portion of the catheter allow pressure to be transmitted from the balloon, through the catheter, to a transducer. The balloon is positioned in the lower third of the esophagus, where esophageal pressure and, therefore, balloon pressure accurately reflect the pressure acting on the lung surface (pleural pressure). Use of an elongated balloon of low volume helps to minimize changes in pressure due to esophageal contractions. By conveying mouth pressure and esophageal pressure to opposite sides of a differential pressure transducer, an output signal is generated that is proportional to the difference between these two pressures—i.e., the transpulmonary pressure Pa – Ppl. To determine the elastic properties of the lungs, the patient, with esophageal balloon in place, is seated in a closed body plethysmograph. The patient then breathes ambient air through a tube to the outside until the volume trace, inscribed by the plethysmograph spirometer, indicates that the endexpiratory level is stable. At this juncture, the patient is instructed to first inspire slowly to TLC and then to expire slowly to the resting end-expiratory level (FRC). This maneuver is then repeated; during the second expiration, the shutter is activated to occlude the airway intermittently. Since each closure of the shutter interrupts the expiration briefly, the recorded trace of expiratory volume vs. time displays a staircase pattern (Fig. 34-8A). The plateau resulting from each closure of the shutter marks a finite period of zero change in lung volume as the lungs empty during expiration. Associated with each plateau is a corresponding plateau in transpulmonary pressure. The relationship between the change in volume and the change in pressure is a measure of the recoil force of the lungs at each of the lung volumes that are registered (Fig. 348B). The resulting curve provides several useful indices of the elastic behavior of the lungs. The slope of the curve over the range corresponding to the tidal volume is the static lung compliance. The transpulmonary pressure attained at TLC is the maximal static recoil pressure. The ratio of the maximal static recoil pressure to the corresponding maximal lung volume is the coefficient of retraction. However, since these values are derived from only small segments of the curve, inspection of the total static pressure-volume curve remains the most comprehensive means of assessing the elastic properties of the lungs.

Static Compliance of the Chest Wall Functionally, the chest wall includes the bony thorax, intercostal muscles, overlying soft tissue, pleura, and diaphragm. The chest wall is distensible and has its own distinctive elastic properties. In the normal, end-expiratory, resting position of the respiratory system (FRC), the inward recoil of the lung is balanced by the outward recoil of the chest wall (Fig. 34-9B). As the volume of the thoracic cavity enlarges

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progressively during inspiration from FRC to TLC, the outward recoil pressure of the chest wall lessens, becoming zero at approximately 70 percent of TLC; beyond this point, the chest wall begins to recoil inwardly (Fig. 34-9C). Conversely, as the chest wall is compressed below FRC by the action of the expiratory muscles, the natural outward recoil tendency is increased (Fig. 34-9A). In practice, assessment of the elastic properties of the chest wall is accomplished by first determining the compliance curve of the respiratory system as a whole and then subtracting the contribution of the lungs. For a given lung volume, the pressure across the chest wall, Ppl – Pbs (Fig. 34-7), is simply the difference between the transthoracic (Pa – Pbs) and transpulmonary (Pa – Ppl) pressures. As indicated above, Ppl is determined using an esophageal balloon catheter.

Elastic Properties of the Respiratory System as a Whole

Figure 34-8 Measurement of the elastic properties of the lungs. A. Recordings of changes in lung volume and transpulmonary pressure (PA -Ppl) using the esophageal balloon technique described in the text. Simultaneous measurements of volume and pressure are obtained during periods of arrested airflow at lung volumes ranging from total lung capacity (TLC) to just below functional residual capacity (FRC). B. Thoracic gas volume is plotted on the ordinate and transpulmonary pressure on the abscissa. The curve formed by the plot using values from A describes the elastic properties of the lungs. The slope of the line, !V/!P, over the range of the tidal volume is the static compliance of the lungs.

The elasticity of the respiratory system as a whole is determined by measuring the change in volume resulting from a change in pressure applied to the system—i.e., the transthoracic pressure (Pa – Pbs)—while the respiratory muscles are completely relaxed. The first method used for this evaluation employed the relaxation technique described by Rahn and colleagues. The subject breathes quietly into an apparatus consisting of a spirometer, a shutter, and a pressure transducer connected to the subject’s side of the shutter (Fig. 34-10). After a period

Figure 34-9 Schematic depiction of elastic recoil vectors across the lung and chest wall as determined by the level of inflation. A. At residual volume (RV), the outwardly directed recoil pressure of the chest wall is large and the inwardly directed recoil pressure of the lung is small. B. At functional residual capacity (FRC), the recoil pressures of the lung and chest wall are equal and in opposite directions. C. At total lung capacity (TLC), both recoil pressures are directed inward, and each contributes substantially to the overall recoil pressure of the respiratory system.

Figure 34-10 Relaxation technique for measurement of elastic recoil pressure of the respiratory system. After a period of normal tidal volume breathing, the subject inspires to total lung capacity (TLC). A shutter in the airway is closed, and the subject relaxes his or her respiratory muscles. The shutter is periodically opened, permitting exhalation of a small volume of air measured by the spirometer. Airway pressures are recorded at times of shutter closure (i.e., during no airflow, when mouth pressure equals alveolar pressure). A pressure-volume curve is then constructed from the simultaneously recorded values for pressure and volume.

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of quiet breathing, the subject is instructed to inspire maximally; the shutter is closed at peak inspiration, and the subject is then asked to relax the respiratory muscles completely while keeping the glottis open. Periodically, the shutter is opened, allowing a small volume of air to move from the subject into the spirometer; the shutter is then closed again. This maneuver is repeated until FRC is reached. During the periods of arrested airflow, pressure at the mouth (Pao) is equal to the pressure in the alveoli (Pa). Provided the pressure at the body surface is atmospheric and the respiratory muscles are completely at rest, this value represents transthoracic pressure. In practice, however, full relaxation of the respiratory muscles is difficult, and a contribution by them to the pressure at the airway opening is frequently unavoidable. A more practical technique entails the application of continuous positive pressure to the airways during spontaneous breathing. The subject breathes quietly into a watersealed spirometer until a constant end-tidal level is achieved. A weight is then placed on the spirometer bell to increase the pressure in the respiratory system and, thereby, to raise the resting end-expiratory lung volume. This procedure is repeated using several different weights so that a pressurevolume curve of the total respiratory system can be constructed. The individual pressure-volume curves for the lungs and chest wall and the composite curve for the intact respiratory system are shown in Fig. 34-11. As illustrated, the elastic recoil of the chest wall alone is determined by subtracting the recoil pressure of the lung from that of the total respiratory system. Chest wall elasticity is an important determinant of the subdivisions of lung volume and the overall compliance

Figure 34-11 The pressure-volume curves of the respiratory system and its components. The elastic recoil pressures of the total respiratory system (solid line) over the vital capacity range are the sum of the recoil pressures of the lung (dashed line) and chest wall (dotted line). At functional residual capacity (FRC), the chest wall recoil pressure is counterbalanced by the lung recoil pressure. The net result is a total system recoil pressure of 0. The total system recoil pressure is obtained by relaxation pressure or continuous positive-pressure breathing techniques. The chest wall recoil pressure is calculated as the difference between the recoil pressure of the entire respiratory system and the recoil pressure of the lungs.

Pulmonary Function Testing

of the respiratory system; the latter is, in turn, an important determinant of the work of breathing. Several features of the pressure-volume relationships shown in Fig. 34-11 are worth emphasizing. As lung volume approaches RV, the elastic recoil pressure of the respiratory system is largely due to the outwardly directed recoil pressure of the chest wall. At RV, the contribution of the lung to the recoil pressure of the respiratory system is minimal. At the other extreme of lung volume, TLC, elastic recoil pressure is high and directed inwardly, due to the combined elastic recoils of the lung and chest wall. At FRC, the outwardly directed recoil of the chest wall balances the inwardly directed recoil of the lung, and the transthoracic pressure is zero (i.e., Pa â&#x2C6;&#x2019; Pbs = 0). Indeed, the system â&#x20AC;&#x153;comes to restâ&#x20AC;? at FRC because of the counterbalancing of these forces at that volume. Since alveolar pressure at FRC is zero, no pressure gradient exists for airflow. Therefore, the system remains stationary until acted upon by the muscles of inspiration or expiration.

Elastic Properties of the Respiratory System in Health and Disease The elastic properties of the respiratory system are altered by a wide variety of diseases that can affect the lung parenchyma or chest wall, either selectively or in concert. Most instances of clinically significant reductions in static compliance are due to abnormalities in the lung. The two standard clinical measures of the elastic properties of the lung are static lung compliance and maximal static recoil pressure. Static lung compliance (Cst,L) is determined over the linear portion of the pressure-volume curve, between FRC and a lung volume corresponding to FRC plus 0.5 L. Normal values vary among laboratories, ranging from 0.147 to 0.375 L/cm H2 O, with a mean of 0.262 L/cm H2 O. Some variability is related to age and sex; Cst,L decreases with age and is higher in males than in females. Maximal static recoil pressure is the recoil pressure at TLC. Once again, normal values vary. Data from one series of 51 normal subjects are shown in Table 34-4. In disease states characterized by an increased elastic recoil pressure, such as diffuse interstitial fibrosis, the pressurevolume curve is shifted to the right and the static lung compliance decreases (Fig. 34-12A and B). The increased elastic recoil pressure contributes to a decrease in FRC and TLC. By expressing the volume axis of the pressure-volume curve in terms of percent predicted TLC (Fig. 34-12B), instead of absolute TLC (Fig. 34-12A), the reduction in maximal lung volume is clearly evident (i.e., maximal recoil pressure is increased, despite the reduced TLC). In contrast to the effects of fibrosis, emphysema, which destroys alveolar walls and enlarges alveolar spaces, reduces lung elastic recoil pressure (Pel). This change increases both TLC and FRC. The shift of the pressure-volume curve upward and to the left (Fig. 34-12A and B) indicates that lung compliance increases and that the maximal recoil pressure decreases. If the volume axis is expressed as percent predicted

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Table 34-4 Normal Maximal Static Recoil Pressures for Adults (cm H2 O) Male Age (Years)

Female Age (Years)

25–35

36–64

65–75

25–35

36–64

65–75

Mean ± SD

35.9 ± 8.5

33.0 ± 8.7

33.0 ± 2.9

36.4 ± 5.8

25.7 ± 4.0

23.7 ± 3.9

Range

24.0−48.0

21.5−48.0

17.0−42.2

21.0−48.0

20.0−30.0

18.0−31.6

Source: Data from Knudson RJ, Clark DF, Kennedy TC, et al: Effect of aging alone on mechanical properties of the normal adult human lung. J Appl Physiol 43:1054–1062, 1977.

TLC (Fig. 34-12B), the increase in lung volume is more clearly demonstrated. As noted previously, disorders affecting primarily the chest wall can also significantly alter the elastic properties of the respiratory system. Among these are obesity, kyphoscoliosis, and fibrothorax. These disorders limit chest wall excursion and lung expansion and reduce FRC. In addition, they produce decreases in static compliance of the lung and chest wall and maximal recoil pressure.

Respiratory Muscle Strength Ventilatory performance depends not only on the mechanical properties of the lungs and chest wall, but also on the strength of the respiratory muscles. Evaluation of respiratory muscle strength was undertaken as early as the midnineteenth century. Subsequently, using simplified methods of measurement, Black and Hyatt established normal values (Table 34-5).

The maximal pressure generated by an isometric contraction varies directly with the resting length of the muscle. Consequently, values for maximal inspiratory and expiratory pressures depend on the lung volume at which the tests are performed (Fig. 34-13). When TLC is less than 70 percent of the predicted value, the maximal expiratory pressure will be low. Similarly, when RV exceeds 40 percent of the predicted TLC, the maximal inspiratory pressure will be low. The only equipment required for measurement of maximal inspiratory or expiratory pressure is an aneroid vacuum and pressure gauge. To determine maximal expiratory pressure, the patient is urged to inspire fully to TLC and then to expire as forcefully as possible into the gauge. The highest pressure attained and held for at least 1 s is the maximal expiratory pressure (Pemax ). The maximal inspiratory pressure (Pimax ) is determined by having the patient inspire maximally from the gauge after having expired completely to RV. The value recorded is the lowest pressure attained and held for at least 1 s.

Figure 34-12 Pressure-volume curves of the lungs in health and disease. A. Volume expressed as percent of actual total lung capacity (TLC). Differences in transpulmonary pressures in normal and diseases states are evident. Changes in lung volume that occur with disease are demonstrated on the plots. B. Volume expressed as percent of predicted TLC. In addition to the differences in transpulmonary pressures, alterations in lung volumes in the disease states are evident.

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Table 34-5 Prediction Equations and Lower Limits of Normal for Maximal Inspiratory (Pimax ) and Maximal Expiratory (PEmax ) Pressures (cm H2 O)∗ P imax

Pemax

Predicted Mean (cm H2 O)

Lower Limit of Normal

Predicted Mean (cm H2 O)

Lower Limit of Normal†

Male

143 − (0.55 × age)

268 − (1.03 × age)

111

Female

104 − (0.51 × age)

170 − (0.53 × age)

∗ Age

range = 20 to 86 years. of age. Source: Equations and lower limits of normal from Black LF, Hyatt RE: Maximal respiratory pressures: Normal values and relationship to age and sex. Am Rev Respir Dis 99:696–702, 1969. † Independent

Measurement of maximal static respiratory pressures is particularly important in evaluating respiratory muscle weakness in patients with neuromuscular disease, as described in Chapter 93. In such patients, spirometric tests are often normal, despite respiratory muscle weakness, because maximal pressures are not required to achieve maximal expiratory flow rates. Another useful function of these measurements is in examining patients whose coordination in performing spirometry or whose degree of motivation is suspect. In such patients, determination of maximal pressures is often helpful in determining whether optimal efforts are being expended during pulmonary function testing (see “Approach to Interpreting Commonly Performed Pulmonary Function Tests,” below).

DYNAMIC MECHANICAL PROPERTIES OF THE RESPIRATORY SYSTEM The static tests of pulmonary function described in the previous section are based on measurements of volume and pressure made while airflow is arrested. These static tests are particularly useful in defining the elastic properties of the respiratory system. Considerable additional information can be gained from tests done during airflow (i.e., under “dynamic” conditions). Although measurements of static lung volumes began about 300 years ago, the assessment of pulmonary function during airflow began in 1933, when the test now known as the maximal voluntary ventilation was first proposed. This test did not become popular until a few years later, when Cournand and Richards developed regression equations to determine normal values. Subsequently, investigators proposed that the volume of air expired during specific time intervals be determined. In 1955, determination of the average airflow during the middle half of a forced expiratory vital capacity was described. Determination of these indices of dynamic lung function is now generally part of the battery of tests, both static and dynamic, included under the designation spirometry. The more practical tests of dynamic function can, for convenience, be divided into four categories: forced vital capacity, flow-volume curves, maximal voluntary ventilation, and airway resistance. Other dynamic tests, including assessment of airway reactivity and the function of small airways, will be considered separately.

Forced Vital Capacity Figure 34-13 Effect of lung volume on maximal inspiratory (dashed line) and maximal expiratory (solid line) pressures. See text for discussion.

Both expiratory and inspiratory measurements of the forced vital capacity are routinely made in pulmonary function laboratories. Unless otherwise specified, FVC refers to the forced expiratory maneuver.

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Forced Expiratory Vital Capacity The forced expiratory vital capacity is measured during expiration. The maneuver entails two steps: a full inspiration to TLC, followed by a rapid, forceful, maximal expiration (to RV) into a spirometer. The forced expiratory vital capacity (FVC) is normally equal to the relaxed or slow vital capacity (VC). However, a discrepancy between FVC and VC appears in obstructive disease of the airways: the FVC is less than the VC. The relationship between expired volume and time during an FVC maneuver is used to determine airflow during expiration and the volume of air expired within designated intervals; these values provide an indirect measure of the flowresistive properties of the lung. The FVC is displayed in one of two ways: expired volume plotted against time (Fig. 34-14) or airflow plotted against lung volume—i.e., an expiratory “flow-volume curve” (see below). The normal volume-time display of the FVC consists of a smooth curve with a gradually and progressively decreasing slope. Irregularities in the curve suggest either a failure of coordination or a suboptimal effort. At times, the onset of the forced expiration is unclear (Fig. 34-15) because of hesitation on the part of the patient. When this occurs, the start of expiration (“zero time”) is determined with the “back extrapolation” method (Fig. 34-15): a tangent taken through the part of the curve with the steepest slope is extrapolated back to the maximal inspiratory volume; the point of intersection is considered to be the time of onset of expiration. Several values are commonly determined from the volume-time plot of the forced vital capacity (Table 34-6, Fig. 34-14): (1) the volume expired in the first second, expressed either as an absolute volume (FEV1 ) or as a percentage of the forced vital capacity (FEV1 /FVC%); (2) the volume expired in the first 3 seconds,

Figure 34-15 Technique of back extrapolation for determining the zero time in calculation of FEV1 . Zero time is determined as the point of intersection of a tangent drawn through the steepest portion of the spirogram and a line drawn horizontally through the maximal inspiratory level.

expressed either as an absolute volume (FEV3 ) or as a percentage of the forced vital capacity (FEV3 /FVC%); and (3) the forced mid-expiratory flow rate (FEF25−75% ). The FEF25−75% is determined by locating the points on the volume-time curve corresponding to 25 and 75 percent of the FVC and then calculating the slope of a straight line passing through those two points. The slope of this line represents the average airflow over the mid-portion of the FVC. Although the relaxed or slow vital capacity (VC) may be normal or only modestly reduced in patients with obstructive disease of the airways, the volume-time relationship of the FVC maneuver is usually distinctly abnormal in such

Table 34-6 Values Obtained from Forced Expiratory Volume-Time Curves

Figure 34-14 Forced expiratory vital capacity maneuver. After an initial period of tidal volume breathing, the patient inspires maximally to total lung capacity (TLC) and then exhales as rapidly and as forcefully as possible into a spirometer. Shown on the left of the tracing are a series of tidal volume breaths and the maximal inspiration to TLC. The forced expiration begins at time 0. Nearly all the volume is exhaled in the first 3 s of the maneuver. The values for FVC, FEV1 , and FEV3 are measured from the maximal inspiratory level. The FEF25−75% is the slope of the line connecting the points on the volume-time trace that correspond to 25 percent and 75 percent of the FVC.

FVC (BTPS), L

Forced vital capacity; the total volume expired

FEV1 (BTPS), L

Volume of air expired in the first second

FEV1 /FVC%

Volume of air expired in the first second, expressed as percent of the FVC

FEV3 /FVC%

Volume of air expired in the first 3 s, expressed as percent of the FVC

FEF25−75% (BTPS), L/s

Forced mid-expiratory airflow

Note: BTPS = body temperature and pressure, saturated with water vapor.

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Figure 34-16 Representative spirograms from a normal subject (A), a patient with obstructive lung disease (B), and a patient with restrictive lung disease (C), obtained during a forced expiratory vital capacity maneuver. In the normal subject, expiration is completed within 3 s, and 83 percent of the volume is expired in the first second (FEV1 /FVC% = 83). In the patient with obstructive disease, expiration is prolonged, and only half the volume is expired in the first second (FEV1 /FVC% = 50). In the patient with restrictive disease, although the magnitude of the reduction in exhaled volume is the same as in the obstructed patient, most of the volume is exhaled within the first second (FEV1 /FVC% = 90).

patients (Fig. 34-16A and B). Most obvious is a flattening of the slope of the curve at any given lung volume, reflecting the reduced airflow. In addition, the duration of the forced expiratory maneuver is prolonged. Normally, expiration is complete within 6 s; in obstructive airway disease, expiratory airflow may continue for 10 to 12 s. These changes in the expiratory airflow reduce the FEV1 and FEV3 , the FEV1 /FVC%, the FEV3 /FVC%, and the FEF25−75% . Restrictive lung disorders reduce the slow VC. However, the configuration of the volume-time relationship may not be abnormal (Fig. 34-16C). Although the FEV1 and FEV3 are reduced because of the reduced vital capacity, the FEV1 /FVC% and FEV3 /FVC% remain normal or even exceed normal values. Often, because of the reduced VC, the FEF25−75% is also less than predicted.

Pulmonary Function Testing

Figure 34-17 Forced inspiratory volume-time curve. The FIF25−75% is the slope of a line between the points on the trace corresponding to 25 percent and 75 percent of the inspired volume.

Flow-Volume Relationships In addition to analysis of the relationship between volume and time depicted on a spirogram, examination of the relationship between flow and volume provides useful information about lung function. A flow-volume curve, which shows the relationship between lung volume and maximal airflow as lung volume changes during a forced expiration, is shown in Fig. 34-18. The test comprises four phases of breathing into a

Forced Inspiratory Vital Capacity Measurement of the forced inspiratory vital capacity (FIVC) consists of two steps: (1) full expiration to RV, followed by (2) a rapid maximal inspiratory effort (Fig. 34-17). The rate of airflow over the middle half of the forced inspiratory vital capacity (FIF25−75% ) is determined using a procedure similar to that described previously for the FEF25−75% . In normal subjects, the FIF25−75% is greater than the FEF25−75% . Since inspiratory flow is more dependent on effort than is expiratory flow, a fall in the FIF25−75% is usually a more sensitive indicator of respiratory muscle dysfunction or a suboptimal effort than is the FEF25−75% . When airway resistance is high, a disproportionate fall in FIF25−75% relative to FEF25−75% suggests an extrathoracic site of airway obstruction (see “Approach to Interpreting Commonly Performed Pulmonary Function Tests,” below).

Figure 34-18 Flow-volume plots during forced expiration (outer trace) and quiet expiration (inner trace). A. The subdivisions of lung volume. B. The common flow measurements. PEFR = peak expiratory flow rate; V˙ max 75% , V˙ max 50% , and V˙ max 25% = flows at 75, 50, and 25 percent of the vital capacity, respectively.

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Figure 34-19 Comparison of the flow-expired volume curve (solid line) with a simultaneously recorded flow-thoracic gas volume curve (dashed line). The difference between the two curves results from the compression of gas in the lungs during a forced expiration.

spirometer: (1) tidal breathing for several breaths, (2) a maximal inspiratory effort to TLC, followed by (3) a maximal expiration to RV done as forcefully and quickly as possible, and (4) another maximal inspiratory effort to TLC. Volume is displayed on the horizontal axis and airflow on the vertical axis. Airflow is measured at the mouth using a pneumotachograph; volume is measured either by integrating the pneumotachographic record during expiration or as a change in thoracic gas volume, determined by a pressure-corrected flow plethysmograph. The records obtained by the two techniques for determining volume differ because the body plethysmograph senses compression of intrathoracic gas during a forced expiration, whereas measurements of volume made at the mouth do not (Fig. 34-19). Differences between curves obtained with the two techniques for measuring volume are most marked in patients with airway obstruction in whom considerable gas compression occurs during a forced expiration. For the sake of comparison, tracings of flow vs. volume and volume vs. time, recorded during the same forced vital capacity maneuver and aligned by using a common volume axis as the abscissa, are shown in Fig. 34-20. Selected measurements are more evident in one tracing or the other (e.g., maximal expiratory flow in the flow-volume curve and FEV1 in the volume-time curve). Comparison of serial curves from a single person or curves from different subjects requires that the curves be aligned on the volume (horizontal) axis so that points of maximal inspiration or maximal expiration coincide. As may be seen in Fig. 34-21A, which illustrates typical curves from a normal subject and two patients, one with pulmonary fibrosis and the other with obstructive airway disease, the information provided by this form of representation is limited (i.e., the vital capacities and airflows from the patients are abnormally low). The limitation stems from the fact that the change in volume during expiration is shown relative to the maximal inspiratory level rather than to an absolute volume of gas in the lungs (i.e., RV or TLC). When RV or TLC is known so that absolute volumes can be plotted on the horizontal axis (Fig. 34-21B), additional insight is gained into the flow-volume relationship depicted in Fig. 34-21A. The patient

Figure 34-20 Flow-volume and volume-time curves depicting the same forced expiration aligned along a common volume axis (abscissa). Points corresponding to the FEV1 , FVC, and FEF50% obtained from the volume-time plot are shown on the flow-volume curve.

Figure 34-21 Airflow at different lung volumes. A. Flow-volume curves aligned at total lung capacity (TLC). B. Flow-volume curves displayed relative to thoracic gas volume. Although the curves aligned at TLC (A) show striking differences in the pattern of airflow, they provide no insight into the relationship between lung volumes and airflow. See text for discussion.

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pulmonary parenchymal diseases, other tests are required to pinpoint specific disorders. The difference between the MVV and the resting minute ventilation is the breathing reserve. At one time, a low breathing reserve was correlated with the breathlessness in lung diseases. However, this determination is now primarily of historical interest.

Respiratory Resistance Total respiratory resistance (Rrs) is the resistance to airflow and chest expansion offered by the airways (Raw), chest wall (Rw), and lung tissue (Rti): Figure 34-22 Maximal voluntary ventilation (MVV). After a period of relaxed breathing, the subject breathes rapidly and as forcefully as possible. The total volume of air inspired over 12 s and expressed in L/min is the MVV.

with obstructive disease of the airways manifests a reduction in expiratory airflow at elevated lung volumes, which should enhance airflow. In contrast, the reduced rate of airflow in the patient with pulmonary fibrosis is normal, or even supranormal, when the lung volume at which the airflow occurs is taken into account (i.e., the reduced airflow is primarily a function of the reduced lung volume, rather than of airway obstruction).

Maximal Voluntary Ventilation The previous considerations of dynamic lung function focus on a single timed maximal expiratory or inspiratory maneuver. In contrast, the maximal voluntary ventilation (MVV) depends on the movement of air into and out of the lungs during continued maximal effort throughout a preset interval (Fig. 34-22). The MVV is a simple, informative test that provides an overall assessment of effort, coordination, and the elastic and flow-resistive properties of the respiratory system. In performing the test, the patient is urged to breathe as hard and as fast as possible. As a rule, the patient automatically adjusts frequency and tidal volume for optimal performance. However, extremes of frequency or tidal volume are to be avoided, since neither panting nor slow deep breathing leads to the highest possible values. The total volume that is expired during a 12-s interval, expressed in liters per minute (BTPS), is the maximal voluntary ventilation. In some patients the test cannot be done because of an inability to continue the necessary effort for 12 s. A normal value for MVV indicates that the overall integrated performance of the respiratory system is intact, thereby excluding moderate to severe restrictive or obstructive disease. In addition, a normal value suggests that the elastic and flow-resistive properties of the respiratory system, respiratory muscle strength, coordination of respiratory performance, and motivation of the patient are all normal. Although this test is very useful in detecting overall disturbances in integrated performance and diffuse tracheobronchial and

Rrs = Raw + Rw + Rti Although the overall resistance of the respiratory system can be determined with a technique employing forced oscillation, this approach has, to date, exhibited limited practical usefulness. In addition, further methodologic refinements permitting determination of pulmonary resistance—the sum of airway and tissue resistances (Raw + Rti)—have not proved to be worthwhile clinically, particularly since measurement of transpulmonary pressure with an esophageal balloon is necessary. Other variations of the determination of resistance measurements have also been explored. However, the only clinically useful measurement of resistance is airway resistance, which is now routinely determined in pulmonary function laboratories. Airway Resistance Airway resistance (Raw) is defined as the ratio of the driving ˙ along pressure (P) for flow to the actual rate of airflow (V) the airways (i.e., the mouth, nasopharynx, larynx, and central and peripheral airways): Raw =

!P V˙

where !P, the drop in pressure over the entire length of the airways, is determined as the difference between alveolar pressure (Pa) and pressure at the mouth (Pm) or airway opening (Pao). Although airflow and pressure at the airway opening are easily measured, the difficulty in measuring alveolar pressure prevented the routine determination of airway resistance until DuBois and colleagues introduced the plethysmographic technique in 1956. With this technique, the patient, seated in the body plethysmograph, pants at a rate of about two breaths per second while airflow is measured using a pneumotachograph. During inspiration and expiration, gas in the alveoli is alternately rarefied and compressed, causing changes in pressure within the sealed plethysmograph. The relationship between plethysmograph pressure and airflow during the panting maneuver is displayed on the X and Y axes of an oscilloscope (Fig. 34-23). While the panting continues, a shutter at the airway opening is closed so that airflow is transiently interrupted.

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˙ vs. body plethysmograph presFigure 34-23 Plot of airflow (V) sure (Pbx). The slope of this curve, in the range of 0 to 0.5 L/s of inspiratory flow, divided into the slope of the loop obtained when the shutter is closed (see Fig. 34-7) provides a measure of airway resistance (Raw).

Using the technique employed in the determination of FRC, changes in pressure in the plethysmograph (equivalent to changes in lung volume) and at the mouth are displayed on the X and Y axes, respectively, of the oscilloscope (Fig. 34-6). However, since airflow is zero while the shutter is closed, the pressure at the mouth equals alveolar pressure (Pao = Pa). Panting while the shutter is open allows the determina˙ and plethysmotion of the relationship between airflow (V) ˙ graph pressure (Pbx)—i.e., V/Pbx. Similarly, panting against a closed shutter enables the determination of the relationship between alveolar pressure (Pa) and plethysmograph pressure—i.e., Pa/Pbx. Airway resistance is calculated by dividing the slope of the loop obtained by plotting Pa vs. Pbx while the shutter is closed by the slope obtained by plotting V˙ vs. Pbx while the shutter is open: Raw =

Pa/Pbx Pa = ˙V/Pbx V˙

where Raw = airway resistance, cm H2 O/L/s Pa = alveolar pressure, cm H2 O V˙ = airflow, L/s Raw is measured during a panting maneuver for several reasons: (1) The rapid respiratory frequency in panting circumvents the poor low-frequency response characteristics of many plethysmographs. (2) The small inspired and expired volumes, which minimize temperature fluctuations in the plethysmograph that would otherwise occur as tidal breaths of air at body temperature, are exchanged with breaths of air at room temperature. (3) During panting, the glottis remains open, thereby minimizing its contribution to overall airway resistance. Use of plethysmographs linked to microprocessors that automatically correct for temperature-related volume differences has made possible the determination of airway resistance during quiet breathing instead of during panting.

Figure 34-24 The relationship between airway resistance (A) and airway conductance (B). The shaded area represents the predicted normal range. Values are shown for an asthmatic patient before (dashed line) and after (dotted line) bronchodilator therapy. Airway resistance increases as lung volume decreases. Conversely, airway conductance, the inverse of resistance, decreases as lung volume decreases.

Airway resistance varies inversely with lung volume: it is low at large lung volumes and increases curvilinearly as lung volume and, consequently, airway diameters are reduced (Fig. 34-24A). In contrast, the inverse of airway resistance, airway conductance, is linearly related to lung volume (Fig. 34-24B). Interpretation of a given value for airway resistance or airway conductance requires that the lung volume at which the measurement is made be taken into account. Specific conductance (SGaw) is calculated by dividing airway conductance by the lung volume.

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Table 34-7 Categorization of Increased Airway Resistance (Raw) Category Mild

Pulmonary Function Testing

Raw (cm H2 O/L/s) 2.8–4.5

Moderate

4.54–8.0

Severe

>8.0

Source: Modified from Ries A and Clausen JT, in Wilson AF (ed), Pulmonary Function Testing: Indications and Interpretations, Orlando, FL, Grune and Stratton, 1985.

Defining the range of normal for Raw is difficult because of the lack of data obtained from populations sorted into smoking and nonsmoking groups and because of the inter- and intraindividual variations of Raw with lung volume. One classification scheme proposed for defining normal and abnormal Raw in adults in whom FRC exceeds 2 L is given in Table 34-7. At times, an apparent discrepancy occurs between forced expiratory flow rates and values for airway resistance. For example, although the FEV1 and FEF25−75% may be abnormally low (suggesting some degree of airway obstruction), Raw may be within normal limits (arguing against appreciable airway obstruction). This apparent contradiction arises because Raw is determined during inspiration, when airways are enlarged because of surrounding negative pleural pressure, whereas FEV1 and FEF25−75% are determined during a forceful expiration, when airways are compressed by high positive pleural pressures. Therefore, the discrepancy is simply a manifestation of dynamic airway obstruction in which the narrowing is confined to expiration.

Measurement of Exhaled Nitric Oxide Over the last two decades, the important role of nitric oxide (NO) in a variety of biologic processes has been described. The concept that NO is a marker of airway inflammation, and, hence, has a potential role as a measure of airway function in the setting of inflammatory airway diseases, has been investigated. Studies have demonstrated that, at least in asthma, levels of exhaled NO are elevated during exacerbations (when other measures of airway inflammation show activity), even in the absence of symptoms or changes in spirometry. Levels of NO decrease with inhaled corticosteroid use and rise with corticosteroid tapering. Some advocate measurement of exhaled NO as part of routine chronic asthma management. Standards have been developed for measuring exhaled NO levels. While exhaled NO measurement has not yet assumed the status of a “standard” pulmonary function test, pulmonary function laboratories will likely soon add the test to their repertoires.

The dynamic tests of airway function described previously are designed to determine intrinsic properties of the airways in a subject breathing room air at rest. In many clinical situations, such as evaluation of chronic cough, assessment of airway hyperresponsiveness is desirable. This section reviews bronchoprovocation testing (BPT), which assesses reactivity of the airways to selected pharmacologic or environmental agents.

Background One test of bronchial reactivity that has been incorporated into routine pulmonary function testing is determination of the effect on airflow of administration of a nebulized bronchodilator agent. However, BPTs are designed to quantify the degree of bronchoconstriction following the application of a particular stimulus. A number of tests of bronchial reactivity are currently in clinical use (Table 34-8). Among the agents

Table 34-8 Tests of Bronchial Reactivity Test

Reference

Inhalational challenges Pharmacologic agents Methacholine Chai et al: J Allergy Clin Immunol 56:323–327, 1975 Histamine Chai et al: J Allergy Clin Immunol 56:323–327, 1975 Carbocholine Orehek et al: Br Med J 1:123–125, 1975 Specific antigens Toluene diisocyanate Bacillus subtilis Pollen Molds House dust

Salvaggio: J Allergy Clin Immunol 64:646–649, 1979 Salvaggio: J Allergy Clin Immunol 64:646–649, 1979 Spector: J Allergy Clin Immunol 64:580–586, 1979 Spector: J Allergy Clin Immunol 64:580–586, 1979 Spector: J Allergy Clin Immunol 64:580–586, 1979

Exercise-induced asthma Cold-air challenge Strauss et al: N Engl J Med 297:743–747, 1977 Dry-air challenge Hahn et al: Am Rev Respir Dis 130:575–579, 1984 Isocapnic Eschenbacher et al: Am Rev hyperventilation Respir Dis 131:894–901, 1985

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used for inhalation challenges are methacholine, histamine, carbocholine, and specific antigens chosen in accord with the patient’s history. In addition to the inhalation challenge tests in which pharmacologic agents are used, tests of bronchial reactivity may be based on inhalation of cold or dry air, isocapnic hyperventilation, or exercise.

Indications for Bronchoprovocation Testing The principal indication for BPT is a history suggestive of bronchospasm induced by an environmental or occupational agent, generally in the setting of normal pulmonary function tests (including determination of airflow before and after administration of an inhaled bronchodilator). For example, comparison of FEV1 before and after administration of a pharmacologic agent such as methacholine or histamine can be useful in establishing the diagnosis of asthma. Also, inhalation of a suspected specific antigen may be useful in uncovering asthma when skin tests are equivocal, or in proving that asthma is occupation-related. In some instances, exercise testing may disclose airway hyperreactivity in persons who are free of bronchoconstriction while at rest. Airway hyperresponsiveness to methacholine may presage an accelerated decline in pulmonary function. However, the impact of therapy with agents like inhaled bronchodilators or corticosteroids in preventing progression is unclear.

Methods of Bronchoprovocation Testing Several methods of BPT are in general clinical use. These include methacholine challenge, exercise challenge, and antigen challenge, each of which is described briefly below. Inhalation Challenge: Methacholine Inhalation challenge using methacholine has become popular because of standardization of the technique, ease and safety of performing the test, and high sensitivity of the test in detecting asthma. Methacholine is a synthetic cholinergic agent that evokes airway smooth-muscle constriction. Because baseline pulmonary function and breathing pattern influence the site of deposition of the inhaled methacholine particles and, thereby, the response, a standard method for aerosolizing the agent is used to ensure reproducible results. One method in common use is that of intermittent aerosol generation. Standardization entails the delivery of a 0.6-s pulse of airflow at 20 lb/in2 to a nebulizer, which, in turn, discharges particles that range from 0.3 to 4 µm in diameter into the airways. Methacholine for delivery by aerosol is prepared in concentrations ranging from 0.1 to 25 mg/ml using bicarbonate-buffered isotonic saline (containing 0.4 percent phenol) as the diluent. The cumulative dose delivered is expressed in inhalation units. One inhalation unit is equivalent to the single inhalation of a solution containing 1 mg of methacholine per milliliter (Table 34-9). At the outset, the patient is challenged with five inhalations containing only aerosolized diluent. The necessity of the diluent step has been recently questioned. In addition to

Table 34-9 Concentrations and Cumulative Doses of Methacholine Employed in the Methacholine Challenge Test Methacholine Concentration (mg/ml)

Cumulative Dose (Inhalation Units)∗

0.1

0.5

1.0

2.0

5.0

10.0

25.0

218

∗ After five inhalations of a nebulized solution containing methacholine in a

concentration of 1 mg/ml.

adding time and expense, it may force a greater absolute drop in FEV1 needed to prove bronchial hyperreactivity. A fall in FEV1 below 90 percent of the baseline value (i.e., the prechallenge control FEV1 ) establishes that the airways are hyperreactive, and therefore, the test is terminated. However, if the FEV1 does not fall below 90 percent of the control value, increasing concentrations of methacholine are given in stepwise increments of five-breath inhalations. The breaths are taken slowly from FRC to TLC. Then, 1 to 1.5 min after each dose, an FVC maneuver is performed. The interval between each increase in concentration is kept to a minimum because the response is judged in terms of the cumulative dose. However, the deep inspiration that immediately precedes the expiratory portion of the FVC maneuver may decrease bronchomotor tone in airways narrowed by methacholine. This effect lasts up to 6 min, thus limiting the shortest acceptable interval between dosage steps. If the postchallenge FEV1 falls below 80 percent of the control FEV1 , or if the patient experiences cough or chest tightness at any step, the test is stopped. The magnitude of the bronchoconstrictor response to inhalational challenge is related to the control FEV1 . A lower baseline FEV1 (even in the normal range) correlates with increased bronchial reactivity. Additional measurements of dynamic airway function (e.g., specific conductance) may provide supplemental data but also prolong the study. Another dosing option in use is the 2-min tidal breathing protocol. This protocol typically yields results similar to the one previously described. The results are plotted on four-cycle semilog graph paper: the number of cumulative inhalation units, expressed logarithmically, against the FEV1 , as percent of control

587 Chapter 34

FEVl, % CONTROL

NORMAL

PD20

ABNORMAL

CUMULATIVE INHALATION UNITS

Figure 34-25 Plot of FEV1 , percent control vs. cumulative dose of methacholine administered by inhalation (logarithmic scale), to a normal subject and a subject with hyperreactive airways. The PD20 is the cumulative dose, which results in a 20 percent drop in the FEV1 from the baseline measurement (after inhalation of diluent alone). In the subject with normal airway reactivity, the maximal cumulative dose of methacholine administered fails to elicit a 20 percent drop in FEV1 .

(Fig. 34-25). A curve is constructed through the points; the dose corresponding to the point at which the FEV1 is 80 percent of the control FEV1 is designated as the provocation dose, or PD20 FEV1 . Exercise Challenge Persons without a history of asthma who develop cough, wheezing, or dyspnea after exercise may have exerciseinduced bronchospasm (EIB). In these individuals, an exercise test may prove useful in establishing the diagnosis. Such exercise testing in asthmatics can be useful to assess the degree of impairment during exercise, or the impact of therapies. Several factors that may influence the outcome of the test should be kept in mind. The temperature and humidity of the laboratory should be tightly controlled. Some centers use dry air inhalation during exercise. In addition, the duration of the test needs to be monitored. The goal of testing for EIB is to produce at least 4 min of exercise at the target heart rate and ventilation. Exercise should not continue for more than 6 to 8 min, in order to avoid â&#x20AC;&#x153;run-throughâ&#x20AC;? of the bronchospasm (i.e., reversal at the end of the test). The type of exercise also influences the outcome. As a rule, the more intense the exercise, the more likely is bronchoconstriction to occur. Free-range running provides the most potent stimulus for bronchoconstriction, followed by treadmill running, bicycle ergometry, swimming, and walking. An asthmatic may swim comfortably at a level of exercise that is incapacitating on the treadmill. The motor-driven treadmill or electromagnetically braked cycle ergometer are the preferred modes of exercise for formal testing. The FEV1 is the most useful measurement made during testing for EIB. Measurements are made just before and immediately after the exercise and at 5-min intervals for the

Pulmonary Function Testing

following 30 min. A decrease in FEV1 of 10 percent or more below the pre-exercise value constitutes a positive test. Some have suggested that a decrement of 15 percent is of greater diagnostic value. False- positive responses can occur in patients with vocal cord dysfunction or abnormal posterior arytenoid motion. Inhalation Challenge: Antigen Compared with the relatively safe methacholine challenge test, BPT using a specific antigen is unpredictable and potentially hazardous. Since establishing the minimum dose required to induce bronchoconstriction is difficult, too much of the antigen may be given. A late response, far more severe than the initial one, often develops about 6 h after the challenge. Despite these reservations about antigen challenge, testing is warranted under certain circumstances: (1) to uncover a particular agent in the environment that causes bronchoconstriction; (2) to establish the diagnosis of occupational asthma; (3) to prove that bronchoconstriction is caused by a particular antigen after routine skin tests have failed to support the clinical suspicion; and (4) to convince a skeptical patient about the cause of his or her asthma. Recommendations for preparing concentrations of antigens and the technique of antigen challenge testing are specific to the antigen in question and may be found in the literature. These tests should only be performed in laboratories that have considerable experience with BPT.

Precautions and Contraindications in Bronchoprovocation Testing Although the overall risk of serious complications is low, BPT may be unnecessary, invalid, or even dangerous in some circumstances (Table 34-10). For example, the patient who manifests appreciable airway obstruction by conventional testing may develop life-threatening airway narrowing during BPT. In such a patient, a simple bronchodilator study would be more appropriate and informative. If bronchodilators fail to reverse the increase in airway resistance, and if it is important

Table 34-10 Bronchoprovocation Testing: Precautions and Contraindications

Baseline FEV1 /FVC% <70 Recent upper respiratory tract infection Recent influenza vaccination Recent administration of bronchodilator Ingestion of caffeine within 6 h before testing Cold-air breathing, hyperventilation, exercise within 6 h before testing Recent acute myocardial infarction or cerebrovascular accident, uncontrolled hypertension, or known aortic aneurysm

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to prove that bronchial hyperreactivity does exist, BPT is sometimes done, with extreme caution, on another day, as antigen dosages are titrated carefully and details of the procedure monitored closely. Absolute contraindications include severe airways obstruction (FEV1 less than 50 percent predicted), myocardial infarction or stroke in the preceding 3 months, uncontrolled hypertension, or known aortic aneurysm. Moderate airflow limitation, pregnancy, lactation, and concurrent use of cholinesterase inhibitor medication represent relative contraindications. A recent viral upper respiratory tract infection can cause airway hyperreactivity for up to 6 weeks in normal subjects. Similarly, influenza vaccination increases responsiveness to inhalation challenges in asthmatics for a few days to a week. In these conditions, BPT should not be undertaken until the sensitization effects of the infection or vaccination have worn off. Also, bronchodilators, including caffeine, should be withheld for at least 6 h before BPT, if possible, in order to prevent blunting of the bronchoconstrictor response. Finally, cold air, hyperventilation, and exercise should be avoided for at least 6 h before testing in order to prevent the induction of a refractory period or late response that would overlap the test results.

SMALL-AIRWAY FUNCTION Up to this point, discussion of tests of dynamic lung function has addressed the tracheobronchial tree as a unit. Sometimes, however, particularly in cigarette smokers, obstructive disease is confined to the peripheral airways (i.e., those 2 mm or smaller in diameter). Because of their small contribution to airway resistance, estimated to be about 10 to 38 percent (at a lung volume equivalent to 50 percent of vital capacity), the small airways can undergo considerable damage before the usual tests of either static or dynamic lung function become abnormal. Consequently, efforts have been made to develop tests aimed at early detection of small-airway disease in the hope of early intervention to limit progression of the disease. The nature of small-airways obstruction and its impact on progression of COPD are currently being investigated. In obstructive disease of the peripheral airways, the small airwaysâ&#x20AC;&#x2122; contribution to overall resistance increases, and abnormalities in their function may be detected from the expiratory vital capacity maneuver. In particular, abnormal values for FEF25â&#x2C6;&#x2019;75% , in conjunction with normal values for FVC and FEV1 , are often useful in identifying small-airway disease. The basis for this approach is that FEF25â&#x2C6;&#x2019;75% measures airflow during the effort-independent part of the FVC, when the small airways contribute substantially to the limitation of airflow. In addition to limiting airflow during expiration, obstruction of small airways results in abnormal distribution of ventilation to peripheral lung units. This abnormality forms the basis for two tests that, although not commonly per-

Figure 34-26 Measurement of dynamic lung compliance (Cdyn,L). During the inspiratory and expiratory phases of the respiratory cycle, a loop relating volume to transpulmonary pressure is generated. The slope of a line drawn through the points of zero airflow (at end-inspiration and end-expiration) is the dynamic compliance. Determination of Cdyn, L can be done at a variety of respiratory frequencies to assess the frequency dependence of compliance (Fig. 34-27).

formed, merit additional comment because of the relevant underlying physiology: frequency dependence of dynamic compliance and closing volume.

Dynamic Compliance Dynamic compliance, defined as the change in lung volume during airflow produced by a given change in transpulmonary pressure, is normally independent of breathing frequency. However, under conditions of nonuniformity of ventilation throughout the lung, increases in breathing frequency are associated with a fall in dynamic compliance. This frequency dependence of compliance was first noted in a patient with emphysema. During the test, the patient, with an esophageal balloon in place, first inspires maximally to TLC and then expires to the resting end-expiratory position (FRC); the patient then breathes at a normal tidal volume and respiratory rate (15 breaths/min). In order to enable the patient to monitor these parameters, tidal volume and the resting end-expiratory level are displayed on an oscilloscope within sight of the patient. At the same time, changes in tidal volume and transpulmonary pressure are displayed on another oscilloscope (Fig. 34-26). The slope of the line connecting the endinspiratory and end-expiratory points on the pressurevolume loop (i.e., the points of zero airflow) is the dynamic compliance. This procedure is repeated with breathing frequencies of 30 and 60 breaths per minute. Values for dynamic compliance (Cdyn,L) at the various frequencies are expressed as a ratio of the dynamic compliance to the static inspiratory compliance (Cst,L) or as a percentage of Cst,L (Fig. 34-27) for the same range of tidal volumes. In normal subjects, Cdyn,L/Cst,L remains above 0.8, even at frequencies greater than 60 breaths/min. However,

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frequency increases is the presence of unequal time constants throughout the lung (see Chapter 9).

Closing Volume

Figure 34-27 Determination of frequency dependence of dynamic compliance. Dynamic compliance is determined as shown in Fig. 34-26 and is expressed as a percentage of static lung compliance (Cdyn, L/Cst, L × 100, %) at a variety of respiratory frequencies. Normally, Cdyn, L is ≥80 percent of Cst, L and is independent of respiratory frequency. In patients with obstructive airway disease, including those with disease limited to the small airways, Cdyn, L falls relative to Cst, L as respiratory frequency increases.

in the presence of obstructive disease of the small airways, Cdyn,L/Cst,L falls progressively to values below 0.8 as breathing frequency increases. It is worth emphasizing that interpretation of frequency dependence of compliance with regard to small-airway disease is valid only if the static compliance and overall airway resistance are normal. Abnormalities in these other measurements indicate disease that is not likely to be confined to the small airways and for which frequency dependence of dynamic compliance is another manifestation. The physiological basis for the fall in Cdyn,L/Cst,L as respiratory

In 1949, Fowler described the single-breath nitrogen washout test for assessing the uniformity of ventilation throughout the lungs. In performing this test, the patient first expires maximally to RV before filling his or her lungs by taking a maximal breath of 100 percent O2 . During the subsequent expiration, the concentration of nitrogen at the mouth is continuously recorded and plotted against the volume of expired gas. Originally, interest focused on the initial part of the tracing that depicts the changing concentration in expired nitrogen as the first 750 to 1200 ml of gas is exhaled. Over this range, the change in nitrogen concentration in persons with normal lungs is less than 2.5 percent. In contrast, when abnormal lungs or disease of the tracheobronchial tree result in abnormal intrapulmonary distribution of inspired gas, the change in nitrogen concentration exceeds 2.5 percent. Almost 20 years later, Fowler’s test was modified to include a bolus of xenon at the beginning of inspiration and to record the concentration of xenon during the following expiration. Abrupt changes in the concentration of expired xenon as RV was approached suggested that important information about the small airways could be obtained from the terminal portion of the curve. These observations with xenon rekindled interest in Fowler’s original technique and also directed attention to the terminal portion of expiration. The procedure is depicted in Fig. 34-28. To perform the maneuver for this measurement, the seated patient takes two deep breaths of air and then expires to RV. At the end of this maximal expiration, a valve is opened so that the patient can take a full breath of 100 percent

Figure 34-28 Contributions of different lung regions to the nitrogen concentrationvolume curve obtained during the singlebreath nitrogen washout test. See text for discussion.

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O2 to TLC. The patient then expires slowly to RV while N2 concentration and expired volume are continuously recorded. Four distinct phases can be identified in the continuous record relating N2 concentration to expired volume. Phase 1, the initial expirate, contains virtually no N2 , since it derives from the O2 -containing dead space. Phase 2 represents a mixture of gases from the dead space and the alveoli. Phase 3 is due to a mixture of gases from alveoli located at the apices, midlung fields, and bases. Phase 4, characterized by an upward shift in N2 concentration, is caused by closure of alveoli in the dependent parts of the lungs at low lung volumes. This final expirate derives from alveoli in the middle and upper regions of the lungs, where N2 concentrations are higher than at the bases. The explanation for these phases resides in the intrapulmonary distribution of gases during the respiratory maneuvers used in performing the test. In the normal upright person, a gradient of pleural pressures exists from apex to base, so that pleural pressure is more negative at the apices than at the bases. Because the alveoli at the bases operate on a lower portion of their pressure-volume curve (Fig. 34-11), they expand more than do apical alveoli per unit change in pleural pressure. However, the less negative pleural pressures and decrease in elastic recoil pressure at the bases also cause small airways to close during expiration as lung volume approaches RV. Thus, the pleural pressure gradient from top to bottom of the chest causes nonuniform distribution of gas within the normal upright lungs. In the single-breath nitrogen washout test, a breath of 100 percent O2 is taken, starting from RV. At RV, small basal airways are closed. Therefore, at the start of the O2 breath, the N2 -containing air remaining in the dead space is preferentially drawn into the middle and apical lung zones as 100 percent O2 gradually replaces air in the dead space. As the inspiration continues, the small airways at the bases open. Since their compliances are greater than those in the middle or at the top of the upright lungs, the inspired O2 is then preferentially distributed to the bases. During the expiration from TLC, the four phases then represent, as indicated above, the sequential emptying of dead-space gas and a mixture of dead-space and alveolar gas, followed by mixtures of alveolar gases from different parts of the lungs, as determined by the preceding intrapulmonary distribution of inspired O2 . The volume from the onset of phase 4 to the completion of the full expiratory maneuver is termed the closing volume (CV). In healthy young adults, the normal closing volume averages about 10 percent of the vital capacity. Narrowing or obstruction of small peripheral airways causes closing volume to enlarge. The closing volume also increases progressively as people grow older, so that by the age of 50, the closing volume sometimes reaches 25 percent of the vital capacity. Cigarette smokers consistently experience an increase in closing volume. In both aging normal persons and cigarette smokers at any age, a decrease in pulmonary elasticity seems to be responsible for the increase in closing volume.

Figure 34-29 Maximal expiratory flow-volume curves generated in breathing room air (solid line) and breathing a heliumoxygen mixture (dashed line). The airflows achieved with the less dense helium mixture are higher than those with air at all but the lowest lung volumes. The point of first intersection of these two curves demarcates the volume of isoflow (VIso vË&#x2122; ). The difference between the flows achieved when 50 percent of the vital capacity has been expired is the !Vmax ,% . The use of these measurements as indicators of small-airway disease is described in the text.

Helium-Oxygen Flow-Volume Curves In 1963, the effects of changes in gas density and viscosity on maximal expiratory flow throughout the vital capacity range were described. Almost 10 years later, gas density and viscosity related concepts were applied to determine the site of airway obstruction in asthma. These principles were then applied for the specific purpose of detecting obstruction of small airways when other tests of pulmonary function were within normal limits. The use of a helium-oxygen mixture to detect smallairway disease requires comparison of two maximal expiratory flow-volume curves, one that is generated while the patient breathes air and the other while the patient breathes helium and oxygen (Fig. 34-29). At least three maximal expiratory flow curves are obtained with room air and three with helium-oxygen. In normal subjects, at lung volumes greater than 10 percent of the vital capacity (VC), the primary site of resistance to airflow is in the larger airways, where flow is turbulent and, therefore, density-dependent. At these lung volumes, the flow attained with the helium-oxygen mixture will be higher than that attained with air. At lung volumes less than 10 percent of the VC, the primary site of resistance is in the smaller airways, where flow is laminar and, therefore, not density-dependent. In this circumstance, the less-dense helium mixture has no effect on flow (Fig. 34-29). In disease of the small airways, the primary site of resistance shifts at large volumes from the larger to the smaller airways. As a result, the flow-enhancing effect of the less-dense gas disappears at volumes well above 10 percent of the VC. In practice, two sets of maximal expiratory flow-volume curves are obtained, one while the subject is breathing air and the other after three VC breaths of the helium-oxygen mixture to replace at least 95 percent of the alveolar N2 . Comparisons

591 Chapter 34

are then made of the superimposed curves (Fig. 34-29). One comparison is made at 50 percent of the VC in order to compare maximal expiratory flows (i.e., the !V˙ max,50% ); the other is at the volume at which the flows become identical—i.e., the ˙ The curves are superimposed at RV volume of isoflow (Viso V). or TLC, as long as the vital capacities of each curve are within 2.5 to 5.0 percent of the largest VC recorded. The percentage change in expiratory flow while breathing helium-oxygen compared to air at 50 percent of the VC, ˙ max,50% , is calculated as: !Ve ˙ max,50% !Ve ˙ max,50% (helium-oxygen) − Ve ˙ max,50% (air) Ve × 100 = ˙ max,50% (air) Ve ˙ max,50% (air) are ˙ max,50% (helium-oxygen) and Ve where Ve the expiratory flows at 50 percent of the VC during heliumoxygen and air breathing, respectively. As noted previously, the volume of isoflow is normally less than 10 percent of the VC; when it is increased, it indicates small-airway obstruction. ˙ max,50% is also specific for small-airway disease, and The !Ve unlike the closing volume, it is considered to be unaffected by changes in the elastic properties of the lung. Questions remain, however, about the validity and sensitivity of tests of density dependence of flow in assessing small-airway disease. Although they are conceptually attractive, the practical value of helium-oxygen flow-volume curves in detecting small-airway disease is debatable.

GAS EXCHANGE FUNCTIONS Traditional measurements of the gas exchange functions of ˙ 2 ), carbon dioxide elimthe lung include oxygen uptake (Vo ˙ ination (Vco2 ), respiratory dead space (Vd), alveolar gas composition (Pao2 and Paco2 ), diffusing capacity for carbon monoxide (DlCO ), and arterial blood gas tensions (Pao2 and Paco2 ). These determinations require a steady state of the ventilation and circulation and constant body stores of O2 and CO2 . A steady state with respect to O2 implies that O2 uptake measured at the mouth equals the rate of O2 transport across the alveolar membrane, and that, in turn, both rates are equal to O2 consumption by the tissues. The same type of definition applies to CO2 exchange in the tissues, in the alveolar capillaries, and at the mouth.

Ventilation, Oxygen Uptake, and Carbon Dioxide Elimination ˙ is the minute The total volume of air breathed per minute (Ve) ventilation. It is equal to the product of the tidal volume (Vt) and the breathing frequency (f). As a rule, minute ventilation is determined by measuring the volume of expired gas relative to time. When the measurement is performed manually, the necessary equipment includes gas-collecting bags, low-resistance directional valves, a stopwatch, and a device

Pulmonary Function Testing

for measuring gas volume. In practice, the patient, with nose clip in place, breathes through a mouthpiece for at least 3 to 5 min while expired gas is vented to the atmosphere. This preliminary period is intended to put the patient at ease and to achieve a steady state of respiration and circulation. When steady heart rate and breathing pattern are achieved, a valve is turned without the patient’s knowledge, and expired gas is collected for 3 min. The minute ventilation is determined by dividing the total volume of expired gas collected in the spirometer by the time of collection (3 min). The average tidal volume is ˙ by the number of breaths per minute. obtained by dividing Ve Values for minute ventilation and tidal volume are expressed in terms of body conditions (BTPS). In the resting adult, the minute ventilation is typically 6 to 8 L/min; the corresponding tidal volume is 0.4 to 0.6 L. The quantity of CO2 in inspired air is negligible. Con˙ 2) sequently, the amount of CO2 produced per minute (Vco can be calculated as the product of the expired volume of ˙ and the concentration of CO2 in the expired ventilation (Ve) air (Feco2 ): ˙ 2 = VE × Feco2 Vco ˙ 2 ) is calculated as the difference between Oxygen uptake (Vo the amounts of O2 in inspired and expired air: ˙ × Fio2 ) − (Ve ˙ × Feo2 ) ˙ 2 = (Vi Vo where ˙ = inspired volume of ventilation, L/min Vi Fio2 = concentration of O2 in the inspired air Feo2 = concentration of O2 in the expired air In the steady state, O2 uptake by alveolar capillary blood exceeds CO2 output from alveolar capillary blood. As a result, the expired volume of gas is less than the corresponding inspired volume. Since N2 does not undergo exchange in the lungs, the difference between CO2 output and O2 uptake results in a higher concentration of N2 in expired air than in inspired air. Based on the change in nitrogen concentration, the inspired volume of ventilation can be calculated from the expired volume of ventilation: V˙ I = V˙ E

FEN2 FIN2

where FEN2 = concentration of N2 in expired air FIN2 = concentration of N2 in inspired air In the normal, resting subject who is tested after several hours of fasting, the ratio of CO2 output to O2 uptake, the respiratory exchange ratio (R), is about 0.8. The respiratory exchange ratio at any instant is calculated by simultaneously determining the Po2 and Pco2 in an alveolar gas sample. As indicated above, in the steady state, the R determined by sampling alveolar gas equals the R of alveolar capillary blood, which, in turn, equals the R of the tissues. The steady-state R, when

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alveolar gas, blood, and tissue are all in dynamic equilibrium, is the respiratory quotient (RQ). Hence, in the steady state, when the O2 and CO2 stores of the body are not changing, the RQ, reflecting cellular metabolism, can be determined by analyzing alveolar gas for O2 and CO2 . Unlike tidal volume and ventilation, which are ex˙ 2 and Vco ˙ 2 are given in terms pressed in terms of BTPS, Vo of standard temperature and pressure, dry (STPD).

Dead Space Not all of the air breathed participates in gas exchange. Part of each breath remains in the mouth, nose, pharynx, larynx, trachea, bronchi, and bronchioles. This volume, the anatomic dead space, is about equal, in milliliters, to the subject’s ideal body weight, in pounds (e.g., about 150 ml in a typical adult male). Inspired air reaching alveoli that are not exposed to pulmonary capillary blood also does not participate in gas exchange. This volume plus the anatomic dead space equals the physiological dead space. In a normal person, the anatomic and physiological dead spaces are virtually identical and constitute about one-third of the tidal volume. Determination of the physiological dead space has proved to be of practical importance in a variety of clinical conditions. It is calculated by considering each breath (Vt) to consist of dead space (Vd) and an alveolar volume that participates in gas exchange (Va): Vt = Vd + Va Physiological dead space can be calculated using a modification of the Bohr equation, which recognizes that all of the test gas expired derives from two sources: the physiological dead space and the alveolar gas-exchanging volume. If we use CO2 as the marker gas, the total amount of CO2 eliminated per minute equals the sum of the CO2 coming from the dead space per minute and from the alveolar compartment per minute: ˙ × Fico2 ) + (Va ˙ × Faco2 ) ˙ × Feco2 = (Vd Ve where ˙ = minute ventilation, L/min Ve Feco2 = fractional concentration of CO2 in expired gas ˙ = minute dead space ventilation, L/min Vd Fico2 = fractional concentration of CO2 in inspired gas ˙ = alveolar ventilation, L/min Va Faco2 = fractional concentration of CO2 in alveolar gas Since, in a subject breathing room air, Fico2 is practically zero, the last equation is generally simplified as follows. Ve × Feco2 = Va × Faco2 where Ve and Va represent volumes of ventilation, rather than rates.

Recalling that Va = Vt – Vd and substituting partial pressures for the fractional concentration terms, the relationship becomes: Ve × Peco2 = (Vt − Vd)Paco2 where Peco2 and Paco2 are the partial pressures of CO2 in mixed expired gas and alveolar gas, respectively. Assuming that arterial blood and alveolar gas are in equilibrium with respect to CO2 , when Paco2 is substituted for Paco2 and the equation rearranged, it becomes: VD = VT

PaCO2 − PECO2 PaCO2

Thus, if arterial blood is sampled during collection of expired gas, and if the partial pressures of CO2 in expired gas and arterial blood are determined, the physiological dead space can be calculated. In order for the physiological dead space to be separated from the total dead space determined by the above equation, the dead space of the apparatus is subtracted from the value for total dead space.

Alveolar Gas Composition In normal subjects, values for Po2 and Pco2 in an end-tidal sample approximate mean alveolar values. However, when imbalances exist in alveolar ventilation and blood flow because of lung disease, inhomogeneity in alveolar gas composition often invalidates the use of end-tidal gas tensions as a measure of mean alveolar gas composition. ¯ 2 ) and mean alveIn practice, mean alveolar Po2 (Pao ¯ olar Pco2 (Paco 2 ) are often determined indirectly. Arterial Pco2 is assumed to equal mean alveolar Pco2 on the grounds of the narrow arteriovenous difference for Pco2 across the lungs, the high solubility of CO2 , and the presumed role of pulmonary capillary blood as a tonometer. Mean alveolar Po2 is calculated using the alveolar gas equation: 1 + FIO2 P¯ ACO2 = PIO2 − P¯ ACO2 FIO2 + R The alveolar gas equation takes advantage of the fact that the total pressure of gases in the alveoli is equal to the sum of the partial pressures of the individual gases. This equation simply states that the mean alveolar Po2 is the difference between inspired Po2 and mean alveolar Pco2 , allowing for a correction factor when the respiratory exchange ratio differs from 1.0.

Diffusing Capacity The diffusing capacity of the lung for carbon monoxide (DlCO ) can be determined by steady-state, rebreathing, and single-breath methods. The most frequently used method is a modification of the single-breath method first described in 1915 and subsequently modified in 1957. Although the single-breath test has been shown to exhibit a large interlaboratory variation, it has proved to be a valuable measure of lung function in a wide variety of disease states. In fact, with continuing refinement of the standards, the variability, which

593 Chapter 34

may be as much as 12 percent or greater, is likely to decrease; however, the variability will probably not be reduced to the range for vital capacity measurements (about 4 percent). The diffusing capacity is intended to provide an estimate of the rate at which test molecules—usually carbon monoxide (CO)—move by diffusion from alveolar gas to pulmonary capillary blood. Factors that influence the measurement are the physicochemical properties of the test gas, the extent and thickness of the alveolar-capillary barrier, the resistance to diffusion offered by the red blood cell membrane, and the reaction rates of the test gas and hemoglobin, and pulmonary capillary blood volume. As a rule, the diffusing capacity is interpreted as an index of the surface area engaged in alveolar-capillary diffusion. Clinical entities that can reduce the diffusing capacity include parenchymal lung diseases, particularly interstitial lung disease, emphysema, pulmonary hypertension, and anemia. Polycythemia and alveolar hemorrhage syndromes, on the other hand, may increase the diffusing capacity. Carbon monoxide has emerged as the most practical test gas because of its affinity for hemoglobin. The diffusing capacity for CO is defined as the amount of CO transferred per minute per mmHg of driving pressure: DlCO =

V˙ CO ¯ CO − Pc ¯ CO Pa

a source of the special inspired gas mixture, a device for measuring the volume of gas inspired and expired, rapid response analyzers to measure the concentration of gases (see below), a timer, and appropriate valving and collection devices to trap the desired portion of the expirate. The diffusing capacity of the lung for CO is calculated according to the following equation. DlCO =

Since the blood Pco in nonsmokers is essentially zero, the ¯ CO is customarily neglected. In practice, DlCO is deterterm Pc mined by calculating V˙ CO as the difference between inspired and expired samples and estimating the mean alveolar Pco. Generally, one of two techniques is used to determine DlCO : the single-breath or the steady-state technique. The Single-Breath Method The breathing maneuvers required for the single-breath method consist of tidal breathing for a few breaths, unforced expiration to RV, and then a single full, rapid inspiration of a gas mixture containing approximately 0.3 percent CO and an inert gas—traditionally, 10 percent helium. (Some newer systems use methane.) The breath is held for 10 + 2 s and then rapidly expired. An inspiratory time of less than 4 seconds, and a sample collection of no more than 3 s are required. Longer expiratory times and sample collection time greater than 3 s should be noted in the test report. The initial portion of the expirate containing dead-space gas is discarded; the remainder is collected, and the concentrations of CO and helium are measured. A variety of automated systems are commercially available for performing the single-breath diffusing capacity. However, the essential components in all systems are

VA × 60 (barometric pressure − 47) FaCO , initial × time × ln FaCO , final

where Va = alveolar volume FaCO , initial = alveolar concentration of CO at start of breath hold FaCO , final = alveolar concentration of CO at end of breath hold The concentration of CO in the alveoli at the start of the period of breath holding (FaCO , initial) is calculated from the inspired concentration of CO and, for helium-based systems, the inspired concentration of helium and the expired concentration of helium, according to the equation FaCO , initial =

where DlCO = the diffusing capacity of the lung for CO, ml/min/mmHg (STPD) V˙ CO = the amount of CO transferred, ml/min ¯ CO = the mean alveolar PCO, mmHg Pa ¯ CO = the mean capillary PCO, mmHg Pc

Pulmonary Function Testing

FeHe × FiCO FiHe

where FeHe = expired concentration of helium FiHe = inspired concentration of helium Fico = inspired concentration of CO The concentration of CO in the alveoli at the end of the breathholding period (FaCO , final) is equal to the concentration of CO in the expired gas. The alveolar volume (Va) is determined in one of two ways. Originally, Va was calculated as the sum of the RV, determined by the closed-circuit helium or body plethysmograph techniques described previously, and the volume of inspired gas, as recorded on the spirometer. Later, Va came to be calculated from the single-breath dilution of helium that occurs during the determination of DlCO . Finally, the time of breath holding is measured (in seconds) from the spirometer recording of the maneuver. Although the single-breath method is relatively simple and has the advantage of requiring no blood samples, breath holding is clearly artificial, and the maneuver is difficult for dyspneic patients. Therefore, a steady-state method is sometimes used. The Steady-State Method In the steady-state method, a gas mixture containing 0.1 percent CO is breathed until the rate of CO uptake from the lung is constant. CO uptake (V˙ CO ) is determined from the difference between the amount of CO in the inspired and expired gas using an equation similar to that presented previously for calculation of O2 consumption.

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Comparison of Single-Breath and Steady-State Methods Certain differences between the single-breath and steadystate techniques merit special mention. The single-breath method is more popular because it is relatively easy to perform; it is well standardized, and it is less affected by nonuniformity of ventilation in comparison to the steady-state method. However, one drawback is that the patient is required to perform an inspiratory vital capacity maneuver of at least 88 percent of the VC and to hold his or her breath for 10 s. Another is that the test is extremely difficult to perform during exercise. The steady-state method is more attractive intrinsically than the single-breath method, since it requires no respiratory maneuvers and can be done during exercise. However, it does require an arterial blood sample (for determination of Pco2 ), and it is technically more difficult to perform. The steady-state method for determining diffusing capacity tends to give lower values for the resting subject than does the single-breath method. The discrepancy is generally attributed to the fact that the surface area for diffusion is smaller during the quiet tidal breathing employed in the steady-state method than during the full inspiration to TLC, as required in the single-breath method. Also, during quiet breathing, some areas of the lung receive considerably less ventilation than during a breath hold at TLC. Factors Other than Diffusion That Influence Test Results A low DlCO need not indicate a diffusion defect. A number of additional respiratory and nonrespiratory factors may reduce or increase the DlCO . A reduction in the lung volume alone can reduce the DlCO . Therefore, some laboratories â&#x20AC;&#x153;normalizeâ&#x20AC;? the diffusing capacity for lung volume by dividing DlCO by alveolar volumeâ&#x20AC;&#x201D;a manipulation that assumes a linear relationship between DlCO and Va, which is not the case. Anemia artificially decreases the DlCO as determined by either method, but the effect of low hemoglobin concentration can be adjusted by application of a correction factor. Conversely, polycythemia and intrapulmonary hemorrhage tend to increase the value for DlCO . In fact, an unexpectedly high value for DlCO may be a helpful clinical clue in detecting radiographically occult pulmonary hemorrhage. Although the equation for DlCO assumes that the CO back pressure in blood is negligible, the blood of a heavy smoker sometimes contains as much as 10 percent CO Hb. Such levels of CO Hb will be accompanied by appreciable concentrations of dissolved CO in the plasma. The resulting back pressure of CO will reduce the DlCO . A correction equation may be applied to adjust the DlCO for this effect. Altitude also affects the DlCO . Pao2 falls with increasing altitude above sea level. The reduction in Pao2 allows CO to diffuse more rapidly into the blood. A specific adjustment should be made for inspired oxygen partial pressure. Measurement of diffusing capacity is quite useful in the evaluation of patients with a number of pulmonary conditions. Decrement in DlCO has been shown to predict exertional hypoxemia. In addition, DlCO levels have been correlated with disease severity and prognosis in primary

pulmonary hypertension, idiopathic pulmonary fibrosis, and alveolitis associated with systemic sclerosis.

Arterial Blood Gas Composition The determination of arterial Po2 and Pco2 provides useful information about the overall efficiency of external gas exchange. Heavy reliance is placed upon them for this purpose in managing acute respiratory failure, particularly in intensive care units. Less dramatic, but important, is their use in a variety of other settings (e.g., exercise testing) and for assorted calculations (e.g., the alveolar-arterial O2 gradient and respiratory dead space). Technique for Sampling Arterial Blood Arterial blood is sampled either through an indwelling arterial catheter or by percutaneous arterial puncture. Sampling through an indwelling catheter avoids the acute changes in ventilation that can result from apprehension and pain associated with percutaneous puncture. Three anatomic sites are generally used for obtaining arterial blood samples: the radial, brachial, and femoral arteries. For several reasons, the radial artery is the preferred sampling site. Because of its superficial location at the wrist, the radial artery is easy to palpate and easy to compress by direct pressure, facilitating hemostasis when sampling is complete. In addition, no large veins lie in its immediate vicinity. Furthermore, the ulnar artery usually provides an adequate collateral circulation to the hand in the rare instance of postsampling thrombosis of the radial artery. Arterial blood samples are drawn anaerobically into plastic or glass syringes coated with heparin. Because room air at sea level has a Po2 of approximately 150 mmHg and a Pco2 of approximately zero mmHg, air bubbles in the syringe will artificially increase the arterial Po2 and reduce the arterial Pco2 . The sample either is immediately analyzed or is placed on ice in order to minimize the metabolism of blood cells, particularly the white cells. If the icing precaution is neglected and the analysis is delayed, the Paco2 of the sample will increase and the Pao2 and pH will decrease; the rate of change depends on the temperature of the sample and the elapsed time before analysis (Table 34-11). Interpretations Analysis of arterial blood gases as part of pulmonary function testing is based primarily on determination of Pao2 , Paco2 , and pH. As a rule, these parameters are measured directly. Other values, including O2 saturation, bicarbonate concentration, and base excess (or deficit), are usually calculated. This section deals with the interpretation of Pao2 , Paco2 , and pH. Additional consideration of arterial blood gases, with particular reference to acid-base balance, is found in Chapter 14. Arterial Po2 (Pao2 )

The physiological determinants of normal Pao2 have been described elsewhere. For example, normal values for arterial Po2

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Table 34-11 In vitro Changes in Arterial Blood Gas Values at 37◦ C Measurement

Change over 10 Min

pH (units)

−0.01

PCO2 (mmHg)

+1.000

O2 content (vol %)

−0.001

Source: Data from Kelman GR, Nunn JF: Nomograms for correction of blood P O2 , PCO 2 , pH, and base excess for time and temperature. J Appl Physiol 21:1484–1490, 1966.

depend on altitude (Table 34-12). Therefore, normal values for arterial Po2 in Denver (altitude of approximately 1500 m) are less than those at sea level by about 20 mmHg. Arterial Po2 also decreases with age. A regression equation can be used to predict the decrease: Pao2 = 109 − 0.43 (age in years)

Pulmonary Function Testing

The standard deviation of this relationship is ±4.10 mmHg. A third physiological influence is body position. Assumption of the supine position causes abdominal contents to displace the diaphragm cephalad, thereby closing small airways at the lung bases and creating ventilation-perfusion inhomogeneities that decrease Pao2 . Many more pathological conditions than physiological states can lower Pao2 . In each instance, however, arterial hypoxemia may be attributed to one or more of the following generic mechanisms: alveolar hypoventilation, ventilationperfusion mismatch, diffusion impairment, and venous admixture (“shunt”). Considerations of the individual disorders within these categories and the mechanisms leading to hypoxemia are found throughout this book. Arterial Pco2 (Paco2 ) and pH

In a steady state, the level of Paco2 reflects the level of alveolar ventilation. In the absence of a disorder in metabolic acid-base balance, an increase or decrease in Paco2 beyond normal limits indicates a primary disorder in alveolar ventilation. A summary of these disorders and useful criteria for distinguishing among them, based on arterial blood gas composition, are given in Table 34-13. Acute respiratory alkalosis, produced by alveolar hyperventilation, is characterized by hypocapnia (Paco2 less than

Table 34-13 Table 34-12 Effect of Altitude on Mean Alveolar and Arterial O2 Pressures Barometric Pressure (mmHg)

Ambient PO2 (mmHg)

Alveolar PO2 (mmHg)

760

159

103

1000

733

154

2000

707

148

3000

681

143

4000

656

138

5000

632

133

6000

609

128

8000

565

118

10,000

523

110

12,000

484

101

Altitude (Feet)

Source: Modified from Wasserman K: Clin Notes Respir Dis 12:3–10, 1973.

Classification of Primary Respiratory Disorders of Acid-Base Balance Disorder

Definition

Acute respiratory alkalosis (acute alveolar hyperventilation)

PaCO2 below lower limit of normal (<36 mmHg), with accompanying alkalemia (pH > 7.44)

Chronic respiratory alkalosis (chronic alveolar hyperventilation)

PaCO2 below lower limit of normal, with pH normal (or near normal) due to renal compensation and lowered serum bicarbonate concentration (<19 mEq/L)

Acute respiratory acidosis (acute alveolar hypoventilation

PaCO2 above upper limit of normal (>44 mmHg), with accompanying acidemia (pH < 7.36)

Chronic respiratory acidosis (chronic alveolar hypoventilation)

PaCO2 above upper limit of normal, with pH normal (or near normal) due to renal compensation and elevated serum bicarbonate concentration (>30 mEq/L)

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36 mmHg) and an appropriately elevated pH (greater than 7.44). In time (e.g., 24 h or more), renal compensation occurs, and the concentration of bicarbonate in serum decreases. If alveolar hyperventilation continues, a chronic respiratory alkalosis, partly or completely “compensated,” ensues. A low Paco2 is not necessarily indicative of a primary disturbance in alveolar ventilation. Instead, it may be a consequence of respiratory compensation (partial or complete) for metabolic acidosis; this possibility is signaled by the coexistence of hypocapnia and a low pH (under 7.36). Since the kidney and respiratory system do not overcompensate for acid-base derangements, the coexistence of hypocapnia and acidemia suggest the presence of two primary disturbances. Acute respiratory acidosis, caused by alveolar hypoventilation, is characterized by an abnormally high Paco2 (over 44 mmHg) and a subnormal pH (under 7.36). Again, in time (24 h or more), renal compensation for the primary respiratory disorder restores the serum bicarbonate concentration and blood pH toward normal. A high value for Paco2 may also reflect respiratory compensation for a primary metabolic alkalosis ([HCO− 3 ] greater than 30 mEq/L). In this circumstance, however, blood pH will be abnormally high (pH over 7.44), rather than low. In general, the elevation in Paco2 in compensation for metabolic alkalosis does not exceed about 55 mmHg. A Paco2 exceeding this value in the setting of a metabolic alkalosis suggests the likely coexistence of a primary respiratory acidosis. This discussion has been limited primarily to alterations in arterial blood gas values in primary respiratory acidosis or alkalosis. Metabolic derangements often complicate the picture. These disorders are considered elsewhere (see Chapter 14).

FEV2 %Pred

PaO2 Sea Level 91 90 89 88 87 86 85 84 83 82 81 80 79 78 76 75 74 73 72 71 70 69 68 67 66 65 64 63 62 61 60

PaO2 (8,000 feet)

62 61 60 59 58 57 56 55 54 53 52 51 50 49 48 47 46 45 44 43 42 41 40 39

3 2

Testing for Air Travel-Related Hypoxemia Travel in commercial jet airliners typically results in exposure of passengers and crew to conditions equivalent to about 6000 to 8000 feet above sea level. For individuals with normal pulmonary gas exchange, the resulting Pao2 falls within a clinically acceptable range. However, for many patients with lung disease, the resulting Pao2 may well be problematic, even in those patients who do not require supplemental oxygen at sea level. Consequently, assessment of patients with chronic lung diseases, particularly COPD and interstitial lung diseases, has become part of the repertoire of tests offered by many pulmonary function laboratories. One approach to estimating the resultant Pao2 during air travel is based upon use of regression equations (Fig. 34-30). Using the patient’s resting Pao2 at sea level and his or her FEV1 percent of predicted, the expected in-flight Pao2 can be estimated. Some experts advocate use of the nomogram for determining which patients ought to undergo hypoxia inhalation testing (HIT), while others advocate performance of HIT for all traveling patients at risk for in-flight hypoxemia. HIT is based on the observation that exposure to hypoxic gas mixtures can reproducibly mimic the Pao2 arising

60% 59% 58% 57% 56% 55% 54% 53% 52% 51% 50% 49% 48% 47% 46% 45% 44% 43% 42% 41% 40% 39% 38% 37% 36% 35% 34% 33% 32% 31% 30% 29% 28% 27% 26% 25% 24% 23% 22%

Figure 34-30 Nomogram for predicting in-flight oxygen tension. Using a straight edge, the patient’s resting PaO 2 at sea level (Column 1) is aligned with his or her FEV1 % of predicted (Column 2). The expected in-flight PaO 2 (Column 3) is estimated as the value where the line crosses the center scale. (From Dillard TA, Ewald FW: The use of pulmonary function testing in piloting, air travel, mountain climbing, and diving. Clin Chest Med 22:803, 2001.)

under true hypobaric conditions. Exposure to 15.1 percent oxygen for 20 min reliably duplicates the resultant Pao2 at 8000 feet. During performance of the test, the patient, with nose clips in place, breathes from a reservoir though a mouthpiece. The electrocardiogram is monitored, and arterial blood gases are obtained at the conclusion of the test. Supplemental oxygen can then be titrated and prescribed according to the findings.

CONTROL OF BREATHING The rate, depth, and pattern of breathing reflect a complex interplay of neurohumoral and chemical regulatory

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mixture of 7 percent CO2 in O2 ; O2 is substituted for air in this mixture to avoid the ambiguity of a hypoxic stimulus to ventilatory drive. The result of the CO2 rebreathing test is described by use of two terms: (1) the slope of the line relating change in ven˙ tilation response to change in end-tidal Pco2 (!Ve/Pco 2 ), determined by using the method of least squares linear regression analysis, and (2) the x-intercept of the relationship ˙ and end-tidal Pco2 . between Ve

Figure 34-31 Linear relationship between minute ventilation (V˙ E) and arterial PCO 2 . The dashed lines show the increased slope of the relationship of V˙ E vs. PCO 2 as PaO 2 decreases.

mechanisms that drive the respiratory apparatus. Tests used to evaluate the control of breathing, based on assessment of the ventilatory response to controlled hypercapnia or hypoxia, are uncommonly performed in the clinical setting. However, since these tests highlight important physiological mechanisms that affect the level and pattern of ventilation, they are summarized below.

Ventilatory Response to CO2 The ventilatory response to changes in Paco2 is linear over a broad range (Fig. 34-31). Determination of the ventilatory response to controlled hypercapnia generally is based on one of two methods: the steady-state method or the rebreathing method. Steady-State Method After a control period in which CO2 -free air is breathed to establish a baseline, the patient is subjected to two or more periods of breathing CO2 -enriched air. Care is taken to achieve a steady state of ventilation and circulation during each exposure. Especially at the higher concentrations of inspired CO2 , at least 10 to 20 min is required for a steady state to be reached in alveoli, arterial blood, cerebrospinal fluid, and the chemosensitive areas of the brain. The ventilatory response ˙ vs. Paco2 . In to CO2 is then determined from a plot of Ve patients without underlying lung disease, end-tidal CO2 concentration is often substituted for Paco2 . In addition, in order to eliminate the influence of variations in arterial PO2 on the ventilatory response to CO2 , the inspired gas is enriched with O2 during the control and test periods. Rebreathing Method This method entails rebreathing a CO2 -enriched gas mixture from a bag for approximately 4 min. The validity of the approach requires rapid equilibration of CO2 among alveolar gas, arterial and mixed venous blood, and the chemosensitive areas of the brain. The bag is filled at the outset with a

Normal Response to CO2 and Modifying Influences As indicated above, the normal increase in ventilatory response to increasing concentrations of inspired CO2 is linear. Normal responses are categorized as low (under 1.5 L/ min/mmHg), intermediate (1.5 to 5.0 L/min/mmHg), or high (more than 5.0 L/min/mmHg). Most normal persons (about 80 percent) have an intermediate ventilatory response. A variety of factors, both genetic and environmental, seem to influence the ventilatory response to CO2 (Table 34-14).

Ventilatory Response to Hypoxia The response to acute hypoxia in normal persons is largely determined by the peripheral arterial chemoreceptors, as long as the level of hypoxia is mild to moderate. Even at sea level, the level of arterial Po2 in normal persons provides an appreciable chemoreceptor drive, accounting for about 10 percent ˙ to of the minute ventilation. Unlike the linear response of Ve progressive hypercapnia, the response to hypoxemia is curvilinear (Fig. 34-32). The magnitude of the ventilatory response to a decrease in arterial Po2 depends on the Paco2 , increasing as the concentration of CO2 in arterial blood is increased. As may be seen from the hyperbolic curves in Fig. 3432, the rate of change in ventilation is greater over the lower range of oxygenation (when Pao2 falls below 60 mmHg). Not shown in Fig. 34-32 is the depression of ventilation brought about by severe hypoxemia, presumably because of the central depressing effect of severe hypoxia on respiratory neurons. Although tests for assessing the ventilatory response to hypoxia are less well standardized than those for measuring the hypercapnic response, they, too, may be conveniently categorized into steady-state and non–steady-state methods. In one steady-state method, successive ventilatory responses are determined to a series of increasingly severe hypoxic gas mixtures, each administered for at least 10 min; Paco2 is kept constant by the addition of CO2 to the inspired gas mixture as hypoxia-induced hyperventilation develops. In another, the ˙ vs. Pco2 , as Po2 effect of hypoxia on the slope of the plot of Ve is lowered from hyperoxic (at least 200 mmHg) to hypoxic (40 mmHg) levels, is determined. The normal response to diminished inspired oxygen concentrations is characterized by an increase in sensitivity (slope) without a change in the CO2 threshold. Three non–steady-state techniques are currently in use. In the hypoxic rebreathing test, the subject rebreathes a hypoxic gas mixture containing 7 percent CO2 . As arterial hypoxemia intensifies, causing an increase in ventilation and

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Table 34-14 Factors Associated with an Altered Ventilatory Response to CO2 Factor Depressed Response Endurance training Aging Genetic/racial predilection Metabolic alkalosis Narcotics, barbiturates, and other CNS depressants Neurological disorders (encephalitis, brain stem disease) Myxedema Obesity-hypoventilation syndrome Chronic obstructive pulmonary disease (COPD) Accentuated Response Metabolic acidosis Drugs (e.g., aminophylline, salicylates, thyroxine, progesterone)

Reference

Byrne-Quinn et al: J Appl Physiol 30:91–98, 1971 Peterson et al: Am Rev Respir Dis 124:387–391, 1981 Beral et al: Lancet 2:1290–1294, 1971 Koboyashi et al: Am Rev Respir Dis 147:1192–1198, 1993 Heinemann, Goldring: Am J Med 57:361–370, 1974 Lambertsen: Handbook of Physiology, section 3, Respiration, vol I. Washington DC, American Physiological Society, 1964, pp 545–555. Plum, Brown: Ann NY Acad Sci 109:915–931, 1963 Zwillich et al: N Engl J Med 292:662–665, 1975 Duranti et al: Am J Med 95:29–37, 1993 Zwillich et al: Am J Med 59:343–348, 1975 Flenley, Millar: Clin Sci 33:319–334, 1967

Heinemann, Goldring: Am J Med 57:361–370, 1974 Lambertsen: Handbook of Physiology, section 3: Respiration, vol I. Washington, DC, American Physiological Society, 1964, pp 545–555

in CO2 elimination into the closed circuit, the Pco2 in the system is held constant at a predetermined level by the diversion of a fraction of the expired gas through a CO2 absorber. The ventilatory response is determined at two or more levels of Pco2 , since the hypoxic response is influenced by Pco2 . An

Figure 34-32 The curvilinear relationship between ventilation and arterial PO 2 at various levels of arterial PCO 2 . The rate of change of ventilation as PO 2 falls (slope) increases precipitously at a PO 2 of approximately 60 mmHg when PCO 2 is 40 mmHg. The abrupt increase in ventilation occurs at a higher PO 2 when the level of PCO 2 is elevated, and at a lower PO 2 when the prevailing PCO 2 is lower.

alternative rebreathing test induces progressive hypoxemia by adding N2 to the inspired gas mixture over a 20-min period. Finally, in a relatively simple test, the patient induces a transient drop in arterial Po2 by inhaling pure N2 for a few breaths. ˙ and Pao2 is plotted; the slope of The relationship between Ve the relationship is the sensitivity to hypoxia. Because the duration of the hypoxia is brief, presumably only the peripheral chemoreceptors are stimulated. No adjustment is made for the drop in Pco2 that occurs during the hypoxia-stimulated increase in ventilation. Normal Responses to Hypoxia and Modifying Influences The normal ventilatory response to acute hypoxia varies among individuals. Several factors may influence the relationship (Table 34-15). A high ventilatory response to CO2 may be associated with a high sensitivity to hypoxia; in addition, higher levels of arterial Pco2 are associated with a higher ventilatory response to hypoxia. Interestingly, in long durations of hypoxia before the test period, as is the case in native residents at high altitude or persons with cyanotic congenital heart disease, a blunted response to acute hypoxia is observed. Finally, a variety of other clinical disorders, including myxedema and hypothyroidism, autonomic nervous system dysfunction, chronic narcotic addiction, and the chronic use of methadone, are characterized by a reduced hypoxic response.

599 Chapter 34

Table 34-15 Factors Associated with an Altered Ventilatory Response to Hypoxia Factor

Reference

Depressed Response Long-standing hypoxia High-altitude Severinghaus et al: Respir dwelling Physiol 1: 308–334, 1966 Congenital Blesa et al: N Engl J Med 296: cyanotic heart 237–241, 1977 disease Aging Kronenberg et al: J Clin Invest 52: 1812–1819, 1973 Hypothyroidism Zwillich et al: N Engl J Med 292:662–665, 1975 Riley-Day syndrome Edelman et al: J Clin Invest 49:1153–1165, 1970 Chronic use of Marks: Am Rev Respir Dis methadone 108:1088–1093, 1970 Following carotid Wade et al: N Engl J Med 282: endarterectomy 823–829, 1970 Accentuated Response Heightened CO2 response Hypercapnia

Rebuk et al: J Appl Physiol 35: 173–177, 1973 Rebuck, Woodley: J Appl Physiol 38: 16–19, 1975

Nonventilatory Measures of Ventilatory Drive Measurement of ventilation in response to acute hypoxia or hypercapnia provides a useful index of respiratory output when the ventilatory apparatus (thorax, diaphragm, abdominal muscles, lung, and airways) is normal. This situation obviously does not apply in certain neuromuscular disorders in which the thorax and diaphragm behave abnormally. In addition, it does not apply in some instances of pulmonary disease, notably obstructive airway disease, in which the respiratory apparatus may not be capable of responding normally, even though it is intact and chemosensitivity is normal. In this instance, a decrease in ventilatory response may be attributable to the excessive mechanical load placed on the muscles of respiration. When ventilation fails to provide a reliable measure of the ventilatory drive (efferent discharge from the respiratory neurons), the diaphragmatic electromyograph (EMG) or the pressure generated by the inspiratory muscles during the first 0.1 s of an occluded inspiration (the P0.1 ) has been used for the clinical assessment of the control of breathing. The electrical activity of the diaphragm is directly related to neural activity of the phrenic nerve. Therefore, it provides a measure of efferent neural traffic to the diaphragm.

Pulmonary Function Testing

The diaphragmatic EMG may be recorded in patients by placing the tip of an esophageal catheter, containing bipolar electrodes, at the level of the diaphragm. The second approach to obtaining a nonventilatory measure of ventilatory drive is the determination of P0.1 , which is the negative pressure generated by the inspiratory muscles during the first 100 ms of an inspiratory effort made against an occluded airway. During this brief period, contraction of the respiratory muscles is virtually isometric, and the force generated correlates with activity recorded by the diaphragmatic EMG. In performing the test, airflow in the inspiratory line of the breathing circuit is randomly interrupted during the preceding expiration. The 100-ms period has proved to be so brief as to be imperceptible, thereby obviating any corrective action by the subject during the breath against the occlusion. However, the P0.1 is far from foolproof. A major concern is that P0.1 is affected by resting lung volume: P0.1 is reduced when FRC is abnormally high, a common occurrence in obstructive disease of the airways.

ASSESSMENT OF INTEGRATED FUNCTIONS: 6-MINUTE WALK TEST A complete evaluation of a patient with respiratory symptoms often requires assessment of exercise capacity, in addition to traditional pulmonary function tests and radiographic studies. A number of exercise studies can be employed, including cardiopulmonary exercise tests (Chapter 135), cardiac stress tests, and EIB protocols. One of the most widely used, practical modalities is the 6-minute walk test (6MWT). Despite its simplicity, the 6MWT has become a powerful tool in the evaluation of functional status and prognosis of patients with a variety of functional impairments.

Technical Aspects The 6MWT is performed indoors. There is an initial period of rest in a chair for at least 10 min, during which baseline vital signs are taken. The patient then stands and is asked to rate baseline dyspnea and overall fatigue using the Borg scale (from 1 to 10). The patient, walking at a comfortable pace, completes 60-m laps on a walking course that is 30 m in length. Cones are used to mark the turnaround points. For patients using supplemental oxygen, the oxygen is delivered at standard rate, or as prescribed by a physician, or as determined by protocol. The patient should not carry or push the oxygen source during testing. The number of laps and a post-walk Borg scale assessment are recorded, as is the total distance walked over 6 min (6MWD). Although pulse oximetry during the 6MWT is considered optional, it has become standard at many institutions. In some cases, pulse oximetry can be used to titrate levels of oxygen supplementation. Obtaining a high-quality oximeter signal is imperative.

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A number of sources of variability are inherent in the 6MWT. A modest training effect has been reported when two studies are performed within one week. Concomitant medication use can also impact the 6MWT. Improved test performance, for example, occurs after bronchodilator use in patients with COPD. Shorter height, female sex, and higher body weight are associated with reduced performance. Despite these factors, the 6MWT has been found to have excellent reproducibility, especially when performed in evaluation of specific clinical entities, such as idiopathic pulmonary fibrosis. Several modifications of the 6MWT are in clinical use. During a shuttle-walking test, the patient walks on a 10-m course while the walking speed is increased every minute until the patient cannot reach the turnaround point within the set time. The timed walk test (TWT), which has been designed for patients with idiopathic pulmonary fibrosis, has three stopping criteria based on changes in oxyhemoglobin saturation. Absolute contraindications to performing the 6MWT include unstable angina or myocardial infarction within 1 month of the study. Resting tachycardia of greater than 120 beats per minute, systolic blood pressure greater than 180 mmHg, or diastolic blood pressure greater than 100 mmHg are relative contraindications. The study should be terminated if the patient develops chest pain, severe dyspnea, leg cramps, diaphoresis, or profound oxyhemoglobin desaturation.

Recently, a number of publications have established the value of the 6MWT in predicting morbidity and mortality from heart and lung disease. Results from the test have been shown to have an inverse relationship with mortality in severe COPD. Walk distance and velocity, as well as magnitude of oxyhemoglobin desaturation, are correlated with survival in idiopathic pulmonary fibrosis. Similar correlations have been made in heart failure and primary pulmonary hypertension. Finally, at some institutions, results of the 6MWT are used to not only establish the presence of exertional hypoxemia, but also to titrate supplemental oxygen with activity.

QUALITY CONTROL IN THE PULMONARY FUNCTION LABORATORY Meaningful interpretation of pulmonary function tests requires confidence in the accuracy and reproducibility of results provided by the pulmonary function laboratory. Previously, it was tacitly assumed that all data from all laboratories, especially when reported as “percent predicted,” were equally reliable. In recent years, the fallacy of this assumption has been explicitly recognized, and steps have been taken to standardize equipment and procedures and to ensure accuracy, reproducibility, and uniformity in testing and reporting. To accomplish this goal, both analytical and nonanalytical factors must be taken into account.

Interpretation Although the 6MWT is limited in its inability to provide objective measures of functional capacity, such as oxygen uptake, the test provides very useful clinical information. In addition, it realistically represents the patient’s functional capacity during physical effort that more closely reflects his or her daily activity. Reliable reference equations establishing standard performance during a 6MWT in healthy patients are not currently available. The 6MWT has several indications, most notably, measurement of the response to a number of medical and surgical interventions. Pulmonary rehabilitation clearly improves 6MWT performance in patients with COPD, while pharmacologic interventions for pulmonary arterial hypertension and heart failure, among other disorders, have also been shown to favorably affect test results. Lung transplantation (unilateral and bilateral) and lung volume reduction surgery for emphysema have been shown to significantly improve results of the 6MWT. The 6MWT also has been used to assess functional status in patients with COPD, cystic fibrosis, heart failure, and peripheral vascular disease, and in determining eligibility for, and timing of, lung transplantation. In the absence of well-established reference standards, the clinical value of performing a single test in these patient groups is limited. Serial studies are likely to be more useful than a single 6MWT.

Nonanalytical Factors in Quality Control A familiar example of a confounding influence that may distort test results is the anxious patient who pauses outside the laboratory door to “calm the nerves” by smoking one or more cigarettes before undergoing pulmonary function testing. Cigarette smoking before the diffusing capacity of the lungs is determined can generate enough carboxyhemoglobin to reduce a normal value to subnormal levels. Another example of a nonanalytical factor is the failure to achieve patient understanding and comfort for tests that usually require patient cooperation. Unfortunately, a preliminary explanation before the patient arrives at the laboratory or prior exposure of the patient to the laboratory and its personnel is usually impractical. Use of explanatory sheets or descriptive brochures may prove helpful. If such materials are not available, laboratory personnel are obligated to make the patient comfortable and even perform “practice runs” before undertaking final testing. When the patient arrives at the pulmonary function laboratory, an assessment should be made of his or her prior experiences. Did the patient undergo other tests or procedures that could alter the outcome of the pulmonary function tests in question? Is the patient fatigued or in pain? Should a period of rest precede the tests in order to ensure optimal performance? If delay is impractical, the test report should include the fact that the patient was fatigued or in pain.

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Medication use before pulmonary function testing can seriously affect the results. For example, self-administration of bronchodilators before testing can artificially enhance tests of airflow. If medications have been taken before the patient arrives at the laboratory, the time of administration should be part of the record. Also, a request for pulmonary function test results for patients who regularly take bronchodilators should indicate whether the tests are to be done without interruption of the regular schedule of medications, whether bronchodilators are to be discontinued before the test is done, or whether regular bronchodilators are to be discontinued so that the effects of bronchodilation can be tested. Appropriate comments about bronchodilators are part of the report. A major nonanalytical cause of misinterpreting results is the inappropriate application of predicted normal values to the patient population by the laboratory (see “Approach to Interpreting Commonly Performed Pulmonary Function Tests,” below). For example, normal values based on data obtained using physically fit hospital personnel do not necessarily apply to those who have a sedentary existence. Noncomparable race, as well as lifestyle, may complicate comparisons. Anthropological differences among control and test populations are not easily reconciled. Extraordinary height, weight, or age cannot be easily extrapolated if corresponding subjects are not represented in the control group. Using patientreported height, rather than making measurement of patient height, may introduce an error in the selection of appropriate normal values. Comparison of control and test results at different altitudes can be invalid if due regard is not paid to the influence of hypoxia on certain measurements (e.g., diffusing capacity).

Analytical Factors in Quality Control Performance of pulmonary function tests is replete with opportunities for error. The equipment, techniques, use of control values, and calculations are potential sources of error. In an attempt to minimize errors, standardization of techniques has been advocated. For example, with respect to performing the forced vital capacity maneuver, guidelines have been established for the number of attempts required, acceptable variability between efforts, and methods for selecting test data in order to arrive at acceptable results. To avoid misuse of spirometers, criteria have been set for minimal performance with respect to capacity, accuracy, and frequency response of various spirometers; in addition, standards have been developed for determining the single-breath diffusing capacity. Potential sources of discrepancies—such as breath-holding time, concentration of hemoglobin, dead space of the equipment and the patient, Fio2 , volume of the alveolar sample, number of tests, and acceptable variability in results—are taken into account.

Quality Control of Test Results Guidelines for standardization play a major role in reducing discrepancies between laboratories. However, measures are

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also required to ensure accuracy and reproducibility within any given laboratory. Among the elements of control that merit consideration are calibration, validation of calibration, and performance of a control measurement. Calibration is the adjustment of an instrument’s output so that it validly reflects a known input. Verification of calibration entails introduction of the same known input and demonstration that the correct output is reproduced. Performance of a control measurement refers to the testing of a substrate that has known properties, similar to those usually tested, to prove the accuracy of the instrumentation. One example of the application of these principles is blood gas analysis. Use of control measurements derived from tonometered blood or commercially prepared buffer solutions is now widespread. Unfortunately, similar controls do not exist for pulmonary function tests. Therefore, laboratory technologists have the responsibility for continuing to be alert, not only with respect to faithful observance of guidelines for standardization but also to detect in-house sources of error (e.g., a leak in the system, malfunction of gas analyzers, faulty analogto-digital converters, and faulty electronics that reduce frequency response).

Responsibility and Cost in Quality Control All who work in the laboratory must be concerned with quality control, despite the frequent temptation to cut corners. Indeed, one common rationalization for not doing so is the misguided impression that quality control, as described above, is too expensive. Time has to be set aside for the technologist to care for and calibrate equipment, to establish proper control values for the laboratory, to search for inconsistencies in the data and interpretation, and to keep up with changing standards. Also, equipment and supplies, including calibrating syringes and calibrating gases, are expensive. However, when put into the balance, the cost and waste of producing erroneous results exceed, by far, the expense of practicing quality control.

Infection Control Given the relatively close contact between patients and technical staff during performance of pulmonary function tests, the issue of infection control is one that must be carefully considered. To date, the role of pulmonary function equipment in transmission of disease appears to be minimal. Although the presence of potential pathogens on laboratory mouthpieces, valves, and tubing has been well documented, implication of these organisms in the transmission of disease has not been established. Nevertheless, the potential hazards should be recognized and appropriate care exercised. Infection control begins with practice of the basic principles of hygiene. Staff should always wash their hands between patients and use protective gloves when handling potentially contaminated equipment. Care must be taken in working with mouthpieces, nose clips, and any other implements that come in contact with mucosal surfaces. These

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devices, if reused, should be disinfected or sterilized after each use. Other equipment—manifolds, tubing, etc.—should be sterilized on a regular basis. In fact, guidelines from the American Thoracic Society call for the disinfection or sterilization before reuse of any equipment surface with visible condensation from expired air. Because of recent growing concern over crosscontamination among patients and laboratory personnel, manufacturers now produce a variety of in-line filters and disposable pneumotachographs. Care should be taken, however, to assure that response characteristics of the test equipment are not driven to unacceptable levels by use of these devices. Current literature on this topic should be consulted regularly.

APPROACH TO INTERPRETING COMMONLY PERFORMED PULMONARY FUNCTION TESTS A standard battery of pulmonary function tests is commonly used to identify and quantify abnormalities in the performance of the respiratory system. An organized approach to interpreting these studies is critical. Once a patient’s baseline values are established, the tests are valuable in tracking the course of the disorder and its response to treatment. Results of pulmonary function tests are interpreted by comparing individual patient data with reference or predicted values for normal subjects. Ideally, predicted values should be generated from large groups of well-defined, normal or healthy subjects with proper distribution of anthropometric characteristics such as sex, age and height, and ethnic background. Despite dedicated attempts to improve prediction formulas, however, many still fail to take into account important sources of discrepancy, such as the racial and ethnic backgrounds of the patients and the control population, the effects of altitude and exposure to air pollution, and effects of inordinate body size or old age. As a result, not all sets of predicted normals are applicable in pulmonary function laboratories outside the immediate vicinity of the patient populations from whom the data were collected. Extrapolation beyond the characteristics of the reference population should be avoided. Recently published guidelines from a joint Task Force of the American Thoracic Society (ATS) and European Respiratory Society (ERS) recommended that in the United States, ethnically appropriate reference equations from the National Health and Nutrition Examination Survey (NHANES) III be used for individuals between the ages of 8 and 80 years. The ATS/ERS Task Force did not recommend any specific set of reference equations for laboratories in Europe, but it suggested the need for an investigation conducted throughout Europe to derive contemporary equations for prediction of normal lung function. The same ATS/ERS Task Force recommended that each pulmonary function test result falling below the fifth per-

centile of the frequency distribution of values measured in the reference population be considered abnormal. If normal test results fall in a normal distribution, values below the fifth percentile can be estimated using Gaussian statistics. If the distribution of normal values is non-Gaussian, the lower limit of normal is estimated using a nonparametric technique (e.g., the 95th percentile method). Traditionally, but without a sound statistical basis, most laboratories have used an arbitrary cutoff of 80 percent predicted to define normal. While this method may be reasonable in children, errors may arise if it is applied to adult test results.

Interpretation Scheme and Classification of Abnormal Patterns A variety of schemes have been proposed for sorting out abnormalities in pulmonary function test results. Many are based on initial categorization of findings reflective of one of four basic patterns described below. An obstructive pattern stems from narrowing of any portion of the airways—from upper airway to bronchioles less than 2 mm in diameter—that results in a reduction of maximal airflow in relation to maximal volume. A restrictive pattern is elicited by diseases of the lung, chest wall, pleural space, or neuromuscular respiratory apparatus that reduce lung volumes, particularly TLC, and vital capacity. A combined obstructive-restrictive pattern results from pathological processes that reduce lung volumes, vital capacity, and airflow, and that also include an element of airway narrowing. Finally, abnormal gas transfer may be noted as part of one of the aforementioned patterns or in isolation and reflects an abnormality in the alveolar-capillary membrane, impairing oxygen uptake from alveolar gas to pulmonary capillary blood. Overlap among categories is not uncommon. For example, widespread interstitial disease, as in idiopathic pulmonary fibrosis, often shows a pattern that indicates important components of both restrictive disease and abnormal gas transfer. One useful sequence recommended by the ATS/ERS Task Force for analyzing a conventional battery of pulmonary function test results is illustrated in Fig. 34-33. Analysis begins with evaluation of the ratio of FEV1 to VC. While, historically, the ratio of FEV1 to FVC (FEV1 /FVC%) served as the basis for distinguishing obstructive disorders from normality or restrictive disease, the ATS/ERS Task Force currently recommends using as the denominator the FVC, or the VC (“slow” VC or SVC), or the FIVC, whichever is greatest. If the ratio is less than the lower limit of normal (i.e., below the fifth percentile) and the VC (defining VC as any of the three previously noted vital capacity measurements) is at or above the lower limit of normal, the pattern is obstructive. If TLC is not at or above the lower limit of normal, a mixed obstructive-restrictive pattern is

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FEV1/VC ≥ LLN

Yes

VC ≥ LLN Yes

VC ≥ LLN No

Yes

TLC ≥ LLN

Normal

Restriction

DL,co ≥ LLN

Normal

No PV disorders

Yes CW and NM disorders

No TLC ≥ LLN

Yes

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Yes Obstruction

No ILD Pneumonities

No Mixed defect

DL,co ≥ LLN Yes Asthma CB

suggested. Distinction between asthma and chronic bronchitis on the one hand, and emphysema on the other, is based upon whether the DlCO is normal (asthma or chronic bronchitis) or reduced (emphysema). The previous practice of using a value for FEV1 /FVC% of less than 70 percent to define obstruction results in misdiagnosis of airway obstruction in men over 40 years and women over 50 years, as well as overdiagnosis of COPD in elderly, asymptomatic nonsmokers. If FEV1 /VC and VC are each equal to or greater than the respective lower limits of normal, spirometry is considered normal; measurement of the DlCO can then help distinguish between normal pulmonary function and pulmonary vascular disorders. If VC is below the lower limit of normal, a reduced TLC supports a diagnosis of restriction, while a normal TLC indicates an obstructive pattern. Once again, in the setting of a restrictive pattern, measurement of DlCO can be used to distinguish between pulmonary parenchymal disorders and disorders of the chest wall or respiratory muscles. Note that according to these guidelines, an obstructive pattern may be diagnosed in the setting of a normal FEV1 /VC, if VC is reduced and TLC is normal or elevated. Once the predominant abnormality is defined with initial pulmonary function testing, the whole battery may not be necessary in following the course of the disease or in assessing its response to treatment. For example, particular determinations, such as spirometry, may suffice in patients with airway diseases. Notably, according to the ATS/ERS guidelines, the severity of the abnormality in each of the obstructive, restrictive, or mixed patterns is expressed on the basis of the FEV1 (Table 34-16). Standards have been established for defining significant changes in results over time: a 15 percent or greater change in FVC or in FEV1 , or a greater than 10 percent change in DlCO is considered significant.

No Emphysema

Figure 34-33 Proposed sequence of test review in the interpretation of pulmonary function tests (see text for discussion). LLN, lower limit of normal; PV, pulmonary vascular; CW, chest wall; NM, neuromuscular; ILD, interstitial lung disease; CB, chronic bronchitis. (From Pellegrino R, Viegi G, Brusasco V, et al: Interpretive strategies for lung function tests. Eur Respir J 26:948, 2005.)

Assessing Respiratory Muscle Strength and Effort One additional measurement that is frequently useful in assessing results of routine spirometry is assessment of respiratory muscle strength. Respiratory muscle strength is expressed in terms of peak inspiratory (Pimax ) and peak expiratory (Pemax ) pressures, determined under static conditions. The technique was outlined in a previous section. Any of a number of factors may be responsible for low peak inspiratory or expiratory pressures (Table 34-17): suboptimal effort, fatigue, weakness of the respiratory muscles, deformity of the chest wall, or intrinsic diseases of the lungs or chest wall. Although

Table 34-16 Grading of Severity of Abnormal Spirometry Based on FEV1 Severity

FEV1 Percent Predicted

Mild

>70

Moderate

60–69

Moderately severe

50–59

Severe

35–49

Very severe

<35

Source: Modified from Pellegrino R, Viegi G, Brusasco V, et al: Interpretive strategies for lung function tests. Eur Respir J 26:948–968, 2005.

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Table 34-17 Conditions Associated with Reduced Peak Inspiratory (Pimax ) and Expiratory (Pemax ) Pressures Condition

Pimax

Pemax

Poor effort

↓

Fatigue

↓

Neuromuscular disease

↓

Increased lung volume

↓

Decreased lung volume

↓

Note: ↓ = decreased; N = normal.

the first three factors characteristically reduce both peak inspiratory and expiratory pressures, disease of the lungs or chest wall often reduces, selectively, one or the other peak pressure. Thus, diseases that reduce lung volumes (e.g., widespread interstitial fibrosis) and shorten the length of the expiratory muscles at the end-inspiratory position generally reduce maximal expiratory pressure. Conversely, diseases that increase lung volume, such as obstructive airway disease, by decreasing the inspiratory muscle length at end-expiration generally reduce maximal inspiratory pressure.

If airflow during spirometry is reduced, determination of the peak inspiratory and expiratory pressures may be helpful in suggesting the mechanism. Many pulmonary function tests depend on the cooperation of the patient. Poorly reproducible peak flows that are consistently subnormal raise the question of poor effort. Conversely, consistently low values that occur despite maximal effort may signal neuromuscular disease.

Additional Details of Pulmonary Function Test Results in an Obstructive Pattern Included in the obstructive pulmonary disorders (Table 3418) are chronic obstructive diseases of the airways (chronic bronchitis and emphysema), bronchiectasis, asthma, smallairway disease, and upper-airway obstruction. Except for diseases confined to the small airways, as noted previously, the hallmark of the obstructive pattern is a reduction in the FEV1 /VC%. Notably, some healthy subjects have a reduced FEV1 /FVC% and an FEV1 in the normal range. The clinical significance of these findings is unclear. Results of additional tests (e.g., lung volumes, DlCO , assessment of bronchodilator responsiveness) may help distinguish those with airway obstruction from true normals. Measurement of airway resistance (Raw) or specific airway conductance (SGaw) may be useful in assessing airway obstruction in subjects unable to perform a maximal forced expiratory maneuver. Changes in lung volume commonly accompany the abnormal findings on spirometry but, as indicated in Fig. 34-33, lung volume measurement is not mandatory in establishing

Table 34-18 Causes of an Obstructive Pattern Disease Process

Anatomic Location of Lesion

Cause of Reduced Airflow

Large and small (<2-mm diameter) airways Lung parenchyma

Narrowing of airways by fibrosis, secretions, edema Loss of lung elastic recoil

Cystic fibrosis

Large and small airways

Narrowing of airway by fibrosis, retained secretions, edema Loss of elastic recoil

Asthma

Large and small airways

Narrowing of airways by smooth-muscle contraction, edema, retained secretions

Small-airway disease

Small airways

Narrowing, stenosis of small airways

Upper-airway obstruction

Major, central airways (trachea, main bronchi)

Anatomic or functional narrowing of upper airway

Chronic obstructive pulmonary disease (COPD) Chronic bronchitis Emphysema

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the presence of obstruction. Frequently, but not invariably, lung volumes are abnormally high. Typically, all three lung volumes—RV, FRC, and TLC—are increased. In addition to uncovering the pattern of chronic obstructive airway disease described previously, certain additional tests provide insight into the sites and mechanisms of obstructive airway disease.

detection of small-airway disease might reinforce measures, such as cessation of smoking, that would prevent or arrest progression to irreversible obstructive disease of the airways. However, enthusiasm for testing for small-airway disease has waned, since it is still unclear if small-airway disease is a reversible phase in the evolution of clinically significant obstructive airway disease that affects larger bronchi.

Reversible vs. Irreversible Obstructive Airway Disease The response to inhaled bronchodilators traditionally has been used to help distinguish between chronic obstructive airway disease (chronic bronchitis and emphysema), in which airway resistance is virtually fixed, and asthma, in which bronchoconstriction is a prominent feature. This is an oversimplification, since a sizable minority of patients with COPD manifest a bronchodilator response. Furthermore, the absence of a bronchodilator response in a laboratory setting does not necessarily predict lack of a clinical response. A universally agreed upon definition of reversibility is lacking. Expressing change in FEV1 or FVC as a percent of predicted values may be more advantageous than expression of changes in the values relative to baseline. In general, an increase in FEV1 or FVC of at least 12 percent above baseline and an absolute increment of at least 200 ml is considered evidence of significant bronchodilation. If the increase in spirometric values is not significant, a decrease in lung volumes toward normal may be an indication of bronchodilator responsiveness.

Upper-Airway Obstruction The designation upper-airway obstruction is an umbrella for anatomic or functional narrowing of the large upper airways—the larynx, extra- and intrathoracic trachea, and lobar bronchi. Although upper-airway obstruction of any cause may reduce expiratory or inspiratory airflow, an alteration in the contour of the flow-volume loop has proved to be the most reliable abnormality in conventional pulmonary function testing. The observation from routine spirometry that the ratio of FEV1 to PEFR (peak expiratory flow rate) exceeds 8 ml/L/min should prompt careful performance and review of the flow-volume loop, as described below. Upper-airway obstruction can be divided into three major types: (1) fixed obstruction, (2) variable extrathoracic obstruction, and (3) variable intrathoracic obstruction. A fixed obstruction, such as tracheal narrowing by scar tissue at the site of a previous tracheotomy, is one in which the geometry and cross-sectional area of the lesion do not change during the respiratory cycle. Characteristically, both inspiratory and expiratory flows are affected about equally (Fig. 34-34A). A variable obstruction is one in which the configuration of the obstructive lesion changes with the phases of respiration. Depending on its location in the tracheobronchial tree (extra- or intrathoracic), this type of lesion usually affects predominantly either inspiration or expiration. The inspiratory arm of the flow-volume loop is primarily affected by a variable extrathoracic obstruction, leaving the expiratory limb relatively unaffected (Fig. 34-34B). The abnormal configuration of the flow-volume loop is attributable to the following sequence: during forced expiration, tracheal pressure exceeds atmospheric, so that the degree of obstruction decreases; conversely, during forced inspiration, intratracheal pressure becomes less than atmospheric and the trachea tends to collapse. The expiratory arm of the flow-volume loop is primarily affected by a variable intrathoracic obstruction (Fig. 34-34C). The following sequence is responsible for producing this abnormality in the flow-volume loop: during forced expiration, as pleural pressure reaches and then exceeds intratracheal pressure downstream from the lesion (i.e., toward the mouth), the obstruction tends to increase; conversely, during a forced inspiration, as intratracheal pressure exceeds pleural pressure, the intrathoracic obstruction decreases. Variable intrathoracic lesions often coexist with obstructive airway disease. In considering a variable intrathoracic lesion, the respective roles played by obstructive disease of the airways (i.e., chronic bronchitis, emphysema, and

Chronic Bronchitis vs. Emphysema Although chronic bronchitis and emphysema usually coexist, occasionally one or the other exists in virtually pure form. Two pulmonary function tests have proved valuable in distinguishing between the two—diffusing capacity (DlCO ), which is routinely measured, and static lung compliance (Cst,L), which is uncommonly measured clinically. Emphysema, characterized by a loss of alveolar units and a decrease in alveolar surface area, is associated with a low DlCO , whereas the DlCO in chronic bronchitis is usually normal or near normal. The loss of alveolar units in emphysema also causes a decrease in the elastic recoil pressure of the lungs. As a result, Cst,L is increased in emphysema, whereas it is usually not appreciably altered in chronic bronchitis. Small-Airway Disease In obstructive disease of the small airways (i.e., those less than 2 mm in diameter), expiratory flow is usually normal, except at low lung volumes (i.e., the FEV3 and FEF25−75% are abnormally low). Other, uncommonly performed tests for isolated, small-airway disease, including the helium-oxygen flow-volume loop, nitrogen washout test, and frequency dependence of dynamic compliance, would also be anticipated to be abnormal. Lung volumes and DlCO are normal. Bronchodilators are virtually without effect. The practical value of tests of small-airway function is problematic. At one time, high hopes were held that early

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Symptoms and Signs of Respiratory Disease Figure 34-34 Schematic flow-volume loops in four pathological conditions. A. In a fixed upper-airway obstruction, both inspiratory and expiratory limbs are truncated. B. In a variable extrathoracic obstruction, the inspiratory limb is flattened while the expiratory limb is not altered. C. In a variable intrathoracic obstruction, the expiratory limb is flattened while the inspiratory portion is unchanged. D. In chronic obstructive airway disease, although expiratory airflow is reduced, the tapering in airflow during expiration is generally maintained so that the configuration of the loop is different from that in variable intrathoracic obstruction.

asthma) and an obstructive upper-airway lesion (anatomic or functional) in deforming the flow-volume loop must be determined. Fortunately, this distinction is often possible. Although both upper-airway obstruction and obstructive airway disease (reversible and irreversible) do decrease maximal expiratory flow, the shapes of the flow-volume curves are frequently quite distinctive (Fig. 34-34C and D). Thus, in obstructive airway disease, despite a decrease in airflow, the expiratory limb of the loop generally retains its normal configuration (Fig. 34-34D)—i.e., an early peak in flow, followed by gradual tapering. In contrast, in upper-airway obstruction (fixed and variable intrathoracic), the expiratory limb is flat and flow is decreased throughout most of expiration (Fig. 34-34C). In addition to changes in the shape of the flow-volume loop, clues from routine pulmonary function tests often alert the clinician to the possibility of upper-airway obstruction. As noted previously, when FEV1 /PEFR is greater than 8, the

possibility of upper-airway obstruction should be considered. Finally, the presence of any of the following may also provide clues: FEF50% /FIF50% of at least 1, where FEF50% and FIF50% are the forced expiratory flow at 50 percent of FVC and the forced inspiratory flow at 50 percent of FIVC, respectively; FIF50% less than 100 L/min; and FEV1 /FEV0.5 at least 1.5. Distinguishing test features of disorders producing an obstructive pattern are summarized in Table 34-19.

Additional Details of Pulmonary Function Test Results in a Restrictive Pattern The restrictive pattern (Table 34-20) characteristically occurs in several groups of disorders including: (1) a primary disorder of the lung parenchyma in which functional tissue is lost through disease (e.g., an alveolar filling process, such as pneumonia, tumor, atelectasis, or fibrosis); (2) surgical removal of lung tissue (e.g., lobectomy); (3) constrictive disease of the

Table 34-19 Distinguishing Features of Disorders Producing an Obstructive Pattern

Disorder

FEV1

Response of FEV1 Tests of to Administration Small-Airway Lung FVC FEV1 /VC% of Bronchodilator Function Volumes DlCO

COPD Chronic bronchitis

↓

ABN

↑

ABN

Emphysema

↓

ABN

↑

↓

ABN

Asthma

↓

↑

ABN

↑

ABN

Small-airway disease

ABN

Upper-airway obstruction

↓

NL or ABN

NL or ↑

ABN∗

∗ Configuration

frequently characteristic for upper-airway obstruction. Note: ↓ = decrease; ↑ = increase, NC = no significant change; NL = normal; ABN = abnormal.

Flow-Volume Loop

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Table 34-20 Causes of a Restrictive Pattern Disease Process

Anatomic Location of Lesion

Cause of Pulmonary Function Test Abnormality

Primary parenchymal disease

Lung parenchyma

Loss of lung tissue → reduced volumes and flows

Surgical removal of lung tissue

Lung parenchyma

Loss of lung tissue → reduced volumes and flows

Diseases of pleura and chest wall

Pleura, chest wall

Limited expansion of thoracic cavity → reduced volumes and flows

Reduced generation of expiratory force

Central nervous system, peripheral nerves, neuromuscular junction, muscles of respiration

Reduced muscle tension → reduced expiratory flow, atelectasis

pleura and chest wall (e.g., extensive pleural fibrosis, large pleural effusion or pleural mass, kyphoscoliosis, obesity); and (4) neuromuscular diseases, notably those in which the generation of respiratory force is reduced (e.g., disorders of the spinal cord, peripheral nerves, neuromuscular junction, and muscle). The diagnosis of restriction is based upon the finding of a normal FEV1 /VC and reduced VC in the setting of a decreased TLC. While TLC generally is reduced in most disorders producing a restrictive pattern, FRC is usually preserved in disorders characterized by decreased respiratory force (e.g., the neuromuscular disorders) and is reduced in the others. In neuromuscular disorders, ERV is decreased because of loss of expiratory force, so that RV is often increased. In the other types of restrictive disorders, RV is usually reduced. Whether or not the Dlco is reduced in the restrictive disorders depends on the underlying disease process. Primary parenchymal disorders and removal of lung tissue decrease the diffusing surface area and reduce Dlco . Diseases of the pleura and chest wall that limit thoracic excursion during the inspiratory VC maneuver, which is part of the technique for determining Dlco , also reduce this measurement.

tion. The mixed pattern also occurs in complicated situations when there is more than one cause (e.g., a lobar pneumonia or large pleural effusion occurring in a patient with underlying chronic bronchitis or emphysema).

Isolated Decrease in the Efficiency of Gas Transfer An isolated reduction in the DlCO suggests one of two possible abnormalities: (1) interstitial lung disease that is so mild as not to affect measurements of airflow or lung volume, or (2) widespread occlusive disease of the pulmonary microcirculation (e.g., due to an inflammatory process or multiple small emboli). In occlusive vascular disorders, tests of airflow and lung volume are usually normal. Although other disorders can also decrease DlCO , almost invariably they also reduce airflow, lung volumes, or both. Quantification of the degree to which the DlCO is reduced by any of these processes is indicated in Table 34-21. Notably, interlaboratory differences are substantial for measurements of DlCO .

Table 34-21 Additional Details of Pulmonary Function Test Results in a Mixed Obstructive-Restrictive Pattern Occasionally, a battery of pulmonary function tests demonstrates features of both obstructive and restrictive patterns. Most often, the mixed pattern is characterized by a low FEV1 /VC% (indicating obstructive airway disease) and VC and reduced TLC (indicating coexisting restrictive disease). A number of disorders can produce the mixed obstructive/restrictive pattern. Sarcoidosis and interstitial fibrosis, when severe, generally result in this pattern because the parenchymal disease causes restriction and narrowing of the airways by adjacent fibrosis, evoking signs of airway obstruc-

Categorization of Reduction in Efficiency of Gas Transfer: Measurement of DlCO Severity

DlCO , Percent Predicted

Mild

>60, but less than lower limit of normal

Moderate

40–60

Severe

<40

Source: Modified from Pellegrino R, Viegi G, Brusasco V, et al: Interpretive strategies for lung function tests. Eur Respir J 26:948–968, 2005.

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Table 34-22 Characteristic Alterations in Pulmonary Function Tests According to the Major Patterns of Abnormality Pattern

Airflow (FEV1 /VC%)

Airflow Response to Bronchodilators

Volumes

Lung DlCO

Obstructive Irreversible Reversible Small-airway disease Upper-airway obstruction

↓ ↓ ↓ ↓

↔ ↑ ↔ ↔

↑ ↑ ↔ ↔ or ↑

↔ or ↓ ↔ ↔ ↔

Restrictive Parenchymal disease Surgical resection Pleural, chest wall disease Reduced expiratory force generation Mixed obstructive-restrictive Isolated reduction in efficiency of gas transfer

↔ or ↑ ↔ ↔ ↔ ↓ ↔

↔ ↔ ↔ ↔ ↔ or ↑ ↔

↓ ↓ ↓ ↓ ↓ ↔

↓ ↓ ↔ ↔ ↓ ↓

Note: ↓ = decreased; ↑ = increased; ↔= no change or normal.

Summary of Approach to Interpretation Pulmonary function tests are designed to detect common disorders. Test interpretation relies heavily on recognition of major patterns of abnormality (Table 34-22). These patterns often suggest pathogenetic mechanisms and are helpful to the clinician in arriving at a diagnosis. The degree of abnormality provides a quantitative measure of the extent of involvement at a particular time. Moreover, repeated testing makes it possible to pace and quantify the course of the illness and to assess the effects of therapeutic interventions.

SUGGESTED READING ATS Statement: Guidelines for Methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 161:309–329, 2000. ATS Statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 166:111–117, 2002. Britton J, Pavord I, Richards K, et al: Factors influencing the occurrence of airway hyperreactivity in the general population: The importance of atopy and airway calibre. Eur Respir J 7:881–887, 1994. Eaton T, Young P, Milne D, et al: Six-minute walk, maximal exercise tests: Reproducibility in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 171(10):1150–1157, 2005. Hallstrand TS, Boitano LJ, Johnson WC, et al: The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis. Eur Respir J 25:96–103, 2005.

Hankinson JL, Odencratz JR, Fedan KB: Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med 159:179–187, 1999. Hogg JC, Chu F, Utokaparch S, et al. The nature of smallairway obstruction in chronic obstructive pulmonary disease. N Engl J Med 350: 2645–2653, 2004. Hutcheon M, Griffin P, Levison H, Zamel N: Volume of isoflow: A new test in the detection of mild abnormalities of lung mechanics. Am Rev Respir Dis 110:458–465, 1974. Johnson LR, Enright PL, Voelker HT, et al: Volume spirometers need automated internal temperature sensors. Am J Respir Crit Care Med 150:1575–1580, 1994. Kelman GR, Nunn JF: Nomograms for correction of blood Po2 , Pco2 pH, and base excess for time and temperature. J Appl Physiol 21:1484–1490, 1966. Khanna D, Clements PJ, Furst DE, et al: Correlation of the degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis: Results from the Scleroderma Lung Study. Arthritis Rheum 52(2):592–600, 2005. Knudson RJ, Clark DF, Kennedy TC, et al: Effect of aging alone on mechanical properties of the normal adult human lung. J Appl Physiol 43:1054–1062, 1977. MacIntyre N, Crapo RO, Viegi DC, et al: Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 26:720–735, 2005. Miller MR, Crapo RO, Hankinson J, et al: General considerations for lung function testing. Eur Respir J 26:153–161, 2005.

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Miller MR, Hankinson J, Brusasco V, et al: Standardisation of spirometry. Eur Respir J 26:319–338, 2005. Morris AH, Kanner RE, Crapo RO, et al (eds): Clinical Pulmonary Function Testing: A Manual of Uniform Laboratory Procedures, 2nd ed. Salt Lake City, Intermountain Thoracic Society, 1984. O’Connor GT, Sparrow D, Weiss ST: A prospective longitudinal study of methacholine airway responsiveness as a predictor of pulmonary-function decline: The Normative Aging Study. Am J Respir Crit Care Med 152:87–92, 1995. Parker AL, McCool FD: Pulmonary function characteristics in patients with different patterns of methacholine airway hyperresponsiveness. Chest 121(6):1818–1823, 2002. Pellegrino R, Viegi G, Brusasco V, et al: Interpretive strategies for lung function tests. Eur Respir J 26:948–968, 2005.

Pulmonary Function Testing

Pinto-Plata VM, Cote C, Cabral H, et al: The 6-minute walk distance: Change over time and value as a predictor of survival in severe COPD. Eur Respir J 23:28–33, 2004. Rahn H, Otis AB, Chadwick LE, et al: The pressure volume diagram of the thorax and lung. Am J Physiol 146:161–178, 1946. Smith L, McFadden ER Jr: Bronchial hyperreactivity revisited. Ann Allergy Asthma Immunol 74:454–470, 1995. Sorbini CA, Grassi V, Solinas E, et al: Arterial oxygen tension in relation to age in healthy subjects. Respiration 25:3–13, 1968. Townley RG, Bewtra AK, Nair NM, et al: Methacholine inhalation challenge studies. J Allergy Clin Immunol 64:569–574, 1979. Woolcock AJ, Vincent NJ, Macklem PT: Frequency dependence of compliance as a test for obstruction in the small airways. J Clin Invest 48:1097–1106, 1969.

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35 Principles and Applications of Cardiopulmonary Exercise Testing Karl T. Weber Ahmad Munir

I. PRINCIPLES, DEFINITIONS, AND CLINICAL APPLICATION OF CARDIOPULMONARY EXERCISE TESTING Resting Oxygen Uptake and Transport Exercise Oxygen Uptake and Transport Carbon Dioxide Production Clinical Application of Cardiopulmonary Exercise Testing Noninvasive Treadmill Exercise Invasive Treadmill Exercise II. CHRONIC CARDIAC FAILURE Systolic Dysfunction Diastolic Dysfunction Chronotropic Dysfunction Survival and Prognosis Efficacy of Medications Exercise Training Ischemic Heart Disease

Cardiopulmonary exercise testing draws on the recognition that the thorax is a structure for the transport of the respiratory gases involved in metabolism and that the function of its components—diaphragm, heart, lungs, rib cage, and corresponding skeletal muscles—is to transport O2 to and CO2 from metabolizing tissues. The transport of O2 and CO2 must adjust to physiological and pathophysiological stresses that augment the body’s consumption of oxygen (V˙ O2 ) and carbon dioxide production (V˙ CO2 ). During strenuous levels of muscular work, for example, V˙ O2 may rise eightfold, accompanied by increased V˙ CO2 . Cardiovascular or ventilatory disease can disrupt the unit’s functional integrity. Severe disease may elicit abnormality in respiratory gas transport that may be evident at rest, when the O2 requirements of the body

III. CHRONIC CIRCULATORY FAILURE Valvular Heart Disease Obstructive Sleep Apnea Congenital Heart Disease Pulmonary Hypertension IV. CHRONIC LUNG DISEASES Obstructive Lung Disease Restrictive Lung Disease V. EVALUATION OF EXERTIONAL DYSPNEA VI. OTHER APPLICATIONS OF CARDIOPULMONARY EXERCISE TESTING Cardiac Transplantation Surgical Risk Assessment

are modest. Lesser disease may allow resting pulmonary function to be preserved but abnormal respiratory gas transport becomes apparent when the unit is stressed by an increase in the oxygen requirement. Cardiopulmonary exercise testing includes the monitoring of respiratory gas exchange (V˙ O2 and V˙ CO2 ), minute ˙ and its components, tidal volume and respiventilation (Ve) ratory rate, together with blood pressure, heart rate, and the electrocardiogram. Cardiopulmonary exercise testing represents a useful approach in the clinical evaluation of a wide variety of disorders and circumstances. This chapter addresses physiological principles and the clinical application of cardiopulmonary exercise testing in the evaluation of major disorders that impair cardiac or pulmonary function.

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Table 35-1 Oxygen Utilization, Content, Transport, and Extraction O2 utilization 250 ml/min

= Cardiac output · (arterial O2 content − venous O2 content) = 5000 ml/min · (19 ml/dl − 14 ml/dl)

Arterial O2 content 19 ml/dl

= Hemoglobin · % saturation · O2 combining capacity = 14 gm/dl · 0.96 · 1.34 ml/gm

Venous O2 content 14 ml/dl

= 14 gm/dl · 0.96 · 1.34 ml/gm

Arteriovenous O2 difference 5 ml/dl

= Arterial O2 content − venous O2 content = 19 ml/dl − 14 ml/dl

O2 transport 950 ml/min

= Cardiac output · arterial O2 content = 5000 ml/min · 19 ml/dl

O2 extraction 25%

 Arteriovenous O2 difference  · 100%   = Arterial O2 content    = 19 − 14 · 100% 19

Source: Reproduced from Weber KT: Gas transport and the cardiopulmonary unit, in Weber KT, Janicki JS (eds), Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia. Saunders. 1986. pp 15–33.

PRINCIPLES, DEFINITIONS, AND CLINICAL APPLICATION OF CARDIOPULMONARY EXERCISE TESTING The metabolic gas transport unit, also referred to as the “cardiopulmonary unit,” links metabolizing tissues to the atmospheric supply of O2 . O2 transport to the tissues must be precise and based upon prevailing need. CO2 produced by tissues must be eliminated into the atmosphere in an equally efficient manner.

Resting Oxygen Uptake and Transport Concepts and calculations pertaining to V˙ O2 and O2 content, transport, and extraction are reviewed in Table 35-1. The heart and lungs accommodate to the metabolic requirements of tissues on a moment-to-moment basis, according to physiological priorities. Tissue requirements for O2 dictate ˙ and cardiac output. In an average-sized person, a certainVe the resting V˙ O2 averages 250 ml/min or 3.5 ml/min/kg body weight (one metabolic equivalent) and is associated with a ˙ of 8 to 10 L/min and cardiac output of 4 to 6 L/min. O2 Ve transport, also termed O2 delivery, ranges between 730 and 1040 ml/min and is more than adequate to satisfy the resting V˙ O2 . On average, 25 percent of the arterial O2 content is extracted by tissues. O2 delivery and extraction increase during physiological stress in proportion to the increase in O2 demand. Factors that normally determine O2 availability at

rest and during exercise include cardiac output, hemoglobin concentration and the percent of its O2 saturation, and O2 extraction.

Exercise Oxygen Uptake and Transport ˙ and O2 delivery increase during exercise. Strenuous work Ve ˙ eight to ten times its resting level. Ventilation can increase Ve normally poses no limitation on the ability of tissues to conduct aerobic work. In contrast, the extent to which cardiac output rises during progressive work is less dramatic. In untrained subjects, cardiac output increases four to five times its resting value. Cardiac output rises 600 ml/min for every 100 ml/min increment in V˙ O2 . This is considered to be the normal “gain” setting between the heart and its cardiac output and V˙ O2 . O2 availability during physical activity is further ensured by enhanced O2 extraction and circulatory autoregulation. Reflex and humoral influences produce vasoconstriction in tissues that are less metabolically active, permitting a greater apportionment of blood flow to exercising muscle. Physiological limits to the increase in cardiac output and O2 extraction (approximately 75 to 80 percent of arterial O2 content) determine the aerobic capacity of untrained subjects to incremental exercise. Beyond these physiological limits, any additional increment in work is not accompanied by an increase in O2 uptake; a plateau in V˙ O2 is reached. This plateau is termed the maximal oxygen uptake (V˙ O2 max ). The results of cardiopulmonary exercise testing, including the V˙ O2 max , are shown in Fig. 35-1 for a 40-year-old man

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Figure 35-1 Cardiopulmonary exercise response in a 40-year-old man without heart or lung disease. Shown are 2 min of standing rest, followed by incremental treadmill exercise. Individual responses (color coded) include oxygen uptake (V˙ O2 ), carbon dioxide production (V˙ CO2 ), minute ventilation (V˙ E), and heart rate (HR). Maximal O2 uptake, a plateau in V˙ O2 was attained after the crossover of V˙ CO2 and V˙ O2 (arrowhead), representing the anaerobic threshold (AT) and accompanied by a disproportionate (broken line) rise in V˙ E.

without heart or lung disease. The individual responses in ˙ and heart rate are illuminated during proV˙ O2 , V˙ CO2 , Ve, gressive increments in treadmill work. A V˙ O2 max of 2198 ml/min (27.2 ml/min/kg) was attained. This is a true plateau in V˙ O2 , with V˙ O2 remaining invariant for 2.5 stages (5 min) of exercise. V˙ O2 max should not be equated to, or used as synonym for, peak V˙ O2 achieved during symptom-limited exercise. V˙ O2 max reflects the individual’s aerobic capacity—a physiological capacity of the cardiovascular system. In an average-sized, untrained individual whose maximum cardiac output and arteriovenous oxygen difference are 20 L/min and 12 ml/dl, respectively, a V˙ O2 max of 2400 ml/min is expected. In athletes, a greater cardiac reserve and enhanced capacity for oxidative metabolism by trained skeletal muscle provide a greater aerobic capacity. In patients with heart disease, in whom the ability to increase cardiac output during exercise is impaired, V˙ O2 max is proportionally reduced.

Carbon Dioxide Production The right heart “accepts” metabolically produced CO2 , and the alveolar exchange surface expels the CO2 into the atmosphere. CO2 is a major respiratory stimulant that maintains eucapnia. Between 75 and 80 percent of O2 is converted to CO2 . Accordingly, resting V˙ CO2 averages 190 ml/min and represents a metabolic source of CO2 . The resting V˙ CO2 / V˙ O2 ratio, or respiratory gas exchange ratio (R), typically ranges between 0.75 and 0.85. The absolute value of R depends on the proportion of carbohydrates and fats provided by the diet. V˙ O2 and V˙ CO2 increase proportionally during physical activity as long

as an adequate amount of O2 is available to sustain oxidative metabolism. During strenuous muscular work, V˙ O2 increases to a level at which the heart is unable to provide O2 at the required rate. Consequently, tissue O2 availability becomes inadequate. Working skeletal muscle calls upon less efficient anaerobic metabolism to derive energy. This leads to lactate production from working muscle which exceeds that normally produced. This nonmetabolic source of CO2 is derived from rapid buffering of the lactate by bicarbonate; the CO2 that is generated serves as a respiratory stimulant. The accompanying increase ˙ maintains eucapnia and increases the respiratory gas in Ve exchange ratio which is greater than that associated with aerobic metabolism. Anaerobic metabolism during a progressive ˙ and exercise test is heralded by the disproportionate rise in Ve V˙ CO2 relative to V˙ O2 . The corresponding level of V˙ O2 at which anaerobic metabolism occurs is termed the anaerobic threshold (AT). The point during exercise at which V˙ O2 exceeds ˙ rises disproportionately is shown in Fig. 35-1. V˙ O2 and Ve Anaerobiosis normally occurs when 60 percent or more of a person’s aerobic capacity has been reached. For the 40-yearold man whose exercise response is shown in Fig. 35-1, the AT occurred at a V˙ O2 of 18.8 ml/min/kg, or 69 percent of his ˙ 2 max. Vo

Clinical Application of Cardiopulmonary Exercise Testing In patients with mild to moderate cardiovascular or respiratory disease, symptoms of fatigue or breathlessness frequently limit physical activity. Because their quality of life is compromised, they seek, or are referred for, medical evaluation.

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Re-creating muscular work in a monitored setting permits an evaluation of the nature and severity of such symptoms and the relative importance of abnormal heart or lung function. This strategy provides information that surpasses that available from measures of heart and lung function determined at rest, such as ejection fraction, lung volumes, or airflows. The ˙ respiratory rate, continuous monitoring of V˙ O2 , V˙ CO2 , Ve, and tidal volume during incremental exercise can be performed simply and on a breath-by-breath basis. Data shown in Fig. 35-1 are displayed throughout the test. The choice of a particular cardiopulmonary exercise test depends on the nature and expression of the clinical disorder and the particular problem to be addressed. For most clinical evaluations, isotonic forms of exercise afford an acceptable and reproducible form of exercise for patients with heart or lung disease. However, even though noninvasive cardiopulmonary exercise testing in patients with lung disease may help to identify the impairment in aerobic capacity, the abnormalities in ventilation and the severity of the abnormalities, these parameters are not necessarily diagnostic. For example, V˙ O2 max , AT, or ˙ does not identify the underlying structural defect exercise Ve responsible for a patient’s abnormal response. This diagnosis may require invasive monitoring during cardiopulmonary exercise testing to identify specific hemodynamic abnormalities. Echocardiography and specialized pulmonary function studies may be required.

Table 35-2 Modified Naughton Treadmill Exercise Protocol Stage Speed Grade Physical Activities 1

1.0

Driving a car Sitting and writing or eating

1.5

Dressing; knitting Walking to bathroom Light auto repair

2.0

3.5

Shave self in bathroom Wash entire body Food shopping

2.0

7.0

Sexual activity Raking leaves Plastering

2.0

10.5

3.0

7.5

3.0

10.0

Lifting and carrying 65–80 lb Carpentry Climbing hills (no load)

3.0

12.5

Digging Snow shoveling Climbing stairs (20-lb load)

3.0

15.0

Beyond this level, work loads are equal to very vigorous exercise (e.g., skiing, basketball)

3.4

14.0

3.4

16.0

3.4

18.0

3.4

20.0

3.4

22.0

Noninvasive Treadmill Exercise Walking represents a common daily exercise rather than a specialized skill. A patient who walks into the physician’s office or down a hospital corridor can walk on a treadmill at 1.0 or 1.5 mph, zero grade. Treadmills are programmable. The Bruce protocol, which employs specific increments in treadmill speed and slope over short periods to evaluate myocardial ischemia, may not be useful for patients with limited exercise tolerance. A modified Naughton protocol of gradually progressive exercise (Table 35-2) is useful for patients with heart or lung disease who have a wide range of exercise tolerance. In this protocol, the first two stages of exercise constitute very low workloads and serve as a warmup for patients with heart or lung disease of minor severity; in contrast, these stages represent near-maximal exercise for patients with more advanced disease. V˙ O2 max is defined as V˙ O2 that remains invariant (less than 1 ml/min/kg for 30 s or more) despite increment in workload. An invariant V˙ O2 for at least two stages of exercise is preferred (Fig. 35-1). V˙ O2 max follows the AT, and this definition ˙ 2 max presumes that the AT has already been achieved. of Vo The AT generally occurs at 60 percent of a patient’s aerobic capacity. V˙ O2 max associated with incremental treadmill exercise provides a greater aerobic capacity than does cycle ergometry because it works a larger group of muscles. A patient’s aerobic capacity to incremental treadmill exercise is used to grade the functional impairment (Table 35-3). V˙ O2 max is an objective measure of functional status—in contradistinction to the New York Heart Association classification, which is

Stacking firewood Mowing lawn (powered) Walking down stairs Scrubbing floors Gardening Walking up stairs

Source: Reproduced from Weber KT, Janicki JS, McElroy PA: Cardiopulmonary exercise (CPX) testing, in Weber KT, Janicki JS (eds), Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia, Saunders, 1986, pp 151–167.

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Table 35-3 Classification of Cardiac and Circulatory Failure Class

Severity

V˙ O2 max (ml/kg/min)

Anerobic Threshold (ml/kg/min)

Predicted Cardiac Index (L/m2 /min)

Mild to none

>20

>14

Mild to moderate

16 to 20

11 to 14

6 to 8

Moderate to severe

10 to 16

8 to 11

4 to 6

Severe

6 to 10

5 to 8

Source: Adapted from Weber KT, Janicki JS, McElroy PA: Cardiopulmonary exercise (CPX) testing, in Weber KT, Janicki JS (eds), Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia, Saunders, 1986, pp 151–167.

based on perceptions and biases of the patient and physician. The determination of O2max by treadmill is reproducible in patients with a wide variety of cardiovascular disorders. A V˙ O2 max of under 20 ml/min/kg has been designated as the cutoff for grading impairment of aerobic capacity; adult men and women, including the elderly (over 65 years of age), have an expected V˙ O2 max greater than 20 ml/min/kg. The duration of symptom-free treadmill exercise should not be equated with the V˙ O2 max . Treadmill time suffers from not having an objective, quantitative end point. Differences in gait and body weight create different levels of work for equivalent stages of treadmill exercise. Symptom-limited exercise time is subject to patient motivation and physician bias. Peak heart rate attained during exercise is also a less precise measure of V˙ O2 max . This is particularly true in patients with atrial fibrillation. Determination of the AT can be defined according to one or more criteria. These include: (1) a disproportionate ˙ or R relative to V˙ O2 and (2) a disproportionate rise in V˙ CO2 , Ve, rise in end-tidal O2 relative to end-tidal CO2 . These criteria can best be applied to data on breath-by-breath respiratory gas exchange. In our laboratory, a simple strategy is used. The AT is identified as the level of V˙ O2 attained during treadmill work after the plots of V˙ O2 and CO2 cross, when R exceeds 1.0. Figure 35-1 depicts the crossover in V˙ CO2 and V˙ O2 from breath-by-breath gas exchange data monitored throughout incremental treadmill exercise. It also demonstrates the point ˙ rises disproportionately. Measured days or weeks at which Ve apart, this noninvasive determination of the AT is reproducible in a wide range of patients with cardiac or circulatory failure and correlates with the lactate threshold. The normal ventilatory response to incremental tread˙ created by an inmill exercise consists of an increase in Ve crease in respiratory rate and tidal volume. Ventilatory reserves, represented by maximal voluntary ventilation (MVV) and vital capacity determined during routine pulmonary function testing, are only partly utilized during light, moderate, and maximal exercise by normal persons. The ratio of

˙ to MVV reflects use of this ventilatory maximal exercise Ve ˙ in normal subjects and patients with prereserve. Exercise Ve dominant cardiovascular disease rarely exceeds 50 percent of MVV. The same is true of the ratio between maximal exercise tidal volume and vital capacity. These limitations in ventilatory responses are consistent with a ventilatory effort that can be voluntarily sustained at rest without the appearance of fatigue or breathlessness. An oximeter, worn on either an earlobe or a finger, affords noninvasive monitoring of arterial O2 saturation during exercise. This is a useful screening procedure in patients in whom O2 desaturation might be anticipated (e.g., those with congenital heart disease with right-to-left shunt, restrictive or obstructive lung disease, or pulmonary vascular disease). Normal subjects and patients with chronic cardiac or circulatory failure do not develop arterial hypoxemia (arterial O2 saturation under 90 percent) during exercise. In patients in whom oximetry indicates O2 desaturation, confirmatory evidence from direct measurement of arterial blood gases during repeat exercise may be advisable. Thus, incremental treadmill exercise can be used to determine the following: the AT with a submaximal test, the AT and V˙ O2 max with a maximal test, the ventilatory response to submaximal or maximal exercise, and arterial O2 desaturation during submaximal or maximal exercise.

Invasive Treadmill Exercise Invasive hemodynamic monitoring may be necessary for better definition of the nature and severity of an underlying cardiopulmonary disorder. A triple-lumen flotation catheter can be safely used for hemodynamic monitoring during upright exercise. The hemodynamic response to incremental treadmill exercise in normal subjects is characterized by a progressive increase in cardiac output, accompanied by minimal increments in left and right ventricular filling pressures. The increase in cardiac output occurs because of an increment in stroke volume, which is most apparent at low and moderate

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workloads, and because of an increase in heart rate, which accompanies the exercise response. Systemic O2 extraction increases progressively during incremental exercise to exceed 70 percent at maximal workloads. An increase in the concentration of lactate in mixed venous blood, demonstrated by sampling pulmonary arterial blood, occurs when O2 extraction exceeds 60 percent and when the subject is working at greater than 60 percent of V˙ O2 max . Systolic and mean arterial pressures increase during upright exercise. Because of skeletal muscle vasodilation, arterial diastolic pressure remains essentially unchanged during exercise. Systemic vascular resistance falls by 50 percent to approximately 600 dynes · s · cm–5 during incremental, isotonic treadmill exercise. In normal persons, pulmonary artery systolic, mean, and diastolic pressures increase only minimally during exercise and only at higher workloads. Pulmonary vascular resistance, like systemic vascular resistance, falls 50 percent to about 60 dynes · s · cm–5 during incremental isotonic exercise.

CHRONIC CARDIAC FAILURE In physiological terms, cardiac failure is defined as an impairment in cardiac output secondary to a disease process affecting the myocardium. Ischemic heart disease and dilated cardiomyopathies are examples of disease entities that can result in chronic cardiac failure. V˙ O2 max and the AT each predict cardiac reserve and, thereby, the severity of cardiac failure. These parameters further serve to demonstrate objectively a patient’s functional capacity, which is not predictable by the cardiac ejection fraction. Patients with an ejection fraction of under 20 percent may still be able to swim.

Systolic Dysfunction In patients with chronic cardiac failure, V˙ O2 max attained during incremental treadmill exercise is primarily a function of maximal cardiac output. This conclusion has been confirmed by numerous studies. An impairment in aerobic capacity is gauged according to the exercise AT and V˙ O2 max and assigned a functional class, as reviewed in Table 35-3. These parameters are, in turn, used to predict maximal exercise cardiac index (or cardiac reserve). Examples of V˙ O2 max and the AT attained by two patients with chronic cardiac failure (one class B, the other class C) are given in Fig. 35-2. To measure V˙ O2 max in such patients, they must be exercised to exhaustion. The AT is achieved at submaximal workloads short of exhaustion; it, too, stratifies the degree of cardiac dysfunction. Validation of these concepts was obtained during treadmill exercise using invasive measures of cardiac output and mixed venous lactate concentration. Patients had chronic cardiac failure of varying severity (classes A to D) due to either ischemic or myopathic heart disease. In each exercise class, the arteriovenous O2 difference rose to 12 ml/dl or more at maximum exercise, corresponding to a systemic O2 extrac-

tion in excess of 70 percent, suggesting that O2 extraction had reached maximal physiological levels. The reduction in aerobic capacity of a patient with chronic cardiac failure is, therefore, due primarily to impaired cardiac reserve. The cardiac output–O2 relation to progressive treadmill exercise for these patients is given in Fig. 35-3. For each exercise class, cardiac output is presented as a percentage of V˙ O2 max (set equal to 100 percent) that existed at rest and throughout each stage of exercise. Cardiac output increased by 600 ml/min/m2 for each dl/min/m2 increase in V˙ O2 in each class. This indicates that the heart responds to tissue O2 requirements irrespective of the severity of heart failure, but it is limited by the maximal cardiac output that it can attain. Differences in cardiac output achieved at peak exercise are seen between classes. Progressive reductions in cardiac reserve are responsible for different aerobic capacities observed in these patients. V˙ O2 max , therefore, serves as a noninvasive measure of peak exercise cardiac output and is given for each functional class in Table 35-3. The cardiac output response to exercise is a function of the increases in stroke volume and heart rate. Responses in stroke volume for patients in chronic cardiac failure are shown in Fig. 35-4 for each exercise class. In class A and B patients, stroke volume rises 50 percent during lighter workloads that represent less than 60 percent of V˙ O2 max ; at larger workloads, further increments in stroke volume are less apparent. A 25 percent rise in stroke volume occurs at submaximal exercise in class C patients, whereas in class D patients, exercise stroke volume is no different from its resting value. Exercise stroke volume is a result of several factors, including systolic wall stress, mitral or tricuspid regurgitation that may appear during exercise, and depressed myocardial contractility. For each functional class of chronic cardiac failure, the ˙ 2 response to upright incremental exercise is heart rate–VO represented by a common slope. The average slope is 3.6 beats per minute for every 1-ml/min/kg increment in V˙ O2 . Peak heart rate achieved is a function of maximal workload performed. Maximal exercise heart rate is, therefore, different for each class. In class D patients, the increase in heart rate is the sole mechanism by which cardiac output increases during exercise. Some patients with chronic cardiac failure deviate from this heart rate–V˙ O2 relation by having an inappropriate sinus tachycardia, either at rest and throughout exercise, or simply during exercise. In the presence of a reduced ejection fraction and ventricular dilation, this inappropriately rapid heart rate further compromises exercise cardiac output and reduces aerobic capacity. Under these circumstances, β-adrenergic receptor blockade is useful in attenuating the resting or exercise heart rate. Such chronotropic dysfunction (see below) to exercise may also apply to patients with chronic atrial fibrillation. An example of an inappropriate rapid heart rate during incremental treadmill exercise (Naughton protocol) is given in Fig. 35-5 for a patient with atrial fibrillation and dilated cardiomyopathy of uncertain origin. As in normal persons, lactate production appears in patients with chronic cardiac failure when systemic O2 extraction exceeds 60 percent. Mixed venous lactate concentration

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Figure 35-2 Cardiopulmonary exercise test results for a 45-year-old woman (A) and a 40-year-old man (B ), each with ischemic heart disease and chronic cardiac failure. Only V˙ O2 and V˙ CO2 are shown, to better demonstrate the anaerobic threshold (AT) and V˙ O2 max attained by each patient. In panel A, the AT was seen with a V˙ O2 of 11.6 ml/min/kg and a V˙ O2 max of 16.5 ml/min/kg. This represents a functional class B response. The AT and V˙ O2 max are 8.5 and 13.7 ml/min/kg, respectively (panel B ). This corresponds to functional class C.

during exercise increases above resting values when 60 percent or more of V˙ O2 max is attained. Given differences in aerobic capacity between exercise classes, different workloads are associated with this lactate threshold (Fig. 35-6). In class D patients, in whom the cardiac output response is limited, the lactate threshold occurs at very light workloads (V˙ O2 of 5 to 8 ml/min/kg). Corresponding values for class C, B, and A patients are 8 to 11 ml/min/kg, 11 to 14 ml/min/kg, and more than 14 ml/min/kg, respectively. Thus, the lactate threshold and the V˙ O2 max reflect the severity of chronic cardiac failure, as given in Table 35-3. A noninvasively determined AT

based on measurements of respiratory gas exchange, as discussed previously, corresponds to the invasively measured lactate threshold. In chronic cardiac failure, the left ventricular filling pressure during exercise, as gauged from recordings of the occlusive wedge pressure, increases to a different degree in each exercise class (Fig. 35-7). In class A patients, the rise in wedge pressure during isotonic exercise rarely exceeds 18 mmHg. This resembles a normal response. In class B patients, more dramatic elevations in exercise wedge pressure—to 25 mmHg or higher—frequently occur. Resting filling pressure

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Figure 35-3 Relationship between treadmill exercise cardiac index and normalized aerobic capacity for patients with chronic cardiac failure of diverse origin and severity, subdivided according to each functional class. (From Weber KT, Janicki JS: Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 55:22A–31A, 1985.)

is increased in class C and D patients; a further increase may occur during upright exercise, often to levels in excess of 30 mmHg. Despite these marked levels of pulmonary venous pressure, patients do not develop evidence of pulmonary congestion after exercise. Moreover, elevations in wedge pressure

Figure 35-4 Relationship between treadmill exercise stroke volume index and normalized aerobic capacity for patients with chronic cardiac failure of varying severity, as expressed by each functional class. (From Weber KT, Janicki JS: Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 55:22A–31A, 1985.)

neither predict exercise cardiac reserve and aerobic capacity nor are responsible for exertional dyspnea in these patients. Dyspnea corresponds with the lactate threshold and a dispro˙ relative to V˙ O2 . Despite dyspnea, patients portionate rise in Ve can be encouraged to exercise to exhaustion, attaining V˙ O2 max . In patients with acute cardiac failure, pulmonary congestion

Figure 35-5 Cardiopulmonary exercise test results in a 48-year-old man with atrial fibrillation and dilated (idiopathic) cardiomyopathy. Note the rapid heart rate at rest and throughout incremental treadmill exercise. Predicted maximum heart rate range in this patient is shown by the broken lines. He achieved this rate during the first stage of exercise and exceeded it during the last stage of exercise. This is an inappropriate heart rate response. The anaerobic threshold (AT) is 13 ml/min/kg (arrow), in keeping with functional class B. He did not achieve V˙ O2 max and, therefore, had a peak V˙ O2 of 15 ml/min/kg.

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Figure 35-6 Relationship between mixed venous lactate concentration and V˙ O2 to incremental treadmill exercise for patients with chronic cardiac failure of varying severity, as expressed by each functional class. (From Weber KT, Janicki JS: Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 55:22A–31A, 1985.)

and dyspnea correlate with the increase in wedge pressure; pulmonary edema occurs when hydrostatic pressure exceeds the colloidal osmotic pressure of 25 mmHg. ˙ rises appropriately during incremental exercise in Ve ˙ corpatients with chronic cardiac failure. The response in Ve ˙ responds most closely to VCO2 throughout exercise (aerobic and anaerobic work) and is sufficient to sustain alveolar ventilation, thereby preventing hypoxemia and hypercapnia.

˙ attained during exercise is less than 50 percent Maximum Ve of MVV. Thus, these patients do not exhaust their ventilatory reserve in responding to exercise, even when their pulmonary compliance may be adversely affected by the chronic pulmonary congestion and increments in pulmonary venous pressure that appear during exercise. In order to minimize the work of breathing during exercise, class C and D patients ˙ Thus, use a pattern of rapid, shallow breathing to increase Ve. the rise in tidal volume during exercise above its resting value is modest and compatible with a substantial portion of each breath being wasted in ventilation of the anatomic dead space. The response of class A and B patients more closely approximates that of healthy persons, in whom respiratory rate rises progressively during incremental exercise and the increase in tidal volume occurs early during the transition from rest to low-level exercise.

Diastolic Dysfunction

Figure 35-7 Relationship between treadmill exercise cardiac index and occlusion wedge pressure in patients with chronic cardiac failure, subdivided according to functional class. (From Weber KT, Janicki JS: Cardiopulmonary exercise testing for evaluation of chronic cardiac failure. Am J Cardiol 55:22A–31A, 1985.)

In 30 percent or more of patients with symptomatic heart failure, primary diastolic dysfunction is responsible. The ejection fraction is normal or only minimally impaired in these patients. Diastolic dysfunction relates to an inability of the left ventricle to accommodate left atrial and pulmonary venous blood flow during diastole without a marked increase in filling pressure. Abnormal diastolic relaxation and filling typically appear in patients with chronic ischemic heart disease (with previous myocardial infarction), in those with hypertensive heart disease, and in the elderly. Responsible mechanisms are thought to include abnormal tissue structure, as occurs with the accumulation of fibrous tissue or infiltration with amyloid and abnormal handling of calcium by the sarcoplasmic reticulum. Factors extrinsic to the myocardium may also contribute. Examples include the interaction between the pressure- or volume-overloaded right ventricle with the left ventricle and the interplay between the heart and pericardium.

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Invasive cardiopulmonary exercise testing, together with incremental bicycle exercise, has been used to address the hemodynamic response of patients with primary diastolic dysfunction. Most patients studied had systemic hypertension, and many were elderly; all had a clinical history of pulmonary congestion. Peak exercise V˙ O2 was reduced, owing to a reduction in the responses of the cardiac output and stroke volume; arteriovenous O2 difference increased above 10 ml/dl. The level of V˙ O2 achieved with exercise correlated with the peak response of the cardiac output. In comparison to age-matched controls, expected exercise-associated increments in left ventricular end-diastolic volume were not seen and were accompanied by increased left ventricular filling pressure. Thus, abnormalities in diastolic filling abrogated the Frank-Starling mechanism, thereby restricting the rise in cardiac output during exercise; this finding may explain symptoms of fatigue and breathlessness that these patients experience on exertion. Primary diastolic dysfunction has been observed in patients following cardiac transplantation in which there is an abnormal blunting of the stroke volume and heart rate responses to exercise. Despite the slower exercise heart rate in the transplanted, denervated heart, in which diastolic filling periods would accordingly be longer, diastolic dysfunction is present, limiting the response of the cardiac output to exercise. Abnormal diastolic function has also been observed in the elderly and contributes to impaired exercise cardiac output response.

chronic biventricular pacing than with left ventricular pacing alone.

Survival and Prognosis Various gas exchange parameters have been used to assess prognosis in patients with heart failure, including AT, peak ˙ V˙ CO2 slope (a marker of ventilatory efficiency). V˙ O2 , and Ve/ V˙ O2 at AT and V˙ CO2 slope are less subject to patient motivation or premature cessation of exercise and, hence, are more useful parameters. Class D patients with little or no exercise cardiac reserve (Table 35-3) with AT less than 8 ml/min/kg have a marked reduction in 1- and 2-year survival as contrasted to class A and B patients with respective exercise cardiac index responses of greater than 8 and 6 to 8 L/min/m2 . V˙ O2 at AT, ˙ V˙ CO2 , is a better prognostic indicator than combined with Ve/ peak V˙ O2 alone. A low peak Paco2 with exercise is responsible ˙ V˙ CO2 slope and by itself is for the prognostic power of Ve/ also an independent prognosticator. Resting end-tidal CO2 has been shown to be a predictor of cardiac-related events. Another V˙ O2 kinetics parameter that is a strong predictor of survival and is less dependent on motivation is the mean response time (V˙ O2 deficit/%V˙ O2 ). In the recovery period, slow normalization of V˙ O2 is associated with a poor prognosis. The fluctuations in breathing patterns and its association with prognosis have also been studied in patients with heart failure. Cyclic fluctuations in minute ventilation at rest that persist during effort (external oscillatory ventilation) are associated with poor prognosis whereas oscillations at rest alone are not.

Chronotropic Dysfunction Cardiac reserve during exercise depends not only on systolic and diastolic function but also on heart rate and rhythm, including a coordinated contraction of the atria and ventricles. Cardiopulmonary exercise testing has been used to address the contribution of abnormal heart rate and rhythm on the AT and V˙ O2 max , broadly categorized here as chronotropic dysfunction. This includes abnormal sinus tachycardia, bradyarrhythmias, atrioventricular dissociation, and atrial fibrillation. Cardiopulmonary exercise testing has proved useful in the evaluation of pacemaker function and technique. Improvements in the AT at submaximal levels of work have been demonstrated for single-chamber, activity-triggered pacing compared with fixed-rate atrial or ventricular pacing. It, too, can help determine the optimum upper rate limit in heart failure patients with pacemakers. This can be determined by the highest pacing rate that still produces an increase in oxygen consumption. With recent advancements in pacemaker technology, cardiac resynchronization therapy (CRT) is being increasingly offered to patients with heart failure. In a study involving patients with CRT undergoing cardiopulmonary exercise testing, significant increments in peak V˙ O2 , V˙ O2 at AT and in all ventilation and metabolic parameters occurred. Patients with baseline V˙ O2 of less than 14 ml/min/kg had the most benefit. Similarly, patients with severe heart failure and atrial fibrillation had better hemodynamic performance with

Efficacy of Medications The response to various heart failure medications on gas exchange and hemodynamics has been evaluated. Patients with heart failure who are taking spironolactone have a significant increase in peak oxygen consumption, DlCO , and membrane diffusing capacity. In addition, in one study, use of an angiotensin-receptor blocker (losartan), along with an angiotensin-converting enzyme (ACE) inhibitor, resulted in a significant increase in peak V˙ O2 and exercise capacity. However, in another study, addition of candesartan to an ACE inhibitor had no such effect. Finally, in patients with chronic heart failure who were taking carvedilol, determination of peak V˙ O2 , which has been used as a prognostic marker in this group of patients, was not found to be useful.

Exercise Training Exercise training improves exercise tolerance and peak V˙ O2 in patients with heart failure and left ventricular dysfunction. Exercise training in moderate stable heart failure results in favorable qualitative, rather than quantitative, changes in skeletal muscle. Correction of maximum oxygen uptake for skeletal muscle mass is a more sensitive measure of changes associated with exercise training than is total body mass. Only a

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progressive, increasing workload seems to markedly improve oxygen uptake.

Ischemic Heart Disease Ischemia can be diagnosed during cardiopulmonary exercise testing with the help of ST segment changes during incremental exercise on a treadmill or an ergometer. The sensitivity and specificity of ST changes for ischemia is not high. Parameters of gas exchange on cardiopulmonary exercise testing can be used to improve the diagnostic ability of the exercise-induced ST changes. In one study, which examined the duration of “O2 pulse flattening” and changes in V˙ O2 relative to the work rate slope along with electrocardiographic ST changes, sensitivity increased from 46 to 87 percent and specificity from 66 to 74 percent. In another study, exercise cardiac output, estimated from V˙ O2 at AT, correlated with multivessel coronary artery disease, adverse cardiac events, and clinically driven revascularization. In patients who experienced myocardial infarction and who subsequently underwent 3 weeks of exercise training, a significant improvement in peak V˙ O2 was found.

CHRONIC CIRCULATORY FAILURE Circulatory failure, in physiological terms, refers to an inability of the heart to increase its cardiac output in a manner commensurate with prevailing V˙ O2 . Responsible factors may be extrinsic to the myocardium and include such entities as valvular heart disease, intrinsic pulmonary vascular disease, pericardial disease, and anemia.

Valvular Heart Disease Mitral or aortic valve disease may alter the functional integrity of the cardiopulmonary unit by impairing the heart’s ability to increase cardiac output in accord with increments in V˙ O2 . Pathophysiological alterations that result from chronic valvular disease and that determine the clinical course and outcome following valve replacement include right heart overload and structural remodeling of the pulmonary vasculature and lung interstitium. The more marked the preoperative impairment in cardiac reserve, the poorer the long-term prognosis. Similarly, the greater the elevation in pulmonary vascular resistance, the more delayed is its return to normal levels and the slower the postoperative abatement of symptoms. The decision for surgical intervention requires an assessment of cardiopulmonary status—one that can be assessed noninvasively and monitored over time to detect a decline in cardiac reserve. Noninvasive cardiopulmonary exercise testing serves this purpose. Because of the heightened risk of syncope and the myocardial ischemia and arrhythmias that can occur during exercise in patients with aortic valvular stenosis, these patients should exercise with extreme caution, if at all. Incompetence of the mitral and aortic valves is an example of a disorder that can result in chronic circulatory failure.

Figure 35-8 Relationship between treadmill exercise cardiac index and wedge pressure in patients with chronic mitral or aortic regurgitation, divided according to functional class. (From Weber KT, Janicki JS (eds): Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia, WB Saunders, 1986.)

Each creates a volume overload on the left ventricle. The onset of ventricular dysfunction is generally unpredictable and may initially appear only during vigorous levels of physical activity. As dysfunction progresses, symptoms appear at lower levels of activity and, finally, at rest. Resting cardiac output is often not distinguishable among class A, B, C, or D patients with mitral or aortic regurgitation. Cardiac reserve is reduced, however, and, accordingly, so is aerobic capacity. No impairment in systemic O2 extraction has been reported. Thus, as in chronic cardiac failure, any observed decrease in aerobic capacity must be due to a decline in maximal cardiac output. To the extent that cardiac output can increase, the exercise cardiac output–V˙ O2 relation is preserved among these classes, averaging 600 ml/min/m2 for every dl/min/m2 rise in V˙ O2 . Responses in cardiac output and wedge pressure for each exercise class are given in Fig. 35-8. As in chronic cardiac failure, marked increases in wedge pressure are seen in class C and D patients; this is also true for class B patients with mitral or aortic regurgitation. However, these patients do not develop clinical evidence of pulmonary congestion following exercise, and dyspnea correlates with the lactate threshold. In these patients, exercise wedge pressure does not presage aerobic capacity or functional class. AT can be used as an alternative measure in patients with valvular incompetence who are unable to attain V˙ O2 max . The lactate threshold occurs at 60 to 70 percent of the patient’s aerobic capacity and corresponds to a level of systemic O2 extraction of 60 percent or more. Figure 35-9 depicts the response of mixed venous lactate concentration as a function

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determined cardiac reserve and functional status. A decision regarding surgery should be based on these objective measures and clinical judgment, not simply on a laboratory-based calculation of reduced valve area. A preoperative assessment of patients undergoing valvular surgery using cardiopulmonary exercise testing can help predict the degree of postoperative recovery. Preoperative peak V˙ O2 of 19 ml/min/kg and greater in patients undergoing surgery for mitral and aortic regurgitation correlates with higher percentage of patients attaining New York Heart Association (NYHA) functional class I at 1 year after surgery. V˙ O2 max , along with AT, has been used to follow the course of postoperative rehabilitation and training in patients who have had valve surgery. Exercise parameters can be helpful in assessing patients with valvular disease when there is a discrepancy between symptoms and echocardiographic data. A V˙ O2 max less than 75 percent of predicted in patients with moderate-to-severe mitral stenosis correlates with higher transvalvular gradients and higher pulmonary artery pressures at the end of exercise than in patients who have V˙ O2 max greater than 75 percent of max predicted. Figure 35-9 Relationship between mixed venous lactate concentration and V˙ O2 observed during incremental treadmill exercise in patients with chronic mitral or aortic regurgitation. As in chronic cardiac failure, the lactate threshold (lactate >12 mg/dl) occurs at different levels of V˙ O2 , depending on functional class. (From Weber KT, Janicki JS (eds): Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia, WB Saunders, 1986.)

of O2 for each exercise class with mitral or aortic regurgitation. As in patients with chronic cardiac failure, the lactate threshold occurs at progressively lower levels of work as the severity of valvular disease increases. The invasively measured lactate threshold correlates well with the value obtained using noninvasive respiratory gas exchange measurements (see above). The reduced mitral valve orifice that accompanies rheumatic mitral valvular stenosis leads to left atrial chamber enlargement, pulmonary venous hypertension, and pressure overload of the right heart. Pulmonary vascular resistance in most patients ranges between 200 and 600 dynes · s · cm−5 . Mitral stenosis is responsible for reduced left ventricular filling at rest and during exercise. An exercise-associated increase in heart rate reduces the diastolic filling period, thereby further curtailing left ventricular filling. Cardiac output fails to rise appropriately during exercise in patients with chronic circulatory failure due to mitral stenosis. For most symptomatic patients, cardiac output fails to increase appropriately during symptom-limited exercise because of a limited stroke volume response. Systemic O2 extraction increases markedly during exercise, as do pulmonary capillary wedge and mean pulmonary artery pressures. Preoperative assessment of mitral stenosis should include not only calculation of mitral valve area but also exercise test-

Obstructive Sleep Apnea Cardiopulmonary exercise testing can be performed safely in patients with sleep apnea to evaluate abnormalities in gas exchange and the response to continuous positive airway pressure therapy. Patients with moderate to severe obstructive sleep apnea have impaired exercise capacity, low peak V˙ O2 , and low AT. The abnormal parameters on cardiopulmonary exercise testing can be improved by continuous positive airway pressure therapy. In one study involving patients with severe sleep apnea, 2 months of treatment using nasal continuous positive airway pressure resulted in higher right ventricular ejection fraction, peak V˙ O2 , peak V˙ O2 /kg, AT, and oxygen pulse. In patients with heart failure who have central sleep apnea (CSA) mortality rate is higher than in patients without CSA. Patients with heart failure often lack the classic symptoms of CSA; hence, its presence may be underestimated. Treating CSA in patients with heart failure benefits cardiac function. Patients with heart failure and CSA have a highly augmented ventilatory response to exercise. This is mani˙ V˙ CO2 , which fested by a significantly increased slope of Ve/ correlates with the severity of sleep apnea. Thus, patients with ˙ V˙ CO2 slope should be heart failure who have an increased Ve/ considered for a full sleep study to confirm the presence of sleep apnea.

Congenital Heart Disease Patients with cyanotic congenital heart disease have limitations in exercise tolerance. Cardiopulmonary exercise testing can be used to objectively assess these patients’ exercise limitation and ventilatory efficiency. In a study of 25 adults with uncorrected cyanotic congenital heart disease, peak oxygen uptake and Pao2 were

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significantly reduced compared to normal; Paco2 was only ˙ V˙ CO2 , slightly reduced. Ventilatory efficiency, expressed as Ve/ ˙ V˙ CO2 was markedly impaired at rest and during exercise. Ve/ correlated more strongly with patients’ symptoms than did hypoxemia and peak oxygen uptake. For corresponding NYHA classes, patients with adult congenital heart disease and those with heart failure demonstrate no significant differences in peak V˙ O2 . In adults, cardiopulmonary exercise testing has also been used for assessing the response to transcatheter-based closure of atrial septal defects. Increased peak oxygen uptake, peak oxygen pulse, and vital capacity have been reported, as have improvements in the prolonged V˙ O2 and V˙ CO2 slopes, reflecting improvement in recovery from maximal exercise.

Pulmonary Hypertension Pulmonary hypertension is expressed as an abnormal elevation in resting or exercise pulmonary artery pressure. Chronic left heart failure and the accompanying increase in left atrial pressure remain the most common cause of pulmonary venous hypertension. Pulmonary arterial hypertension (PAH) accompanies intrinsic pulmonary vascular disease or arteriolar vasoconstriction associated with hypoxemia due to intrinsic lung disease. PAH creates right ventricular pressure overload and an impediment to left ventricular filling. Accordingly, exercise cardiac output is compromised and aerobic capacity declines. Patients with PAH have been studied during elective right heart catheterization using a triple-lumen flotation catheter and subsequent exercise testing. Resting and peak treadmill exercise hemodynamic responses are given in Table 35-4. At rest, right heart and pulmonary arterial pressures exceeded the normal range. Right ventricular systolic pressure at rest was in excess of 50 mmHg, and in one-fourth of patients it approximated or exceeded left ventricular (and systemic arterial) systolic pressure. Resting wedge pressure was normal in these patients. Calculated pulmonary vascular resistance exceeded the upper range of normal (170 dynes · s · cm–5 ) in all patients; in more than one-third, it was above 1000 dynes · s · cm–5 , approximating systemic vascular resistance. Peak cardiac output attained with maximal exercise for each functional class (Table 35-3) is similar to that observed for chronic cardiac failure and valvular heart disease. The impairment in exercise cardiac output is related to the extent to which pulmonary vascular resistance is increased. Patients with a markedly increased resting pulmonary vascular resistance (above 1000 dynes · s · cm–5 ) proved to be functional class D. In this group of patients with intrinsic pulmonary vascular disease, arterial O2 desaturation during exercise was not observed, emphasizing the importance of compromised cardiac reserve—a function of the inability of the right ventricle to generate sufficient pulmonary blood flow to sustain left ventricular filling and, thereby, systemic blood flow. Patients with PAH stopped exercising because of breathlessness or fatigue or both; none experienced retrosternal chest pain,

Principles and Applications of Cardiopulmonary Exercise Testing

Table 35-4 Resting and Peak Exercise Hemodynamics for Patients with Nonhypoxic Pulmonary Vascular Disease and Pulmonary Hypertension Resting

Exercise

(mmHg)

29 ± 9

47 ± 20

RVSP

(mmHg)

52 ± 30

86 ± 37

RVDP

(mmHg)

7±4

16 ± 10

PCW

(mmHg)

10 ± 3

22 ± 14

PVR

(dynes · s · cm−5 )

412 ± 319

302 ± 331

(L/m2 /min)

2.8 ± 1.6

5.3 ± 2.2

(mmHg)

106 ± 6

130 ± 8

Art O2 sat

(%)

97 ± 2

96 ± 2

Note: PA = mean pulmonary artery pressure: RVSP and RVDP = right ventricular systolic and diastolic pressures, respectively; PCW = wedge pressure; PVR = pulmonary vascular resistance; CO = cardiac output; AP = mean arterial pressure. Source: Reproduced from Weber KT, Janicki JS: Pulmonary hypertension, in Weber KT, Janicki JS (eds), Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia. Saunders. 1986. pp 220–234.

light-headedness, or syncope; none developed arrhythmias. In most, it was possible to determine the V˙ O2 max ; in all, the AT could be attained (see above). Cardiopulmonary exercise test results for a 42-year-old woman with PAH are shown in Fig. 35-10. In patients with hypoxic pulmonary vasoconstriction, upright isotonic exercise also results in an increase in mean pulmonary artery and right ventricular systolic and diastolic pressures. In many of these patients, pulmonary vascular resistance increases during exercise because of marked hypoxemia, with arterial O2 saturation ranging between 70 and 80 percent. This response can be attenuated with use of supplemental O2 . Patients with PAH have significant ventilationperfusion mismatch; during exercise, ventilation is increased. This abnormality in ventilatory inefficiency is reflected in the reduction in end-tidal CO2 concentration (pETco2 ). The reduction in end-tidal CO2 concentration is proportional to the decrease in percent predicted V˙ O2 and increase in mean pulmonary artery pressure. In normal subjects, pETco2 increases from rest to attainment of AT, whereas in patients with PAH, pETco2 decreases from rest to AT. During cardiopulmonary

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Figure 35-10 Cardiopulmonary exercise test results for a 42-year-old woman with pulmonary arterial hypertension of uncertain origin. The first 2 minutes represent standing rest. The patient attained the anaerobic threshold (AT) (7 ml/min/kg) during stage 2 of exercise (1.5 mph, 0 grade) and a V˙ O2 max of 10 ml/min/kg, corresponding to functional class D.

exercise testing, the slope of regression between CO2 production and minute ventilation can also be used to assess the ventilation-perfusion mismatch. At the same peak V˙ O2 , ˙ V˙ CO2 slope is greater in patients with PAH than those the Ve/ with cardiac dysfunction. Conversely, for the same slope of ˙ V˙ CO2 , patients with left ventricular dysfunction have a Ve/ lower peak V˙ O2 . The measurement of cardiopulmonary exercise testingbased parameters in patients with PAH is reliable and reproducible, even in patients with limited exercise tolerance. The parameters correlate well with decreases in DlCO and NYHA class. Even in children with pulmonary hypertension, peak V˙ O2 strongly correlates with pulmonary vascular index. Cardiopulmonary exercise testing can be used for the objective assessment of safety and efficacy of treatment strategies in patients with PAH. Peak V˙ O2 is an independent, strong predictor of survival in these patients.

CHRONIC LUNG DISEASES ˙ rarely In a normal subject performing maximal exercise, Ve exceeds 50 percent of MVV; similarly, tidal volume uncommonly exceeds 50 percent of vital capacity. Given this large ventilatory reserve, exercise is not normally limited by ventilation. This is not the case in patients with lung disease, in whom ventilatory reserves are reduced. Other factors that may limit exercise in patients with lung disease are altered lung mechanics, impaired gas exchange with arterial hypoxemia and the appearance of pulmonary hypertension, and respiratory muscle fatigue.

Obstructive Lung Disease Exercise intolerance commonly accompanies chronic obstructive pulmonary disease (COPD), with dyspnea limiting physical activity to modest levels of work. Patients with ˙ for any given workload; this is largely COPD have a higher Ve due to increased dead space ventilation. Given their reduc˙ these patients often tion in MVV and greater exercise Ve, ˙ exercise with a ratio of Ve to MVV that exceeds 75 percent. Use of such a large portion of this ventilatory reserve cannot be sustained, accounting for breathlessness and termination of exercise. This generally occurs in patients with moderate to severe COPD before they have reached their AT, implying a ventilatory, rather than cardiac, limitation to exercise. The workload at which patients terminate exercise represents a peak V˙ O2 ; it is not their V˙ O2 max , as can be attained in patients with chronic cardiac or circulatory failure in whom ventilatory responses pose no limitation to exercise. In severe emphysema, DlCO is reduced in keeping with alveolar capillary destruction. In such patients, a significant fall in arterial O2 saturation often occurs during exercise. This is in contrast to patients with chronic bronchitis, in whom arterial O2 saturation may actually increase. The improvement in oxygenation in these patients is a result of improved ventilation in areas with low ventilation-perfusion ratios. DlCO portends exercise-induced arterial O2 desaturation: patients who have a DlCO less than 55 percent predicted are most likely to experience hypoxemia during exercise. Several factors account for limited exercise tolerance in the setting of arterial hypoxemia: (1) reduced O2 delivery to exercising muscles, including those associated with respiration; (2) increased chem˙ ical drive to respiration and corresponding inappropriate Ve

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for a given level of work; and (3) secondary pulmonary vasoconstriction. By measuring V˙ O2 peak in patients with COPD undergoing cardiopulmonary exercise testing, an objective assessment of exercise capacity can be made. Peak V˙ O2 in severe COPD correlates with resting forced expiratory volume in 1 second (FEV1 ) (percent predicted), total treadmill time, and total metabolic equivalent values. Cardiopulmonary exercise testing can better define respiratory limitations than pulmonary function testing alone in patients filing for disability due to COPD-related shortness of breath (see Chapter 39). The increase in breathing capacity during exercise in pa˙ tients with COPD, as measured by the ratio of Ve/MVV, correlates with peak V˙ O2 ; it can be predicted by the FEV1 /percent of forced vital capacity (FVC,%) assessed during routine pulmonary function testing. In chronic COPD, peak V˙ O2 can be estimated using equations that take into account patient walking distance and pulmonary function tests. However, the correlation between measured and estimated peak V˙ O2 is not strong enough to predict exercise capacity. If peak V˙ O2 is to be used for clinical decision making, it should be measured, rather than estimated. Furthermore, patients with COPD have skeletal muscle abnormalities that may contribute to reduced exercise capacity. Peak V˙ O2 in COPD correlates well with fat-free mass, a bioimpedance index of muscle mass. In COPD, physiological parameters measured by cardiopulmonary exercise testing also have prognostic implications. Based on multivariate analysis, the slope of the relationship between Pao2 and V˙ O2 is most closely associated with survival. Similarly, Pao2 max, along with measured FEV1 , have been found to be independent predictors of mortality. Overall, in COPD, a linear relationship exists between peak V˙ O2 and pulmonary function test parameters.

Restrictive Lung Disease Patients with known interstitial lung disease, a diverse group of disease entities, experience limiting dyspnea on exertion. This may be secondary to reduced ventilatory reserve or development of arterial O2 desaturation. Dyspnea may appear on exertion in a patient with an abnormal chest radiograph before pulmonary function studies are abnormal. Exercise testing may be indicated in patients with interstitial lung disease to detect abnormal ventilatory reserve and its response over time. Patients with interstitial lung disease tend to breathe at a higher respiratory rate and lower tidal volume than do normal subjects for any given V˙ O2 . Because they have a reduced MVV, their ability to exercise is limited by nearly full utilization of their reduced ventilatory reserve. As in patients with airway disease, DlCO is a good predictor of arterial O2 desaturation during exercise in patients with interstitial lung disease. Most patients with a DlCO below 60 percent develop arterial O2 desaturation. If a patient has a normal DlCO , he or she is unlikely to develop exercise-

Principles and Applications of Cardiopulmonary Exercise Testing

induced arterial O2 desaturation. Measurement of DlCO can be used to screen patients for exercise studies. Finally, the degree of arterial O2 desaturation during exercise correlates with the reduction in DlCO . Cardiopulmonary exercise testing is a sensitive test for detecting abnormalities in gas exchange. In one study that dealt with biopsy-proven sarcoidosis, cardiopulmonary exercise testing predicted pulmonary dysfunction earlier than did physical examination, chest radiography, or spirometry. In survivors of severe acute respiratory distress syndrome (ARDS), aerobic capacity assessed by cardiopulmonary exercise testing was found to be abnormal in 41 percent of patients in whom mild pulmonary function abnormalities were not enough to explain the low-exercise capacity. Cardiopulmonary exercise testing has also been used prognostically in patients with interstitial lung disease.

EVALUATION OF EXERTIONAL DYSPNEA Normally, a person is unaware of the act of breathing and the fact that 500 to 750 ml of air enters and leaves the lungs 10 ˙ increases to 15 times each minute. Minute ventilation (Ve) secondary to normal or abnormal chemical stimuli (e.g., hypercapnia, hypoxemia, acidemia) or anxiety. When breathing is perceived to be inappropriate relative to the level of physical activity, it is considered to be an abnormal awareness of breathing that is termed breathlessness, shortness of breath, or dyspnea. Dyspnea on exertion is common in patients with heart disease, pulmonary parenchymal or airway disease, and pulmonary vascular disease. Deformities of the chest wall and diseases associated with weakness of the respiratory muscles are also accompanied by breathlessness on exertion. Dyspnea may seriously hinder a patient’s ability to carry out muscular work, thereby compromising quality of life. The evaluation of dyspnea includes historical information that characterizes the symptom onset, severity, and relationship to exercise, and the patient’s underlying physical condition and customary daily activity. Other associated symptoms—such as palpitations, anginal chest pain, and light-headedness—must be taken into consideration. An objective and reliable estimate of dyspnea on exertion and its severity can be gauged from exercise testing. Dys˙ is excessive relative to V˙ O2 , and when pnea occurs when Ve ˙Ve is driven by chemical stimuli or altered lung mechanics. ˙ represents an Dyspnea during exercise can appear when Ve excessive proportion of MVV. An estimation of MVV can be derived by multiplying the patient’s FEV1 by 35. As a corollary, maximal encroachment on the vital capacity by exercise tidal volume cannot be sustained for long. Such ventilatory effort poses a substantial workload on respiratory muscles. An MVV maneuver during pulmonary function testing cannot be sustained for more than a few seconds, while more than 70 percent of the MVV cannot be sustained by normal subjects for more than several minutes. Hence, the ventilatory response to exercise that is associated with dyspnea in

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patients with heart or lung disease follows a similar pattern of short-lived, near-maximal ventilation. The patient with pulmonary vascular disease or advanced interstitial lung disease may be unable to sustain adequate arterial O2 saturation during exercise. Consequently, hypoxemia may compound the patient’s exercise response and may be responsible for a heightened chemical drive to respiration. In the case of COPD, the need to move air through a partly obstructed tracheobronchial tree creates an added workload on respiratory muscles. Airflows in these patients are already compromised at rest and must increase with exercise; they may approach peak expiratory flows observed with maximal effort during pulmonary function testing. Patients with mild, moderate, or severe cardiac or circulatory failure rarely use more than 50 percent of their ventilatory reserve at maximal exercise, and they do not experience arterial O2 desaturation during exercise. If one estimates MVV from the FEV1 (as noted above), for an FEV1 of 1, 2, or 3 L, MVV is expected to equal 35, 70, or 105 L, respectively. In patients with chronic cardiac or circulatory failure, max˙ has been found to range between 62 and imum exercise Ve 29 L per min for class A through D patients. Hence, unless there is a major reduction in MVV (or in FEV1 to less than 3 L), these patients will not have a ventilatory limitation to exercise. Finally, patients are able to cross their AT and, if encouraged, may reach their point of exhaustion attaining V˙ O2 max . By monitoring the breath-by-breath response in V˙ O2 and V˙ CO2 during exercise, the physician can immediately determine when the patient has achieved the AT and V˙ O2 max . These end points are not attained in the patients with lung disease or those with coexistent heart and lung disease in whom the respiratory system is the primary limitation to exercise. Table 35-5 summarizes the salient points used to differentiate primary ventilatory from cardiac or circulatory failure as the cause of exertional dyspnea, as detected by exercise testing.

Table 35-5 Ventilatory vs. Cardiac/Circulatory Failure as the Predominant Cause of Exertional Dyspnea Ventilatory Failure ˙ utilizes > 70% of MVV 1. Exercise maximum Ve 2. Exercise-associated arterial hypoxemia 3. Failure to cross AT and to achieve V˙ O2 max Cardiac/Circulatory Failure 1. Cross AT and can achieve V˙ O2 max ˙ does not exceed 50% of 2. Maximum exercise Ve MVV 3. Does not develop arterial hypoxemia with exercise Note: AT = anaerobic threshold; MVV = maximal voluntary ventilation.

OTHER APPLICATIONS OF CARDIOPULMONARY EXERCISE TESTING Cardiopulmonary exercise testing, with its ability to foretell cardiac and ventilatory reserves, has proved useful in clinical decision making in a variety of circumstances, including assessment of a patient’s candidacy for cardiac transplantation and preoperative assessment of preoperative risk.

Cardiac Transplantation The severity of chronic cardiac and circulatory failure is gauged according to V˙ O2 max and the AT (Table 35-3) and is used to predict exercise cardiac reserve. This approach has been applied to patients with systolic dysfunction secondary to chronic ischemic heart disease or dilated (idiopathic) cardiomyopathy, who are considered to be potential candidates for cardiac transplantation. Neither the ejection fraction nor resting hemodynamic parameters (e.g., resting cardiac index or wedge pressure) help to predict the severity of cardiac failure or functional capacity and are no longer a mainstay in decision making. The same is true for subjective evaluation of functional status using the NYHA criteria. Incremental exercise testing, with identification of AT and peak V˙ O2 achieved thereafter, has emerged as a valuable tool to address cardiac reserve and functional capacity objectively and to predict survival. In fact, consensus has been reached on recommending transplantation using clinical criteria in combination with functional stratification based on the results of exercise tests. Class D patients, having little or no cardiac reserve, have a marked reduction in 1- and 2-year survival and, therefore, are candidates for urgent transplantation. Class C patients, who have a modest increment in cardiac output with exercise, are probable candidates. On the other hand, class A and B patients in whom cardiac reserve remains intact, or class B patients in whom cardiac reserve is only minimally impaired, do not have an adequate indication for transplantation. Decision is deferred, and serial exercise studies are used to assess recovery or deterioration in the setting of optimal medical therapy. Incremental exercise testing may also provide useful information after cardiac transplantation, including recovery of cardiac and ventilatory reserves. The importance of diastolic dysfunction in limiting exercise tolerance following cardiac transplantation was reviewed earlier. A blunted heart rate response to exercise is expected in these patients due to cardiac denervation. Such chronotropic incompetence is demonstrated in Fig. 35-11, along with the results of exercise testing.

Surgical Risk Assessment Preoperative incremental exercise testing has proved useful in assessing postoperative morbidity and mortality in the elderly and in patients with underlying heart or lung disease who are scheduled for major intrathoracic or intra-abdominal

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Figure 35-11 Cardiopulmonary exercise test results for a 62-year-old male cardiac transplant recipient. During this incremental treadmill test this patient attained an anaerobic threshold (AT) and V˙ O2 max of 8 and 11 ml/min/kg, respectively. Note the blunted heart rate response (predicted peak heart rate range shown as broken lines).

surgery. The premise underlying this approach is based on a recognition that during and after surgery, there may be a need to call on cardiac and ventilatory reserves—namely, the ability to increase cardiac output and maintain O2 de˙ and prevent hypoxemia. Several livery, and to increase Ve studies have demonstrated the utility of measuring the AT and peak V˙ O2 using exercise testing to estimate these reserves, and to identify patients prone to postoperative complications. Pulmonary function testing proved insensitive in forecasting postoperative course. Class C and D patients, with little or no cardiac reserve, had a greater number of morbid and mortal events following surgical interventions than did class A or B patients. Class A patients had few, if any, postoperative complications and no mortality. Therefore, the risk of complications could best be gauged by a patient’s preoperative aerobic capacity. Direct assessment of the AT or V˙ O2 max and prediction of cardiac reserve, and, by inference, ventilatory reserve, supersede the value of an age-determined impairment in aerobic capacity. AT is a particularly important parameter in assessing preoperative risk. It provides an objective assessment that is independent of patient motivation and does not require inordinate amounts of exercise. In a large study of elderly patients undergoing major intra-abdominal surgery, an AT of less than 11 ml/min/kg, along with preoperative ischemia, was associated with high mortality. Patients evaluated by cardiopulmonary exercise testing who have an unfavorable AT can be admitted electively to intensive care units for optimization of hemodynamics prior to major surgery. Patients undergoing other major surgeries, such as radical esophagectomy with three-field lymphadenectomy, have also been risk-stratified using cardiopulmonary exercise testing. Extensive fluid shifts are expected in the postoperative period with surgical interventions on the lymphatic system. Cardiopulmonary exercise testing can provide a thorough assessment of the cardiopulmonary reserve in such patients. For example, in one study, a peak V˙ O2 of 800 ml/min/m2 was associated with low risk of complications. Similarly, in another

study of patients undergoing repair of an abdominal aortic aneurysm, those with a peak V˙ O2 less than 20 ml/min/kg had a higher incidence of adverse complications. Finally, a study of patients undergoing liver transplantation demonstrated that patients dying within 100 days of transplantation were more likely to have had a preoperative peak V˙ O2 less than 60 percent of predicted and an AT less than 50 percent of predicted peak V˙ O2 than those who survived. Patients with lung cancer have a high likelihood of concomitant COPD and coronary artery disease due to the common risk factor of smoking. Surgery might offer the only chance of cure in these patients and often implies resection of a variable portion of the lung tissue surrounding the cancer to ensure eradication. Removal of functional lung tissue in an already compromised cardiopulmonary system resection can be risky. It is imperative that a preoperative assessment of cardiopulmonary reserve be made before such a surgery. Cardiopulmonary exercise testing in such patients provides an objective assessment of cardiopulmonary reserve. In addition, peak V˙ O2 , along with FEV1 and DlCO , has been used to risk-stratify these patients. Correcting peak V˙ O2 for weight and expressing it as a percentage of predicted improves the ˙ 2 measurements. Elderly patients, predictive power of peak Vo females, and patients with short stature may have a peak V˙ O2 below the absolute cutoff value, but they may still be eligible for surgery when peak V˙ O2 is expressed as percent of predicted. The predictive value of peak V˙ O2 is greater in patients with an FEV1 less than 70 percent of predicted. Peak V˙ O2 less than 50 percent of predicted is associated with high complication rates. Patients with peak V˙ O2 greater than 50 percent of predicted can undergo surgery without excess mortality. A peak V˙ O2 less than 10 ml/min/kg is generally considered prohibitive for surgery. Risk-stratification based upon peak V˙ O2 is particularly useful in patients undergoing lung resection who have borderline pulmonary function (predicted postoperative FEV1 or DlCO less than 40 percent). In these patients, a peak V˙ O2 less than 15 ml/min/kg is associated with

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an increased risk, and peak V˙ O2 less than 10 ml/min/kg carries a very high risk of postoperative complications (see Chapter 38 for additional discussion).

SUGGESTED READING Bechard D, Wetstein L: Assessment of oxygen consumption as a preoperative criterion for lung resection. Ann Thorac Surg 44:344–349, 1987. Bolliger CT: Evaluation of operability before lung resection. Curr Opin Pulm Med 9:321–326, 2003. Dickstein K, Barvik S, Aarsland T, et al: Reproducibility of cardiopulmonary exercise testing in men following myocardial infarction. Eur Heart J 9:948–954, 1985. Diller GP, Dimopoulos K, Okonko D, et al: Exercise intolerance in adult congenital heart disease: Comparative severity, correlates, and prognostic implication. Circulation 112:828–835, 2005. Fink G, Moshe S, Goshen J, et al: Functional evaluation in patients with chronic obstructive pulmonary disease: Pulmonary function test versus cardiopulmonary exercise test. J Occup Environ Med 44:54–58, 2002. Gallagher CG: Exercise limitation and clinical exercise testing in chronic obstructive pulmonary disease. Clin Chest Med 15:305–326, 1994. Hansen JE, Sun XG, Yasunobu Y, et al: Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension. Chest 126:816–824, 2004. Kim HJ, Ahn SJ, Park SW, et al: Cardiopulmonary exercise testing before and one year after mitral valve repair for severe mitral regurgitation. Am J Cardiol 93:1187–1189, 2004. Leite JJ, Mansur AJ, de Freitas HF, et al: Periodic breathing during incremental exercise predicts mortality in patients with chronic heart failure evaluated for cardiac transplantation. J Am Coll Cardiol 41:2175–2181, 2003. Likoff MJ, Chandler SL, Kay HR: Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 59:634–638, 1987. Mancini DM, Eisen H, Kussmaul W, et al: Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 83:778–786, 1991.

Marciniuk DD, Gallagher CG: Clinical exercise testing in interstitial lung disease. Clin Chest Med 15:287–303, 1994. Older P, Hall A, Hader R: Cardiopulmonary exercise testing as a screening test for perioperative management of major surgery in the elderly. Chest 116:355–362, 1999. Page E, Cohen-Solal A, Jondeau G, et al: Comparison of treadmill and bicycle exercise in patients with chronic heart failure. Chest 106:1002–1006, 1994. Pollock ML, Wilmore JH, Fox SM: Health and Fitness through Physical Activity. New York, Wiley, 1978. Smith TP, Kinasewitz GT, Tucker WY, et al: Exercise capacity as a predictor of post-thoracotomy morbidity. Am Rev Respir Dis 129:730–734, 1984. Sullivan MJ, Higginbotham MB, Cobb FR: Increased exercise ventilation in patients with chronic heart failure: Intact ventilatory control despite hemodynamic and pulmonary abnormalities. Circulation 77:552–559, 1988. Tojo N, Ichioka M, Chida M, et al: Pulmonary exercise testing predicts prognosis in patients with chronic obstructive pulmonary disease. Intern Med 44:20–25, 2005. van den Broek SAJ, van Veldhuisen DJ, de Graeff PA, et al: Comparison between New York Heart Association classification and peak oxygen consumption in the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 70:359–363, 1992. Villani F, De Maria P, Busia A: Exercise testing as a predictor of surgical risk after pneumonectomy for bronchogenic carcinoma. Respir Med 97:1296–1298, 2003. Wasserman K, Hansen JE, Sue DY, et al: Principles of Exercise Testing and Interpretation: Including Pathophysiology and Clinical Applications, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2005. Weber KT, Janicki JS (eds): Cardiopulmonary Exercise Testing: Physiologic Principles and Clinical Applications. Philadelphia, WB Saunders, 1986. Wensel R, Opitz CF, Anker SD, et al: Assessment of survival in patients with primary pulmonary hypertension: Importance of cardiopulmonary exercise testing. Circulation 106:319–324, 2002. Yetman AT, Taylor AL, Doran A, et al: Utility of cardiopulmonary stress testing in assessing disease severity in children with pulmonary arterial hypertension. Am J Cardiol 95:697–699, 2005.

36 Bronchoscopy, Transthoracic Needle Aspiration, and Related Procedures Anil Vachani Luis Seijo Michael Unger Daniel Sterman

I. TYPES OF BRONCHOSCOPY AND GENERAL INSTRUMENTATION Rigid Bronchoscopy Flexible Fiberoptic and Videobronchoscopy II. PATIENT PREPARATION AND MONITORING DURING BRONCHOSCOPY III. DIAGNOSTIC BRONCHOSCOPY ACCESSORIES IV. APPLICATIONS OF DIAGNOSTIC BRONCHOSCOPY Assessment of Airway Anatomy and Function Evaluation of Tracheobronchial Mucosa Evaluation of Hemoptysis Evaluation of Peribronchial Structures Performance of Bronchial and Parenchymal Biopsies Sampling of Airway and Alveolar Constituents Application of Quantitative Microbiologic Techniques V. TECHNIQUES USED IN THERAPEUTIC BRONCHOSCOPY Rigid Bronchoscopic Dilatation or Balloon Dilatation Endobronchial Laser Therapy Endobronchial Cryotherapy and Electrocautery Endobronchial Brachytherapy Photodynamic Therapy Tracheobronchial Stenting

Gustav Killian reported his experience with the first bronchoscopy in 1898. Technological advances during the next century facilitated development of bronchoscopy as a pivotal diagnostic and therapeutic tool in pulmonary medicine. Although a number of bronchoesophagologists contributed to refinement of the technique based upon use of a rigid instrument, the advent of flexible fiberoptic bronchoscopy, pioneered by Ikeda in 1967, opened new horizons to clinicians.

VI. APPLICATIONS OF THERAPEUTIC BRONCHOSCOPY Control of Hemoptysis Endoluminal Airway Obstruction Extrinsic Airway Compression Tracheobronchomalacia Removal of Foreign Bodies Aspiration of Secretions Closure of Bronchial Fistulae VII. SAFETY FACTORS IN BRONCHOSCOPY VIII. COMPLICATIONS OF BRONCHOSCOPY Anesthesia and Related Blood Gas Abnormalities Fever and Infection Airway Obstruction and Perforation Pneumothorax Hemorrhage IX. TRANSTHORACIC NEEDLE ASPIRATION AND BIOPSY Indications and Contraindications Technique Results Complications

More recently, transthoracic needle aspiration and biopsy have been added to the pulmonologist’s diagnostic armamentarium. These techniques are particularly useful for evaluating localized or peripheral lung lesions. Transthoracic needle aspiration permits acquisition of material for cytologic and microbiologic analysis, while transthoracic needle biopsy provides tissue for histological study.

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This chapter comprises an overview of bronchoscopy, transthoracic needle aspiration and biopsy, and related techniques. Following a general discussion of bronchoscopy and associated general instrumentation, indications for the technique and patient preparation are considered. Specific applications of diagnostic and therapeutic bronchoscopy are discussed. Subsequently, safety factors related to bronchoscopy and complications of the technique are reviewed. Finally, transthoracic needle aspiration and biopsy are described.

TYPES OF BRONCHOSCOPY AND GENERAL INSTRUMENTATION In the first three-fourths of the twentieth century, pulmonary endoscopy was performed with open-tube steel bronchoscopes. The advent of fiberoptic technology and, subsequently, miniaturized electronics permitted application of flexible endoscopy, as discussed below.

Rigid Bronchoscopy The initial bronchoscope, developed by Killian in Europe and further perfected by Chevalier Jackson in the United States, was a rigid metal tube that permitted either spontaneous or mechanical ventilation. Over the decades, rigid bronchoscopes of various lengths and sizes, which are adaptable for diverse applications in children and adults, have become available. With development of fiberoptic and advanced electronic technology, the flexible bronchoscope has, to a large extent, replaced the rigid bronchoscope for most diagnostic and some therapeutic indications. Both rigid and flexible modern systems are equipped with optic capabilities for airway observation alone. With the rigid bronchoscope, various types of telescopic rods, equipped with circumferential illumination, permit direct and magnified visualization. Specially designed telescopes allow viewing not only directly forward but also at oblique and lateral angles. Various diagnostic and therapeutic accessories can be inserted through the rigid bronchoscope while the patient remains ventilated. In recent years, development of small cameras based on charge coupled device (CCD) technology has facilitated transmission of bronchoscopic images to television monitors, enhancing the education of trainees and permitting improved documentation of bronchoscopic findings.

Flexible Fiberoptic and Videobronchoscopy Although the optical resolution of early fiberoptic bronchoscopes was inferior to that of rigid devices, their flexibility, ease of manipulation, and simplicity of use, which permit rapid examination under topical anesthesia, have made flexible bronchoscopy the primary endoscopic procedure in pulmonary diseases. Unlike the larger-bore rigid bronchoscope, the flexible bronchoscope varies from ultra-thinâ&#x20AC;&#x201D;allowing for neonatal endoscopyâ&#x20AC;&#x201D;to larger, adult-size therapeutic devices. The

diameter of the working channel permits aspiration of secretions or introduction of accessories required for diagnostic or therapeutic purposes (see below). With flexible bronchoscopy, the patientâ&#x20AC;&#x2122;s ventilation is assured by airflow around the bronchoscope, between the external wall of the device and the tracheobronchial tree. Thus, the appropriate selection of bronchoscope size is crucial. Recent technological advances have permitted the replacement of fiberoptic systems by a miniaturized CCD camera at the tip of the scope that provides electronic transmission of images to a television monitor. Flexible bronchoscopes are more fragile and more prone to damage than are rigid metal instruments. Appropriate care and adherence to safety techniques during procedures, as well as during routine cleaning and maintenance of the instruments, help assure extended instrument life and reduce repair costs.

PATIENT PREPARATION AND MONITORING DURING BRONCHOSCOPY Most fiberoptic bronchoscopies are performed after patient premedication with sedative agents. Most frequently, a combination of a short-acting benzodiazepine (e.g., midazolam) and a narcotic agent (e.g., fentanyl) is used. The sedatives are generally administered along with an anticholinergic medication (e.g., atropine or glycopyrrolate) in order to reduce the risk of vasovagal reactions and to minimize airway secretions. Local anesthesia of the upper airway, larynx, and tracheobronchial tree is achieved with inhaled or bronchoscopically instilled lidocaine. Although rigid bronchoscopy was performed initially with minimal anesthesia and later under general anesthesia, the recent trend has been to perform the procedure with patients either breathing spontaneously or ventilated with a jet ventilator, often under total intravenous anesthesia (TIVA) with drugs such as propofol or remifentanil. With appropriate monitoring, good oxygenation and adequate ventilation can be assured. Success of bronchoscopy, whether diagnostic or therapeutic, depends, in large part, on proper preparation of the patient, including relief of anxiety, muscle relaxation, cough suppression, and adequate anesthesia. Time spent in achieving these goals will be well worth it in reducing the risks of complications and in increasing the ease of performance of the procedure. As with any other procedure, analysis of the risk-benefit ratio helps reduce the complication rate. During and shortly after the procedure, appropriate monitoring of hemodynamic parameters (heart rate, rhythm, and blood pressure), oxygenation, and ventilation contributes to the safety of bronchoscopy.

DIAGNOSTIC BRONCHOSCOPY ACCESSORIES The working channel of the fiberoptic or videobronchoscope, although of relatively small diameter, allows the insertion of

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various diagnostic and therapeutic accessories. Specially constructed accessories of larger caliber have been developed for use with the rigid bronchoscope.

The tip of the needle is protected by a metal hub during the insertion and withdrawal to avoid damage to the flexible scope. Perforation of the working channel of the scope may occur if the needle is advanced in an exposed position. The diagnostic yield depends on two factors: optimization of the bend of the tip of the bronchoscope and proper performance of bronchial wall puncture by the needle through the intercartilaginous space. Familiarity with the type of needle used increases the success rate. TBNA is generally safe, although pneumothorax and hemomediastinum can occur. Clinically significant bleeding is extremely rare, particularly when a 22-gauge needle is used, even if a major vessel is inadvertently punctured or if the patient suffers from superior vena cava syndrome.

Biopsy Forceps Simple visualization of lesions is usually not sufficient to determine a precise diagnosis and to guide management. Pathological confirmation through biopsy is frequently required. A variety of instruments with improved distal control (i.e., control beyond the tip of the bronchoscope) have been developed that permit tissue cutting and retrieval of biopsy specimens. The cutting cups of biopsy forceps may be round or elliptic and may have smooth or jagged edges. The use of nonserrated edges, however, seems to reduce tissue trauma and the concomitant risk of bleeding. The biopsy procedure is simple and generally associated with only minimal complications in the case of a visible lesion. Even peripheral lesions, which are not visible through the bronchoscope, may be biopsied. With diffuse parenchymal or interstitial lung disease, specimens may be obtained without fluoroscopic guidance. With smaller or focal lesions, however, the diagnostic yield of biopsies increases when fluoroscopy is used. The recent development of new electromagnetic and remote guidance systems suggests that further improvement in the diagnostic yield of bronchoscopic biopsies can be expected. Bronchial Brushes Lesions not accessible to direct biopsy with a forceps can be approached with a bronchial brush. This device consists of a rigid central wire surrounded by brushes of various sizes and shapes. To-and-fro movement of the brush against the adjacent tissue produces minor trauma but enables collection of ample specimens for cytologic or microbiologic analysis. In some clinical circumstances, there is a need to obtain from the lower respiratory tract an uncontaminated specimen for microbiologic studies. A brush protected by an additional sheath and tip may be passed through the working channel of the bronchoscope (protected brush specimen, as discussed below). In these cases, special attention is needed not to use an excessive amount of local anesthetic or saline lavage, since these solutions contain bacteriostatic material that may inhibit microbial growth. The diagnostic yield depends on use of proper technique, appropriate choice of brush, and careful collection and preservation of the specimen. Needles for Aspiration and Biopsy The first performance of a transbronchoscopic needle aspiration (TBNA) through a rigid bronchoscope was reported by Schieppati in 1958. Wang then developed a flexible needle technique, using a fiberoptic bronchoscope in 1978. Initially, several models of needles were designed to obtain cytological material; subsequently, histological specimens from peribronchial mediastinal and hilar lymph nodes were obtained with larger-bore needles. These biopsy needles are also useful in the diagnosis of endobronchial and submucosal lesions, and can serve as a complementary technique to percutaneous needle aspiration of peripheral pulmonary nodules or masses.

Dedicated Catheters and Balloons Various investigational protocols for study of lung diseases use the technique of bronchoalveolar lavage (see below) and collection of uncontaminated specimens. In performing this procedure, selective aspiration catheters are necessary. These bronchoscopically guided, double-lumen catheters are wedged in the selected bronchus. After inflation of a balloon and isolation of the bronchus, instillation of fluid through the central lumen of the catheter is followed by aspiration of the fluid. In another application, the low-pressure balloon catheters contribute to estimation of airway diameter before the insertion of a stent (see below). Sometimes, inflation of the balloon at the tip of the bronchoscope permits enlargement of the lumen and eventual penetration of the bronchoscope beyond the area of stenosis, allowing exploration of peripheral airways. Endobronchial Ultrasound Endobronchial ultrasound (EBUS) enhances traditional white light bronchoscopy (WLB) by providing real-time, 360degree images that reach beyond the bronchial lumen, providing information unattainable by airway inspection alone. In general, higher acoustic frequencies afford only shallow penetration, but result in high-resolution images; lower frequencies provide deeper tissue penetration, but impaired image resolution. The quality of the ultrasonic image depends primarily upon adequate contact of the probe with the airway wall, depth of penetration of the ultrasound wave, and spatial resolution of different structures. EBUS uses a frequency in the range of 20 MHz, which allows a tissue penetration depth up to 5 cm. However, the abundant presence of air in the lung, which distorts the ultrasound image by reflecting sound waves, is a major obstacle to obtaining adequate images. Currently, probes reduce artifact arising from air-filled bronchi by transmitting sound through a fluid- or gel-filled balloon. While EBUS has been used in a variety of clinical scenarios, its role in clinical practice remains to be fully defined. Currently, the three main indications for EBUS are: (1) evaluation of endobronchial masses, (2) aspiration of mediastinal lymph nodes (Fig. 36-1), and (3) facilitation of the distinction between neoplastic and benign mediastinal masses.

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Although the initial indications for bronchoscopy described by Killian and Jackson centered primarily on therapeutic applications, both recognized the central role the technique plays in visual examination of the tracheobronchial tree and in diagnosis of various pulmonary diseases. Development of the flexible bronchoscope and various accessory instruments that can be inserted via the working channel has extended bronchoscopic exploration to the lung periphery.

to the integrity of air passages and the function of the nasopharynx and larynx. The vocal cords should be examined for the presence of polyps and tumors, and for evidence of cord paralysis. Once the upper-airway inspection is completed, a systematic evaluation of the lower respiratory tract should be performed. Critically important is the distinction among normal anatomy, anatomic variations without clinical significance, and frankly pathological conditions. These considerations have important implications regarding potential diagnostic and therapeutic approaches. For example, finding an abnormal branching of a bronchus may be of no clinical significance. On the other hand, such an abnormality could explain symptoms of frequent infections due to impaired ventilation and drainage of the affected area. Special skills and observational experience are required for bronchoscopic examination after surgery, especially following creative bronchoplastic procedures or lung transplantation. Assessment of airway integrity, with special attention to dynamic changes in airway caliber during either relaxed breathing or forced expiration and coughing, may be crucial in determining appropriate therapeutic maneuvers. Flexible bronchoscopy is superior to rigid bronchoscopy for this assessment. Relaxation and prolapse of the membranous portion of the trachea and main bronchi secondary to destruction of elastic connective tissue may account for exacerbations of expiratory airflow obstruction. On the other hand, finding localized, posttraumatic chondromalacia has very different therapeutic implications. On the basis of these bronchoscopic determinations, the choice of performing an open surgical approach or bronchoscopic therapeutic correction may be made. Bronchoscopic examination generally permits evaluation and localization of congenital or postsurgical pathological changes in bronchial integrity, such as tracheoesophageal or bronchopleural fistulas. Bronchoscopic observation and early diagnosis of bronchial rupture after chest trauma also greatly influence further therapy and prognosis. The same is true for evaluation of postsurgical anastomoses following reconstructive surgery or lung transplantation. Advances in airway management of critically ill patients who require prolonged intubation or tracheotomy have resulted in reduction in the incidence of tracheal injuries. Tracheal injuries documented by bronchoscopy are not rare, however. Important complications of tracheotomy include tracheal stenosis, tracheomalacia, and tracheoinnominate fistula. Complications specific to the use of percutaneous tracheotomy, which is increasingly used in the intensive care unit, include flaps of cartilage protruding into the tracheal lumen and extraluminal placement of the tracheostomy tube. Such complications can have significant bearing on clinical outcome.

Assessment of Airway Anatomy and Function

Evaluation of Tracheobronchial Mucosa

Thorough bronchoscopic evaluation begins with examination of the upper airways. Special attention should be paid

Careful examination of the mucosal surface is crucial in the formulation of differential diagnosis. Rapid development of

Figure 36-1 Endobronchial ultrasound (EBUS) image of an enlarged lymph node. EBUS image from the left main carina demonstrates an enlarged subcarinal lymph node (white arrow). (Courtesy of Felix Herth, M.D.)

Less frequent indications include assessment of mediastinal infiltration by tumor, evaluation of anastomotic recurrences, and identification of submucosal lesions. Identifying submucosal lesions may be useful prior to planned thoracic resections in determining the likely bronchial margin of an infiltrating tumor. In some cases, patients diagnosed with â&#x20AC;&#x153;earlyâ&#x20AC;? carcinomas are found by EBUS to harbor extensive intraluminal disease as well as regional lymph node metastases. EBUS may also be used as an adjunct to planning of interventional procedures, such as endobronchial stenting, photodynamic therapy (vs. use of brachytherapy), and laser photoablation.

APPLICATIONS OF DIAGNOSTIC BRONCHOSCOPY

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granulation tissue is frequently associated with reaction to a foreign body. Inflammatory mucosal reactions, although not very characteristic, should raise the possibility of mycobacterial infection, nonspecific viral and nonviral infections, and other granulomatous diseases, such as sarcoidosis. The distinction between normal, pale-pink mucosa and hypervascular areas in the tracheobronchial tree may provide important diagnostic clues. Most frequently, changes in mucosal coloration are associated with an inflammatory reaction due to bronchitis. These findings are, however, very distinctive from small hemangiomas or vascular distentions due to compression by enlarged, neoplastic lymph nodes. Similarly, a network of small mucosal lymphatics may be visible, with lymphatic interruption due to surgery, radiation therapy, fibrosis, or malignancy. This is most frequently associated with local edema, which contributes to airflow obstruction. In addition, distinct and characteristic mucosal discoloration can be observed in Kaposiâ&#x20AC;&#x2122;s sarcoma. Ulcerations of the mucosa are more characteristic of Wegenerâ&#x20AC;&#x2122;s granulomatosis or malignancy. Loss of the usual mucosal luster and presence of a roughened surface may alert the expert bronchoscopist to an early infiltrative or neoplastic process. Previously sustained injuries are characterized by the formation of mucosal and submucosal fibrosis, resulting in airway retraction or distortion. Recently, various photosensitizers have been applied for the bronchoscopic evaluation of the tracheobronchial mucosa. Photosensitizers, such as hematoporphyrin derivative

(HPD) and %-aminolevulinic acid (%-ALA), are retained more selectively by neoplastic tissues. When stimulated by blue light (wavelength approximately 440 nm), tissues containing these photosensitizers (i.e., tumors, but not normal tissues) emit weak fluorescence in the red spectrum (wavelength approximately 630 nm). The low-intensity fluorescence can be captured by specially designed image intensifiers. The technique may be helpful in cancer detection or in the delineation of tumor limits. Use of photosensitizers, however, is cumbersome and associated with skin photosensitivity and risk of sunburn. For these reasons, photosensitizermediated photodynamic techniques are not practical for diagnostic purposes. Recent technological developments permit observation and analysis of tracheobronchial mucosal surfaces using the discriminant characteristic of tissue autofluorescence. It is well known that when stimulated with light of a specific wavelength, normal tissues emit specific fluorescence. Changes in the structural integrity of the same tissues due to pathological processes modify or suppress the autofluorescence. The fluorescent emissions are too low in intensity to be seen by the human eye. With the use of a monochromatic light source, computer-controlled image analysis, and a sophisticated camera attached to a fiberoptic bronchoscope, the airways can be examined for varying degrees of autofluorescence as an indicator of early-stage malignant changes (Fig. 36-2). The acquisition of images is obtained in real-time and helps in the detection of minute areas of change in normal

Figure 36-2 White light and autofluorescence images of carcinoma in situ. Standard white light bronchoscopy demonstrates normal-appearing mucosa. Fluorescence endoscopy demonstrates abnormal-appearing tissue (reddish brown area), which was confirmed as carcinoma in situ by histological evaluation. (Courtesy of Xillix Technologies Corp.)

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tracheobronchial mucosal fluorescence. Biopsies from areas of abnormal fluorescence increase the rate of detection of small, premalignant (dysplasia) or early malignant (carcinoma in situ) lesions in the tracheobronchial tree. Confirmation is provided by biopsy of the suspect or abnormal areas under direct bronchoscopic control, followed by pathological review. Attempts are underway to develop bronchoscopic spectrophotometric techniques for study of metabolic functions in vivo and performance of “optical biopsies,” which provide information on specific tissue components—e.g., changes in intracellular concentrations of nicotinamide adenine dinucleotide phosphate (NADPH) or other cellular constituents. Another promising technique, opitical coherence tomography (OCT), is analogous to ultrasound imaging except that infrared light waves, rather than acoustic waves, are used. At present, OCT can resolve structures as small as 3 µm, rendering this imaging technique superior to conventional CT or magnetic resonance imaging for detecting microscopic airway abnormalities. The ability to acquire such precise views in real-time may have important clinical implications in the near future. Figure 36-3 TBNA of subcarinal lymph node using a 21-gauge transbronchial needle.

Evaluation of Hemoptysis One of the most frequent indications for bronchoscopy is hemoptysis. Bronchoscopic evaluation can be of help in determining the precise location and source of bleeding. The choice of instrument (rigid vs. flexible scope) and timing of the procedure are dictated by clinical circumstances. Studies have shown that active bleeding and its site are visualized more commonly with early bronchoscopy (within 48 hours) than with more delayed examination. In the case of a normal chest radiograph and hemoptysis, traces of bleeding are commonly seen, but not the site of origin. In these circumstances, examination using an ultrathin flexible instrument may be beneficial in identifying the source of bleeding in a peripheral airway, once the more proximal airways have been cleared of blood by the therapeutic scope. In some instances, bronchoscopy becomes useful not only as a diagnostic method, but also as a therapeutic procedure (see below).

Evaluation of Peribronchial Structures The trachea and bronchi are surrounded by mediastinal and parenchymal structures. Developmental or pathological changes in these organs may be noted during bronchoscopic evaluation. An enlarged goiter or thymus can compress upper airways, resulting in airflow obstruction. Lymphadenopathy may produce structural changes, including widening of the carina due to subcarinal involvement and compression of other bronchi—as, for example, in the right-middle-lobe syndrome. Calcification of peribronchial lymph nodes may result in erosion of the bronchial wall and formation of a broncholith. These lesions are potential sources of obstruction, infection, or dangerous hemoptysis. Development of the techniques of transbronchoscopic needle aspiration (TBNA) and biopsy (TBNB) has permitted

sampling of peribronchial lymph nodes (Fig. 36-3). These transbronchial approaches provide us with diagnostic options that pose much less risk and a lower complication rate than mediastinoscopy; in addition, they are less costly. Diagnosis and staging of lung carcinoma are the major indications for use of TBNA. The procedure is particularly useful for patients who are marginal or poor surgical candidates; in these patients, more invasive approaches, such as mediastinoscopy or mediastinotomy, may be obviated. TBNA has proven particularly useful with the employment of rapid on-site evaluation (ROSE), where a cytopathologist present in or near the bronchoscopy suite can evaluate obtained specimens in real-time. However, because of a high false-negative rate (approximately 25 percent), a negative result with TBNA should prompt consideration of more invasive staging methods (e.g., mediastinoscopy). A positive TBNA is more likely in the presence of significant adenopathy noted on CT scanning, the presence of endoscopically visible tumors, subcarinal lymph nodes greater than 2 cm in diameter, or an abnormal-appearing carina. The use of image guidance with TBNA, such as CT fluoroscopy, electromagnetic guidance, or EBUS, is promising and may provide higher diagnostic yields with TBNA. The use of EBUS in combination with TBNA for the evaluation of mediastinal adenopathy has been most extensively evaluated. Endobronchial ultrasound-directed TBNA (USTBNA) appears to increase diagnostic accuracy and may be particularly useful in centers where ROSE is unavailable. Until recently, the major limitation with USTBNA has been the need for the EBUS and TBNA components to be performed sequentially. A newly developed bronchoscope with an additional working channel that incorporates EBUS allows

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for real-time needle insertion and aspiration under direct lymph node visualization. Early studies suggest an improved diagnostic yield for hilar and mediastinal adenopathy using this modality. Recently, the use of TBNA has been extended to the diagnosis of benign processes, including infection and granulomatous disease. In HIV-positive patients with mediastinal adenopathy, TBNA can provide a definitive diagnosis in as many as one-third of the patients, sparing them more invasive procedures. The ability to obtain core biopsy specimens using a TBNA histology needle has proven particularly useful for diagnosing sarcoidosis. Traditionally, sarcoidosis is documented by the presence of noncaseating granulomata in lung parenchyma obtained by transbronchial biopsy during fiberoptic bronchoscopy. However, the sensitivity is only about 60 to 70 percent, and many patients require further invasive testing, such as surgical lung biopsy. The addition of TBNA to transbronchial biopsy can provide the diagnosis in over 85 percent of cases of sarcoidosis.

Performance of Bronchial and Parenchymal Biopsies Improvements in bronchoscopic instrumentation since the days of Chevalier Jackson have permitted performance of endobronchial biopsies, as well as biopsy of peripheral lung lesions. Knowledge of the underlying disease process has a significant influence on the choice of study procedures and risk of complications. In the case of diffuse lung diseases, such as sarcoidosis, use of fluoroscopy has not been demonstrated to improve the diagnostic yield of transbronchial biopsies. Fluoroscopy is useful, however, in providing information regarding the proximity of the forceps to the pleura and in more rapidly establishing the diagnosis of complications (e.g., pneumothorax). Bronchoscopically visible lesions are generally biopsied with minimal risk; if bleeding occurs, it can usually be controlled easily (Fig. 36-4). The diagnostic yield of bronchoscopy for peripheral lesions depends on a number of factors, including lesion size, its location in the lung, and on the relationship between the lesion and bronchus. The presence of a bronchus sign on chest CT predicts a much higher yield of bronchoscopy for peripheral lung lesions. In these cases, fluoroscopy is mandatory to assure proper positioning of the brush, biopsy forceps, or needle. An exciting new area is the potential application of EBUS in evaluation of peripheral pulmonary nodules. EBUS allows for acquisition of diagnostic tissue via transbronchial biopsy with fewer passes and may permit differentiation between benign and malignant nodules based entirely on nodule architecture. In the future, peripheral EBUS nodule characterization may even obviate the need for pathological diagnosis in certain patients with suspicious nodules. The diagnosis of various infectious diseases can be established using a variety of transbronchoscopic sampling techniques. The role of bronchoscopic biopsy has been reaffirmed in immunocompromised hosts, in whom documenta-

Figure 36-4 ‘‘Hot” forceps biopsy of a vascular endobronchial lesion. Use of the electrocautery forceps allows for safe, hemostatic biopsy of friable or vascularized endobronchial lesions (such as bronchial carcinoids), while obtaining pathologically interpretable tissue biopsy specimens.

tion of the precise pathogen is crucial for appropriate therapy. For example, while the presence of cytomegalovirus in bronchoalveolar lavage fluid may not be diagnostic, documentation of intracellular inclusion bodies on a biopsy specimen is practically pathognomonic. Simple, cost-effective transbronchoscopic tissue sampling can obviate much more complicated, expensive, and higher-risk transthoracic needle biopsy or thoracic surgical procedures.

Sampling of Airway and Alveolar Constituents Bronchoscopy provides easy and relatively safe access to material in the tracheobronchial tree and distal alveolar spaces. A variety of studies are routinely performed on specimens obtained from the airways and alveolar spaces using several techniques. For example, aspirated secretions can be sent for microscopy and culture to determine the offending organism in cases of infection or suspected infection. Cytologic analysis of bronchoscopically obtained materials can provide proof of malignancy. With the advent of lung transplantation, the success of the procedure depends, in large measure, on the early diagnosis of rejection or infection in these immunocompromised subjects. The most commonly employed bronchoscopic techniques for sampling the airways and alveolar spaces include “bronchial washing,” bronchial brushing (see above), and bronchoalveolar lavage. Bronchoalveolar Lavage A very useful bronchoscopic technique is bronchoalveolar lavage (BAL). BAL is safe, even in critically ill patients, when

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biopsy or brushings are not recommended because of the risk of bleeding. Normal saline solution, devoid of any bacteriostatic material, is instilled into distal airspaces through the “wedged” bronchoscope and then aspirated through the instrument’s suction channel. The fluid collected in this manner is analyzed for gross appearance to detect possible alveolar hemorrhage. The fluid may also be subjected to a variety of tests, depending on the clinical circumstances: microbiologic testing, specific cytologic analysis and cell count, immunologic parameters, presence of various biochemical mediators related to pathological processes, tissue markers, polymerase chain reaction, electron microscopy, flow cytometry, and DNA probes. The value of BAL is well documented in the diagnosis of diffuse parenchymal diseases, such as eosinophilic pneumonia, eosinophilic granuloma, and pulmonary alveolar proteinosis. It remains investigational in the evaluation of many other diseases—e.g., sarcoidosis, hypersensitivity pneumonitis, and idiopathic pulmonary fibrosis. Overall, the diagnostic yield of BAL is very much dependent on specific patient characteristics, underlying pathological process, and many technical factors.

Application of Quantitative Microbiologic Techniques Two bronchoscopic methods that are useful in the diagnosis of pulmonary infections are quantitative BAL and protectedspecimen brush (PSB). They are, perhaps, most useful in the setting of suspected ventilator-associated pneumonia (VAP), wherein a patient who is endotracheally intubated and receiving mechanical ventilation has signs of infection and an abnormal chest radiograph. Intubated patients experience colonization of their upper and lower airways with nosocomial organisms. Because of an abnormal mucociliary clearance mechanism, these patients are at greater risk for developing pulmonary infections. In addition, mechanically ventilated, intubated patients are often treated empirically with broadspectrum antibiotics and, therefore, are at greater risk for infection with resistant organisms and unusual lower respiratory tract pathogens. When quantitative cultures are used, growth above a certain threshold is required to diagnose VAP, whereas growth below the threshold is assumed to be due to colonization or contamination. The American Thoracic Society’s position statement allows for the use of either a quantitative or semi-quantitative strategy (e.g., tracheal aspirates) in suspected VAP. However, evidence suggests that quantitative cultures are more reliable in documenting the presence of pneumonia. Protected Specimen Brush PSB uses a double-catheter system in which an outer cannula and distal, biodegradable plug protect the bronchoscopic brush within the inner cannula from contamination with secretions in the upper airway and suction channel of the bronchoscope. When the bronchoscope is positioned prox-

imal to the segmental orifice of interest, the PSB inner cannula is advanced into a subsegment and the protective distal plug ejected. The brush is then advanced peripherally, rotated gently, and retracted into the inner cannula. The inner cannula is subsequently retracted into the outer cannula and the bronchoscope removed from the airway. The distal portion of the catheter is cleaned with 70 percent alcohol and the brush clipped into saline solution under sterile conditions. The PSB is then submitted for quantitative bacterial culture within 15 minutes of performance of the procedure. The threshold for diagnosis of VAP with PSB is 103 colony-forming units (CFU) per milliliter. PSB appears to have higher specificity than sensitivity for the presence of VAP—a positive result greatly increases the likelihood of pneumonia being present. Quantitative Bronchoalveolar Lavage Quantitative BAL entails the performance of a standardized BAL, with infusion of at least 120 ml of saline for adequate sampling of a pulmonary subsegment. Quantitative culture of the aspirated material is performed to determine the number of CFU recovered. For quantitative BAL, a threshold of 104 or 105 CFU per milliliter is used for the diagnosis of pneumonia. The detection of pneumonia by quantitative BAL culture has a sensitivity of 42 to 93 percent and a specificity of 45 to 100 percent. Quantitative BAL may be superior to PSB in the diagnosis of VAP, since BAL samples a much larger proportion of lung parenchyma; PSB samples only a single bronchial segment. Protected BAL, which requires the use of a balloontipped catheter with a distal ejectable plug inserted through the suction channel of the bronchoscope, has a greater specificity than standard BAL. A quantitative BAL strategy which uses detection of intracellular organisms in recovered cells to diagnose pneumonia provides information in a rapid time frame, but it does not identify the etiologic pathogen. BAL techniques incorporating molecular testing in addition to microbiologic cultures are also being evaluated.

TECHNIQUES USED IN THERAPEUTIC BRONCHOSCOPY Since the introduction of bronchoscopy, the technique has been used not only for observation but also for treatment of local airway disorders. As with any clinical intervention, the guiding rule for treatment always remains, “If I can do no good, I will at least do no harm.”

Rigid Bronchoscopic Debulking or Balloon Dilatation Rigid bronchoscopes have beveled tips, which are ideal for coring through large tumors in the airways and for dilating strictures. In addition, they have large internal diameters, which facilitate debridement of tumors, evacuation of

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clots, and ventilation. Despite advances in other adjunctive endoscopic techniques, rigid bronchoscopic recanalization remains the treatment of choice for life-threatening tracheobronchial obstruction. In less urgent cases of obstruction caused by malignant tumors, balloon dilatation has become an attractive alternative to dissection using a blunt rigid bronchoscope. Highpressure angioplasty catheters with various balloon lengths and diameters were commonly used in the past. Currently available balloons, designed specifically for tracheobronchial use (e.g., CRE balloon, Boston Scientific Corp., Cambridge, MA), are expandable to specific diameters by application of defined atmospheric pressure. The balloons are inserted through the working channel of the bronchoscope under fluoroscopic guidance or direct visualization. The balloon, filled with saline or radiopaque liquid, is inflated at the site of the stenosis until a smooth, uniform lumen of predictable diameter is attained. Major risks of the technique are rupture of the bronchial wall, bleeding, and postprocedure airway edema. This technique is often used in combination with bronchoscopic laser therapy and placement of a tracheobronchial stent for the treatment of airway stenosis. Balloon bronchoplasty has also been used successfully to treat other disorders, including tuberculosis, fibrosing mediastinitis, and strictures associated with lung transplantation or prolonged intubation. The technique is less successful when used alone to treat stenosis accompanied by extrinsic airway compression, and it is contraindicated in patients with tracheobronchomalacia. Although in the majority of cases, balloon dilatation is performed while the patient is under general anesthesia, treatment of many airway lesions (e.g., short fibrotic strictures) can be accomplished with use of a flexible bronchoscope while the patient is under conscious sedation. Complications of balloon dilatation of airway lesions include bronchospasm, chest pain, airway perforation, pneumothorax, and pneumomediastinum.

Recently developed technology has facilitated delivery of CO2 laser energy via unique reflective fiberoptic probes (OmniGuide, Inc., Cambridge, MA), allowing applications with flexible laryngoscopy and flexible bronchoscopy. The CO2 laser, with its fine control of tissue ablation, is ideal in the management of laryngeal lesions (e.g., webs, vocal cord nodules, etc). Interventional pulmonologists primarily use the neodymium:yttrium aluminum garnet (Nd:YAG) laser, which provides deeper penetration of tissue (to a depth of 3 to 5 mm), superior photocoagulation, and improved hemostasis, but with less precision in cutting. Photocoagulation using an Nd:YAG laser can be performed through a rigid or flexible bronchoscope, but rigid bronchoscopy remains the preferred method for treatment of patients who have respiratory distress due to severe tracheobronchial obstruction or active intraluminal bleeding. Use of a laser in the tracheobronchial tree requires careful consideration of the anatomic location and configuration of the lesion. If the lesion is in close proximity to the esophagus or pulmonary artery, endobronchial laser therapy poses a risk of fistula formation. Use of laser therapy in a patient with tracheobronchial narrowing due to extrinsic compression may result in perforation of the airway. In addition, prolonged obstruction of the airway (for more than 6 weeks) may lead to refractory atelectasis or bronchiectasis, minimizing the benefits of endobronchial recanalization. The potential for airway recanalization in the setting of long-standing endoluminal obstruction can be assessed by bronchography or perfusion scanning. Although endobronchial laser therapy is generally safe and well tolerated, complications may arise and include cardiac arrhythmias, airway perforation, pneumothorax, hemorrhage, hypoxemia, or endobronchial fire (ignition of the bronchoscope or endotracheal tube). In rare cases, pulmonary edema or fatal pulmonary venous gas embolism has been reported. Patients with standard silicone endotracheal tubes or silicone tracheobronchial stents, and those who require high concentrations of supplemental oxygen, are at increased risk for endobronchial fire. Fortunately, the overall risk is less than 0.1 percent. The overall rate of mortality attributable to endoscopic laser therapy is quite low, not exceeding 0.3 to 0.5 percent in several large series. Success rates and complications directly related to laser therapy are not different when the procedure is performed under general anesthesia through the rigid bronchoscope or under topical anesthesia and conscious sedation through a flexible bronchoscope. Nd:YAG laser photoradiation therapy has demonstrated a single-modality recanalization rate of greater than 90 percent for endobronchial obstruction of large central airways, but it is less successful with peripheral lesions or with associated extrinsic airway compression. Laser therapy may improve the likelihood of successful weaning from mechanical ventilation in patients with advanced lung cancer who present in respiratory failure. In addition, photocoagulation with an Nd:YAG laser is an invaluable treatment for patients with airway obstruction due to benign endoluminal tumors.

Endobronchial Laser Therapy Perhaps, the most widely known technique in interventional pulmonology is laser bronchoscopy. Lasers produce a beam of monochromatic, coherent light that can induce tissue vaporization, coagulation, hemostasis, and necrosis. Although useful in the ablation of endoluminal malignant tumors, bronchoscopic laser therapy is also beneficial in the treatment of other tracheobronchial disorders, including inflammatory strictures, obstructive granulation tissue, amyloidosis, and benign tumors such as hamartomas. Since the initial report of endobronchial laser ablation of an obstructive neoplasm by Laforet in 1976, several types of lasers have become available for the management of tracheobronchial obstruction. The carbon dioxide (CO2 ) laser, used mainly by otolaryngologists, allows shallow penetration of tissue (to a depth of 0.1 to 0.5 mm) and highly precise cutting; however, it has minimal hemostatic properties and, traditionally, was used in conjunction with rigid bronchoscopy.

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Figure 36-5 Electrocautery. Use of electrocautery accessory devices for (A) treatment of a malignant endobronchial lesion with associated tissue destruction (cautery probe) or for (B) management of an endobronchial web related to posttransplant anastomotic stricture (cautery knife).

Endobronchial Cryotherapy and Electrocautery Cryotherapy and electrocautery are excellent, cost-effective alternatives to laser therapy for the management of tracheobronchial obstruction. The depth of penetration and resulting injury are, however, much more difficult to control. As with the Nd:YAG laser, both electrocautery and cryotherapy can be administered through a rigid or flexible bronchoscope. The effects of electrocautery on tissue are similar to those of the Nd:YAG laser, with tissue destruction induced by intense coagulation and vaporization (Fig. 36-5). Argon plasma coagulation (APC) is similar to electrocautery, except that it uses argon gas to conduct the electrical current rather than a contact probe. APC has a depth of penetration of only a few millimeters and is, therefore, more suitable for treatment of superficial and spreading lesions. Cryotherapy probes induce tissue necrosis through hypothermic cellular crystallization and microthrombosis. Specially designed probes are inserted via the bronchoscope until they contact the target tissue. Through the channel in the probe, liquid nitrous oxide or liquid nitrogen is introduced, resulting in the rapid creation of an “ice ball” (approximate temperature, −20◦ C) at the end of the tip. This freezing effect is maintained for about 20 s; the area is then rewarmed, resulting in thawing. Treatment of an endobronchial lesion using a cryoprobe requires several freeze-thaw cycles. Cryotherapy and electrocautery have been used successfully to relieve airway obstruction caused by benign tracheobronchial tumors, polyps, and granulation tissue. These

techniques—cryotherapy in particular—may be superior to lasers for distal lesions because of the lower risk of airway perforation. Similarly, carcinoma in situ and mucosal dysplasia may be adequately treated using cryotherapy or electrocautery alone, although multiple treatments may be required for optimal results. Cryotherapy is a safe treatment for infiltrative lesions of the airway, and according to anecdotal reports, the technique has proved beneficial in patients with posttransplantation anastomotic stenosis and in those with foreign-body aspiration. In fact, cryotherapy may be the modality of choice for the removal of endobronchial blood clots and mucus plugs. Endobronchial cryotherapy is generally not effective for paucicellular lesions that are relatively impervious to freezing, such as fibrotic stenoses, cartilaginous or bony lesions, or lipomas. Furthermore, endobronchial cryotherapy, unlike either laser therapy or electrocautery, cannot be used to achieve rapid relief of symptomatic airway obstruction. The most common serious complication of both electrocautery and cryotherapy is hemorrhage. The estimated incidence of clinically significant bleeding in patients treated with electrocautery is 2.5 percent.

Endobronchial Brachytherapy Brachytherapy is the treatment of tumors with radiation delivered internally through implanted radioactive seeds or inserted wires. This technique ensures the delivery of a maximal therapeutic dose of radiation to the tumor with

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a minimal effect on normal surrounding tissues. Endobronchial brachytherapy involves the bronchoscopic insertion of a thin, hollow catheter through a malignant obstruction under fluoroscopic guidance. A radioactive implant is then inserted into the catheter and left in position for a predetermined period (2 to 40 hours, depending on the dose rate). In 1922, Yankauer reported the use of rigid bronchoscopic brachytherapy for the palliation of airway obstruction due to malignant tumors. Modern techniques, including the use of flexible bronchoscopes, polyethylene afterloading catheters, and 192 iridium implants, were first described in 1983. Since the development of techniques involving high dose-rate delivery in the 1980s, endobronchial brachytherapy has become a particularly attractive option for outpatient treatment. Relief of airway obstruction is the primary goal of endobronchial brachytherapy, although curative treatment may be attempted in conjunction with external-beam radiation in selected patients. Brachytherapy is safest and most effective for central airway lesions, although in one study, small peripheral tumors proved to be more responsive than bulkier central tumors. Among patients with obstruction due to malignant tumors, rates of recanalization range from 60 to 90 percent, with decreased dyspnea, cessation of hemoptysis, and relief of cough in most cases. Brachytherapy has also been used for the prevention and treatment of airway stenosis related to recurrent growth of granulation tissue in patients with lung transplants. Endobronchial brachytherapy may require multiple treatments to be effective. It is generally used as an adjunct to either Nd:YAG photocoagulation or conventional externalbeam irradiation in an effort to achieve both rapid and sustained recanalization in patients with obstruction due to malignant tumors. Brachytherapy may also be administered in conjunction with placement of an endobronchial stent in patients with extrinsic compression of the airways due to malignant tumors. Brachytherapy works best with submucosal and peribronchial malignant disease. Serious complications of brachytherapy include massive hemoptysis and fistula formation. Because of the risk of fatal hemorrhage, every effort should be made to rule out involvement of central vessels before treatment is administered. The incidence of serious complications varies widely, with rates as low as 0 to 10 percent in some of the largest studies, and as high as 30 to 40 percent in smaller studies.

occurs as a result of cellular destruction through the generation of oxygen-free radicals or by ischemic necrosis mediated by vascular occlusion resulting from thromboxane A2 release. The selective effect of PDT on malignant cells is thought to be due to the differential uptake and retention of photosensitizing agents in neoplastic cells rather than in normal cells. This selectivity effect appears to be most pronounced approximately 24 to 48 hours after infusion of the photosensitizing agent. For this reason, bronchoscopic treatment of target lesions is often performed 1 to 2 days after the agent has been injected. Given the delayed onset of action of PDT, it is not useful in patients with acute respiratory distress from tracheobronchial obstruction. Frequent bronchoscopies are often required to debride necrotic tissue. Ideal candidates for PDT include patients with airway obstruction due to malignant polypoid endobronchial masses, those with minimal extrinsic airway compression, and patients with minimally invasive tumors of the central airways. Although surgical resection remains the treatment of choice for early lung cancer, some patients refuse surgery or are deemed inoperable because of high surgical risk. PDT may represent an appropriate alternative. Response rates are highest in patients with small tumors and minimal depth of penetration. In patients with bulky tumors, endobronchial PDT may substantially reduce the obstruction, with objective increases in spirometric measurements and subjective improvements in dyspnea and the quality of life. Metastatic tumors have also been treated successfully with PDT. Complications of PDT include increased skin photosensitivity and hemoptysis resulting from extensive tumor necrosis.

Photodynamic Therapy Photodynamic therapy (PDT) is currently approved by the Food and Drug Administration for the palliation of airway obstruction caused by malignant tumors and as an alternative to surgery in selected patients with minimally invasive central lung cancer. PDT works on the principle that certain compounds, such as hematoporphyrin derivatives, function as photosensitizing agents, rendering malignant cells susceptible to damage from monochromatic light. Tumor necrosis

Tracheobronchial Stenting The medical term â&#x20AC;&#x153;stentâ&#x20AC;? was first used to denote a device that supported the healing of gingival grafts, developed by the British dentist, Charles R. Stent. The term has since been used to refer to any device designed to maintain the integrity of hollow tubular structures, such as the coronary arteries and the esophagus. Anecdotal reports of attempts to use stents in the tracheobronchial tree date back to 1915. The Montgomery T tube, designed in the 1960s, was the first reliable, dedicated airway stent. However, stent implantation in the lower trachea and bronchi did not become standard medical practice until Dumonâ&#x20AC;&#x2122;s 1990 report on the safety and ease of placement of a dedicated airway stent made of silicone. Two main types of endobronchial stents are in use today: tube stents made of silicone or plastic and selfexpandable metallic stents (SEMS). Silicone stents, including the Dumon stent, are usually placed via rigid bronchoscopy while the patient is under general anesthesia. These stents are inexpensive and easy to remove from the airway; they provide protection from tumor ingrowth and cause minimal irritation to adjacent normal tissues. Potential complications of silicone stents include migration, formation of granulation tissue, and inspissation of secretions. Bifurcated silicone and composite stents are also available for the palliation of distal tracheal and main carinal lesions. These stents have been

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success rate among patients with tracheal stenosis caused by other disorders. The most common complications are stent migration, granulation tissue formation, and secretion inspissation. In limited studies, success rates, broadly defined as symptomatic relief, have ranged between 78 percent and 98 percent. In studies of patients who had been intubated because of respiratory failure due to unresectable tracheobronchial and mediastinal disease, stent placement facilitated extubation in nearly all the patients. The benefits of stent placement appear to persist in patients who survive for a period of several months or years after implantation. Long-term follow-up data, however, are limited to benign disease, since the mean follow-up period in patients with airway compression due to malignant tumors does not usually exceed 3 to 4 months. Some authors have reported poor long-term results with use of metal stents in patients with fibro-inflammatory stenosis due to nonmalignant disorders. In addition, case reports describe massive hemorrhage associated with the use of stents in patients with extrinsic compression attributable to aneurysmal dilatation or congenital malformations of the aorta. Figure 36-6 Self-expandable metallic stent (SEMS). Uncovered stent placed in right main-stem bronchus for malignant extrinsic compression (Ultraflex, Boston Scientific Corp., Cambridge, MA).

effective in the management of carinal compression associated with malignant tumors, tracheoesophageal fistulas, and tracheobronchomalacia. Unlike silicone stents, SEMS can be placed with the use of a flexible bronchoscope, and they are less likely to migrate and are more likely to preserve normal mucociliary clearance (Fig. 36-6). Metal stents remain fairly expensive, however, and if they are misplaced in the airway, rigid bronchoscopy is often required for their removal. In addition, mucosal inflammation and the formation of granulation tissue are common at the proximal and distal ends of metal stents, and endoscopic intervention may be required to restore airway patency. Longstanding SEMS often require rigid bronchoscopic techniques for complete removal. For all these reasons, SEMS are not recommended for most patients with nonmalignant airway stenoses. Endobronchial stents have a critical role in a multimodal endoscopic approach to both benign and malignant stenoses of the airways. Stenosis due to locally advanced bronchogenic carcinoma, for example, can be treated with a combination of endoscopic laser therapy and stent implantation in order to prevent respiratory failure. Stent placement can also be used to maintain airway patency after endobronchial brachytherapy or can be combined with laser therapy and balloon dilatation in the endoscopic management of fibrotic strictures. Most studies of the efficacy of endobronchial stent placement have had impressive results. Dumon and colleagues reported excellent clinical outcomes and few complications with the use of silicone stents in patients with extrinsic airway compression due to malignant tumors, but a lower

APPLICATIONS OF THERAPEUTIC BRONCHOSCOPY Therapeutic bronchoscopy may be used in a wide variety of settings, the most common of which are described below.

Control of Hemoptysis In cases of hemoptysis, bronchoscopy may be of value not only for diagnosis, but also for emergency management of endobronchial bleeding. Because of difficulties with visualization, instruments with large and maximally effective suction channels should be used. In assessment of massive bleeding, when the need to remove large clots is anticipated, rigid bronchoscopy is generally preferred. When continuous suctioning of blood fails to clear the airways, other means can be used. An iced saline solution can be instilled along with vasoactive drugs, such as epinephrine, to induce spasm of the bleeding vessels. The bronchoscope itself can also be used to stem the bleeding by tamponade of the bleeding site or to occlude the lumen of the bronchus from which the bleeding originates. The same effect, perhaps with better local control, can be achieved using bronchoscopic balloon catheters. Specially designed catheters have been developed for introduction through the working channel of the flexible bronchoscope, some permitting subsequent removal of the scope while the tamponading balloon remains in place. Another effective method for control of visible sources of bleeding, particularly from endobronchial neoplasms, is Nd:YAG laser photocoagulation.

Endoluminal Airway Obstruction Endoluminal obstruction of the tracheobronchial tree may result from various benign and malignant processes. The most

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Figure 36-7 Algorithm for the management of central-airway obstruction due to malignant tumor. This treatment algorithm addresses both acute and subacute central-airway obstruction, as well as the location and type of lesion characteristics that can be determined using CT and diagnostic bronchoscopy.

common cause of endobronchial obstruction is advanced bronchogenic carcinoma. In patients with inoperable tumors of the central airways, restoration of airway patency may provide palliation and may even prolong life, particularly in the case of impending respiratory failure. Signs and symptoms of central airway obstruction vary, but often include wheezing, cough, stridor, hoarseness, hemoptysis, and chest pain. A careful pretreatment evaluation should be performed to distinguish symptoms attributable to focal tracheobronchial lesions from those related to underlying diffuse airflow obstruction, parenchymal lung disease, or both. Mild-to-moderate tracheal stenosis, for example, may contribute only marginally to the degree of dyspnea experienced by a patient with severe chronic obstructive lung disease. Although pulmonary function testing and thoracic imaging techniques such as computed tomography (CT) and magnetic resonance imaging may be useful in the evaluation of a patient with suspected obstruction of the central airway, bronchoscopy—either rigid or flexible—remains the diagnostic gold standard. Increasingly, however, threedimensional reconstruction CT imaging—so-called “virtual bronchoscopy”—is being applied as a reliable, noninvasive method of assessing the nature and extent of airway obstruction.

The bronchoscopic approach to the management of endoluminal obstruction depends on the location of the lesion, presence or absence of associated extrinsic compression, and degree of clinical urgency (Fig. 36-7). Rigid-bronchoscopic debulking, with adjunctive laser therapy or electrocautery, is recommended when airway recanalization must be performed on an emergency basis. If endobronchial obstruction is accompanied by marked extrinsic compression, placement of a stent may be beneficial. The complexity of a lesion is equally important in determining the best approach to resection. Tracheal webs, for example, are often managed by laser resection alone, whereas complex fibrotic strictures may warrant the combination of rigid-bronchoscopic or balloon dilatation, laser resection, and stent placement. For focal tracheal stenoses in low-risk patients, surgical resection and primary reanastomosis should remain the first-line therapy.

Extrinsic Airway Compression Extrinsic airway compression usually results from malignant involvement of structures adjacent to the central airways, such as mediastinal lymph nodes or the esophagus, but it may be associated with a benign process, such as fibrosing mediastinitis,

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tuberculosis, aneurysmal dilatation of the aorta, or sarcoidosis. Clinical signs and symptoms of extrinsic airway compression often mimic those of endobronchial obstruction. The diagnosis is established on the basis of bronchoscopic evidence of marked airway narrowing in the absence of an endoluminal mass. Chest CT, and increasingly, EBUS have important adjunctive roles in identifying anatomic structures external to the narrowed lumen. Therapeutic options in the management of extrinsic airway compression are limited. Ablative endoscopic approaches, such as laser therapy, cryotherapy, PDT, and electrocautery are contraindicated because of the risk of airway perforation. Although some patients with malignant disease may benefit from endobronchial brachytherapy, tracheobronchial stent placement is the palliative treatment of choice for patients with symptomatic extrinsic airway compression.

Tracheobronchomalacia Diffuse or focal tracheobronchomalacia is perhaps the most challenging disorder encountered by the interventional pulmonologist. Cartilaginous tracheobronchomalacia, as seen in patients with postintubation injury or relapsing polychondritis, reflects a loss of the structural integrity of the trachea or main-stem bronchi due to destruction of the airwayâ&#x20AC;&#x2122;s cartilaginous rings. Membranous, or crescentic, tracheobronchomalacia is manifested by airway collapse during exhalation as a result of laxity of the membranous portion of the trachea and main bronchi and is usually seen in patients with long-standing chronic obstructive pulmonary disease. Focal tracheobronchomalacia may be a complication of longstanding intubation or an anastomotic complication after lung transplantation. Tracheobronchomalacia is best diagnosed on the basis of flexible bronchoscopy, with the patient breathing spontaneously, although dynamic CT scanning, with images obtained on inspiration and expiration, is often helpful. The endoscopic treatment of choice for patients with diffuse tracheobronchomalacia is the insertion of a standard or bifurcated silicone tracheobronchial stent. This intervention is more likely to be successful in patients with the cartilaginous type of tracheobronchomalacia than in those with the membranous type. For those patients with membranous tracheobronchomalacia, a trial of stenting with a silicone endoprosthesis should be performed. For those who benefit in terms of decreased respiratory symptoms and improved pulmonary function, surgical placation or buttressing of the posterior membrane can be performed with good results. For many patients with focal tracheobronchomalacia, surgery is the best therapeutic option. An alternative treatment for selected patients with diffuse tracheobronchomalacia is the pneumatic stent afforded by noninvasive ventilatory techniques, such as nasal continuous positive airway pressure.

Removal of Foreign Bodies Foreign body aspiration is more likely to occur in children than in adults, with most occurring in children younger than 3 years. In children the obstruction most often involves a

main-stem bronchus, whereas in adults the majority of foreign bodies are wedged distally, most commonly in the right lower lobe. Prior to the development of bronchoscopy, most foreign body aspirations resulted in high morbidity and mortality, commonly from postobstructive pneumonia. Until the introduction of the flexible bronchoscope, all foreign body removals were accomplished with the rigid bronchoscope. Even at present, it is well accepted that the rigid bronchoscope is the tool of choice for the removal of foreign bodies, especially in children. The advantage of the rigid instrument resides in its larger access channel, permitting use of more adaptable retrieval tools, and its ability to provide and control the patientâ&#x20AC;&#x2122;s ventilation. In adults, a flexible bronchoscopy is the most common initial diagnostic tool and allows for successful removal of the foreign body in the majority of cases. Various types of instruments have been developed for use with bronchoscopy for the removal of foreign bodies, including grasping forceps, balloon catheters, retrieval baskets, snares, and magnetic extractors. The choice of instrument depends on the specifics of the type of foreign body and its location in the tracheobronchial tree. Grasping forceps may be helpful in the retrieval of hard objects with an irregular surface. Smooth objects or organic material (e.g., nuts or food particles) may require use of expandable baskets or a combination of balloon catheters, suction devices, and grasping forceps. A frequently used technique employs a Fogarty balloon catheter to dislodge the foreign body and to bring it proximally into the trachea prior to attempting removal using other instruments (Fig. 36-8).

Figure 36-8 Flexible bronchoscopic-mediated foreign body removal from the distal right bronchus intermedius using balloon catheter.The Fogarty embolectomy balloon catheter is inflated beyond the foreign body and used to dislodge it to a more proximal location where it can be easily grasped and removed with a basket or snare.

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Special attention should be paid to the period after removal of the foreign body—a time when complications can occur. Patients should be observed for any signs of hemoptysis or subglottic edema. Trauma inflicted during the extraction or forceful manipulation of instruments greatly accentuates the risk of postoperative complications, particularly if oversized instruments are used or if the bronchoscopy is prolonged.

better, with a higher rate of success of bronchoscopic sealing. It is much more difficult to achieve good obliteration of the fistula when the fistula is infected or is due to an underlying malignancy.

SAFETY FACTORS IN BRONCHOSCOPY Aspiration of Secretions According to a survey of bronchoscopists conducted in the United States, removal of retained secretions is cited as a leading indication for therapeutic bronchoscopy. Bronchoscopic aspiration of secretions may be indicated in patients presenting with weakness of respiratory muscles (e.g., due to underlying neuromuscular disease or the postoperative state) or disorders leading to recurrent aspiration of food or excessive upper-airway secretions. In critically ill or mechanically ventilated patients, removal of secretions and mucous plugs usually can be rapidly achieved with the flexible bronchoscope. A flexible scope with a large-diameter suction channel should be chosen for this procedure. The nature of the retained material—its consistency and viscosity—may dictate frequent bronchoscopies to relieve segmental or lobar atelectasis due to inspissated mucous plugs. Underlying pulmonary diseases, such as bronchiectasis, may aggravate the retention of airway secretions. Bronchoscopic aspiration of secretions should not be considered “routine” in the postoperative period or in other conditions where good chest physiotherapy and maintenance of adequate pulmonary toilet can be more effective. Two specific disorders are worth highlighting in the context of therapeutic bronchoscopy: pulmonary alveolar proteinosis (PAP) and allergic bronchopulmonary aspergillosis (ABPA). In PAP, BAL for clearance of alveolar material is a time-honored therapeutic procedure that may be facilitated by use of a bronchoscopic approach. In ABPA, lavage with saline solution may be insufficient to remove tenacious impactions (described as “plastic bronchitis”). In these circumstances, use of bronchoscopic forceps or snare may prove helpful.

Closure of Bronchial Fistulae Flexible bronchoscopy can be a useful intervention in confirming the diagnosis of suspected bronchopleural fistula and specifying its precise location. Depending on the location and the size of the fistula, it can be approached bronchoscopically and an attempt made to seal it. Simple tamponade using the body of the flexible bronchoscope or a balloon catheter provides only temporary relief. Many different techniques have been employed, including introduction of irritating substances—e.g., silver nitrate, with the object of stimulating reactive granulation tissue formation. Several potentially useful agents have been described, including Gelfoam, autologous blood patch, cryoprecipitate, and thrombin injection to create fibrin clot. Small bronchial openings in an otherwise normal bronchus following thoracic surgery respond much

Bronchoscopy is a specialized procedure that requires extensive training. Familiarity with both the physiology and anatomy of the airways and other intrathoracic structures is essential. Any diagnostic or therapeutic manipulation should be considered in relation to the underlying condition of the patient, localization of the area of investigation, and other surrounding structures in the thorax. It is essential to develop good communication between the bronchoscopist and other members of the team. While the bronchoscopist concentrates on the field of work—which, as seen through the bronchoscope, is two-dimensional—other team members are responsible for monitoring the patient (oxygen saturation, blood pressure, heart rhythm, etc.) and checking and maintaining the adequacy of ancillary equipment (suction, oxygenation, and accessories such as forceps, balloons, catheters, and laser light guides). Risks are decreased if, for example, special attention is paid to the control of accessories during their manipulation beyond the tip of the bronchoscope. Premature deployment of the needle biopsy device or inappropriate bending of the bronchoscope while an instrument is inside the flexible portion can result in perforation of the bronchoscope. Activation of the laser with a broken light guide inside the bronchoscope or inadequate protrusion of the tip of the fiber beyond the bronchoscope may result in airway fires or severe burns to the patient. Attention to details and proper maintenance of the equipment, including accessories, enhance safety for the patient and staff. Diagnostic yield and therapeutic results are also improved. Last, but not least, proper knowledge and application of safety standards and maintenance procedures decrease the cost of bronchoscopy.

COMPLICATIONS OF BRONCHOSCOPY Bronchoscopy is a potentially hazardous procedure. Complications are generally due to inappropriate preparation of patients before bronchoscopy, effects of local or general anesthesia, and manipulation of various instruments. Appropriate training and experience of the bronchoscopist and supporting team are crucial in reducing the rate of complications.

Anesthesia and Related Blood Gas Abnormalities Approximately half of the life-threatening complications of diagnostic bronchoscopy are associated with premedication and use of topical anesthesia. Risk is significantly increased

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in the elderly, and in those with serious concomitant illnesses. Predisposing factors include cardiovascular disease, chronic pulmonary disease, renal and hepatic dysfunction, seizures, and altered mental status. Mild sedation, anxiolysis, muscular relaxation, and anterograde amnesia increase patient cooperation and permit quicker and less traumatic procedures. Doses of benzodiazepines, opiates, anticholinergics, and topical anesthetics must be adjusted if there is underlying organ dysfunction. Conscious sedation using short-acting benzodiazepines (e.g., midazolam) offers significant anterograde amnesia; its use has reduced the incidence of potentially dangerous hypotension and respiratory depression. Inadequate topical anesthesia potentiates coughing, gagging, and patient discomfort and increases the risk of injury during bronchoscopy. However, topical anesthetics such as lidocaine, the most frequently used agent, are absorbed systemically through the respiratory mucosa, increasing the risk of cardiac or central nervous system toxicity. These complications are more likely to occur in patients with underlying low cardiac output, hepatic dysfunction, and oropharyngeal candidiasis. Another, less frequent complication of excessive lidocaine use is methemoglobinemia and resultant tissue hypoxia. Skillful manipulation of rigid and flexible bronchoscopes reduces the risk of injury to the upper airways, which can result in life-threatening laryngospasm during or after completion of the procedure. Particular caution must be exercised in patients with underlying bronchospastic disorders, superior vena cava syndrome, or history of angioedema. Introduction of the bronchoscope under general anesthesia or under conscious sedation with topical anesthesia frequently results in a decrease in oxygenation and in hypoventilation, with demonstrable increases in PaCO2 . In patients with underlying chronic lung disease, severe hypoxemia may occur, triggering life-threatening cardiac arrhythmias. All patients undergoing bronchoscopic procedures should be monitored continuously (electrocardiogram, blood pressure, O2 saturation, and, if indicated, expiratory CO2 concentration). Use of supplemental oxygen during the procedure should be routine. Bronchoscopy probably should not be performed in patients who are unable to maintain a PaO2 of 65 mmHg while an FIO2 of 1.0 and full ventilatory support are administered. Significant oxygen desaturation may occur during BAL. The degree of desaturation is directly related to the duration of the procedure and the volume of lavage fluid used. Return to the prebronchoscopy level of O2 saturation may be prolonged after removal of the bronchoscope, and supplemental O2 should be continued throughout the procedure and during the postbronchoscopy observation period.

Fever and Infection In patients with underlying valvular cardiac disease and those predisposed to endocarditis, the American Heart Association recommends use of prophylactic antibiotics before rigid

bronchoscopy, but not before flexible bronchoscopy. Antibiotic prophylaxis is mandatory, however, in patients with prosthetic valves, surgical vascular shunts, or a history of endocarditis. Appearance of transient fever after bronchoscopy is not unusual and generally does not require any therapy. However, persistent fever in the setting of progressive radiographic infiltrates necessitates antibiotic therapy. The incidence of fever is increased in the elderly, in those with underlying chronic pulmonary disease or documented endobronchial obstruction, and in those with bronchoscopic interventions for malignancy. The incidence of fever and extension of pulmonary infiltrates increase with the volume of BAL fluid and the total number of pulmonary segments lavaged. In most cases, these complications resolve spontaneously within 24 h. The incidence of postbronchoscopic infections is higher in immunocompromised hosts and those with chronic suppurative lung disease (e.g., cystic fibrosis).

Airway Obstruction and Perforation The advent of interventional bronchoscopy has resulted in complications not ordinarily seen with diagnostic bronchoscopy. Inappropriate use of lasers has resulted in endobronchial burns and bronchial perforations associated with catastrophic bleeding, pneumomediastinum, or pneumothorax. Endobronchial edema may also occur as a result of laser thermal effects. As noted previously, airway stent insertion is associated with several complications. Stents may not be properly adapted to the diameter of the airway, resulting in either incomplete stent deployment or stent migration, possibly engendering life-threatening airway obstruction. The presence of this palliative endoprosthesis in the airway may predispose to difficulties with secretion clearance and accumulation of inspissated mucus. Placement of SEMS may result in severe local airway reactions, particularly at the edges of the device, producing granulation tissue, hemorrhage, or bronchial perforation.

Pneumothorax Most of the serious complications directly due to bronchoscopic intervention have been reported in association with performance of transbronchial biopsies. Pneumothorax following transbronchial biopsy occurs in about 4 percent of cases, even when the procedure is done under fluoroscopic guidance. The impact of fluoroscopy on the incidence of pneumothorax remains controversial. Uncontrolled studies have not found a difference in the incidence of pneumothorax following transbronchial biopsy when performed with and without fluoroscopy. The risk of pneumothorax is not related to the size of the bronchoscopic biopsy forceps. The incidence of pneumothorax is increased, however, in immunocompromised hosts. This is likely due to the increased risk of pneumothorax associated with Pneumocystis pneumonia (PCP). The

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risk is also elevated in mechanically ventilated patients, with peripheral lung biopsies, and in the presence of bullous lung disease. For these reasons, a postbronchoscopic expiratory chest radiograph is routinely performed. In case of a significant pneumothorax, a chest tube should be inserted immediately to avoid oxygen desaturation and/or tension physiology.

Hemorrhage One of the most frequently reported complications related to bronchoscopy is hemorrhage—a complication that can be largely avoided by proper evaluation of the patient before the procedure. An incidence of postbronchoscopy hemorrhage of 45 percent has been reported in uremic patients. For these reasons, a blood urea nitrogen (BUN) level above 30 mg/dl or a creatinine level above 3 mg/dl should be considered relative contraindications to bronchoscopy. Similarly, patients with known underlying bleeding disorders, especially those caused by platelet dysfunction or thrombocytopenia, have an increased risk of bleeding (epistaxis or hemoptysis) during bronchoscopy. Bronchoscopy should not be performed if the platelet count is below 50,000/mm3 ; transbronchial biopsy or aggressive interventional procedures (laser therapy, bronchoplasty, or stent placement) are probably safe only with platelet counts above 75,000/mm3 . Manipulation of the bronchoscope, mechanical trauma, vigorous suctioning, endobronchial brushing, and biopsy may result in bleeding in 1 to 4 percent of patients without underlying risks for hemorrhage. Hemorrhage can also occur with inadvertent perforation of pulmonary vessels during transbronchial needle aspiration or biopsy. Overall, when bronchoscopy is performed by an experienced endoscopist, backed up by a well-trained team and appropriate facilities, mortality and morbidity are very low.

TRANSTHORACIC NEEDLE ASPIRATION AND BIOPSY Indications and Contraindications Transthoracic needle aspiration (TTNA) was first used for the diagnosis of pulmonary disease in 1883, when Leyden performed the procedure on three patients with pneumonia. In 1886, M´en´etrier reported the use of TTNA in the diagnosis of lung carcinoma. Since that time, many published series have described the use of TTNA for the diagnosis of a variety of benign and malignant thoracic lesions, using fluoroscopic, CT, or ultrasound guidance. The related technique of transthoracic needle biopsy (TTNB) provides core biopsy material from pulmonary nodules for histological examination. The ability to analyze histology is critical in establishing a definitive diagnosis for certain disease states (e.g., histoplasmosis, sarcoidosis) in which cytologic aspiration is inadequate in documenting the characteristic noncaseating

Figure 36-9 Transthoracic needle aspiration of pulmonary nodule. CT scan image of TTNA performed for a 2-cm right-lower-lobe nodule using a 22-gauge Westcott needle (Becton Dickinson & Co, Franklin Lakes, NJ). The needle can be seen entering the nodule. (Courtesy of Ana Kolansky, M.D.)

granulomas. TTNB also provides improved diagnostic accuracy in lymphoma, both Hodgkin’s and non-Hodgkin’s varieties, in which anatomic structure is important in delineating the type of lymphoma and in distinguishing between clonal, neoplastic processes and inflammatory conglomerations of lymphocytes. Histological specimens may improve the yield in the diagnosis of pulmonary hamartomas, characterized by the presence of cartilage and/or adipose tissue. The major indications for TTNA or TTNB include evaluation of solitary lung nodules and masses (Fig. 36-9), mediastinal and hilar lesions, metastatic disease to the lung from a known extrathoracic malignancy, chest wall invasion by lung carcinoma, and pulmonary consolidation or infiltrates that are likely to be of infectious origin. With the “reemergence” of thoracoscopy and recent development of video-assisted thoracic surgical techniques, patients can more easily undergo complete excision of pulmonary nodules. In the past, many pulmonologists performed TTNA as the initial diagnostic procedure for intrapulmonary lesions, especially those in the lung periphery. Physicians are now faced with the dilemma of whether to send patients directly to thoracoscopic biopsy for a definitive answer. Two commonly used strategies—the use of positron emission tomography (PET) or serial CT scanning—can be used to obtain additional evidence regarding the likelihood of malignancy. In appropriately selected patients, the presence of a PET-positive lesion or a lesion increasing in size on serial CT scans may obviate the need for TTNA. Few absolute contraindications to TTNA exist. These include an uncooperative patient or one with an intractable cough, as patients must be able to suspend respirations for 5

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to 10 s while the needle crosses the pleura. In addition, TTNA is absolutely contraindicated in patients with a suspected pulmonary hydatid cyst because of the risk of capsule rupture and systemic dissemination. Relative contraindications include bullous emphysema, pulmonary arterial hypertension, and coagulation or platelet disorders. Patients with bullous emphysema are at increased risk of developing symptomatic or tension pneumothoraces after TTNA, although most induced pneumothoraces are small and can be treated conservatively. Those with pulmonary hypertension who undergo TTNA have a higher chance of developing pulmonary hemorrhage and significant hemoptysis.

Technique Proper technique in performing TTNA is critical in obtaining adequate material for reliable interpretation. In addition to the mechanics of needle insertion and aspiration, the choice of needle type and careful specimen processing are important aspects of the procedure. Choice of Needle Many needle types are available for TTNA. They vary in both length and width. In the early 1960s, TTNA was performed using large-bore cutting needles; significant hemorrhagic complications were reported. More recently, thin-needle aspiration has become standard with devices ranging in size from 18- to 22-gauge. Coaxial needle systems have been introduced for the purpose of obtaining multiple samples from a single pleural penetration. These systems are also useful for procuring specimens for histological evaluation. Radiographic Guidance Most transthoracic needle procedures are performed with fluoroscopic guidance, which allows for real-time imaging of pulmonary lesions during needle insertion and specimen retrieval. CT has been used to guide TTNA of pulmonary lesions, typically those that are too small to be seen fluoroscopically or are centrally located and adjacent to major vascular structures. Because CT-guided TTNA is not typically done using real-time visualization, the procedure takes longer to perform and requires several transthoracic passes to obtain diagnostic material. Not surprisingly, CT-guided TTNA is associated with an increased incidence of pneumothorax (up to 60 percent in some series). Ultrasound guidance of TTNA offers the advantage of real-time lesion imaging, easy portability, and absence of exposure to ionizing radiation for both the clinician and the patient. Ultrasound is used most commonly for peripheral lung lesions that extend to the pleural edge, or for the diagnosis of mediastinal masses. The sensitivity of ultrasound-guided TTNB of pulmonary and mediastinal lesions larger than 3 cm may be as high as 96.8 percent; the rate of pneumothorax is less than 2 percent.

Needle Insertion The lesion is localized by fluoroscopic guidance, and the overlying skin is marked and anesthetized with 1 percent lidocaine. With the patient lying as still as possible, the aspiration needle is inserted perpendicularly through the anesthetized region into the lesion, as seen under fluoroscopy. The needle may be seen to displace the lesion, or if properly positioned, the needle will move in concert with the lesion during quiet breathing. If the needle is seen to move independently of the lesion during respiration, it is positioned unsatisfactorily. Ideal aspiration technique necessitates having the tip of the needle as close to the center of the lesion as possible. A 20-ml lockable syringe containing approximately 3 ml of sterile saline is attached to the needle hub, and the tip is maintained in proper position using fluoroscopic guidance. Suction is then applied by pulling the syringe plunger back and locking it into position with clockwise rotation. While suction is sustained with the locked syringe, the needle tip is advanced and withdrawn about 0.5 to 1 cm within the lesion under real-time fluoroscopic guidance. The needle is then removed from the chest, suction is released, and the aspirated material is flushed into a specimen container. Several samples should be obtained to increase the diagnostic yield. With a necrotic mass, aspiration should also be performed in peripheral locations of the lesion in order to obtain viable cells and to decrease the risk of false-negative results.

Results TTNA and TTNB have excellent success rates in the diagnosis of primary or metastatic pulmonary malignancies; for TTNA, the sensitivity is 85 to 95 percent. Major causes of false-negative results in malignant disease are inadequate sampling of the lesion and aspiration in an area of necrosis or postobstructive pneumonia. In addition, small, central malignant lesions may be difficult to diagnose accurately with TTNA. Aspiration of vascular tumors, such as angiosarcoma, carcinoid, or metastatic renal cell carcinoma, may yield a bloody aspirate with few, if any, malignant cells. TTNA rarely leads to misclassification of primary pulmonary neoplasms, with a reported rate of misdiagnosis of small-cell carcinoma of 0 to 1.1 percent. False-positive results are extremely rare (under 0.5 percent) and are typically reported in the setting of inflammatory processes, such as tuberculosis, radiation fibrosis, organizing pneumonia, and pulmonary infarction. Specific diagnosis of a benign lesion with TTNA is more problematic, with published sensitivities ranging widely, from 11.7 to 68 percent. A TTNA that is negative for malignancy does not rule out the presence of neoplastic disease, especially if the aspirate was unsatisfactory. The degree of suspicion of malignancy in a particular clinical situation becomes extremely important in dictating the next step following a negative TTNA. For a smoker with a high risk of bronchogenic

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carcinoma, the proper course may lead to videothoracoscopic biopsy of the lesion, whereas in a young, otherwise healthy nonsmoker, close observation with serial CT scans may be the preferred option.

ditionally treated with surgery. These opportunities will need to be accompanied by well-designed studies to delineate the appropriate use of these techniques in clinical practice.

Complications As mentioned previously, the most common complication of both TTNA and TTNB is pneumothorax; incidence rates reported in the literature vary from 8 to 61 percent. A small percentage of the pneumothoraces are clinically significant; only about 8 percent require thoracostomy tube drainage. Preexisting lung disease—in particular, bullous emphysema—is the most significant predisposing factor to development of pneumothorax after TTNA or TTNB. Other risk factors are deep lesions, increased number of transthoracic passes, crossing more than one pleural surface with the needle, and increased patient age. The vast majority of patients who develop clinically significant pneumothoraces after the procedure have an underlying diagnosis of chronic obstructive pulmonary disease. Uncommon complications of TTNA and TTNB include hemorrhage and hemoptysis, although these are typically minor. Cases of fatal hemorrhage from tracheobronchial obstruction from clot and subsequent asphyxia after use of large-bore (18-gauge) cutting needles have been reported. Air embolism is a rare complication caused by creation of a communication between atmospheric air and a pulmonary vein. To minimize this risk, the needle should never be left open to air while in the chest, and the patient should be discouraged from deep breathing, straining, or coughing during the procedure. The procedure should be halted and the needle withdrawn if the patient is actively coughing. If an air embolism is suspected, 100 percent oxygen should be administered through a non-rebreather face mask and the patient placed in the left lateral decubitus position, with the head down: this position optimizes capture of air in the right heart. The patient should be transferred immediately to a hyperbaric chamber.

SUMMARY Technological advances in diagnostic and therapeutic bronchoscopy continue to improve our ability to perform minimally invasive, accurate evaluations of the tracheobronchial tree and to perform an ever-increasing array of therapeutic and palliative interventions. The continued development of imaging technologies will certainly provide improvements in many of the modalities described above. Future improvements will include refinements in video and ultrasound imaging technology and the development of newer modalities, such as molecular imaging. With the continued refinement of interventional modalities, therapeutic bronchoscopy may soon provide alternative therapies for conditions that are tra-

SUGGESTED READING Anders GT, Johnson JE, Bush BA, et al: Transbronchial biopsy without fluoroscopy. A seven-year perspective. Chest 94:557–560, 1988. Baharloo F, Veyckemans F, Francis C, et al: Tracheobronchial foreign bodies: Presentation and management in children and adults. Chest 115:1357–1362, 1999. Bolliger CT, Mathur PN, Beamis JF, et al: ERS/ATS statement on interventional pulmonology. European Respiratory Society/American Thoracic Society. Eur Respir J 19:356–373, 2002. Cavaliere S, Venuta F, Foccoli P, et al: Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 110:1536–1542, 1996. Cortese DA, Edell ES, Kinsey JH: Photodynamic therapy for early stage squamous cell carcinoma of the lung. Mayo Clin Proc 72:595–602, 1997. Dumon JF: A dedicated tracheobronchial stent. Chest 97:328– 332, 1990. Dweik RA, Stoller JK: Role of bronchoscopy in massive hemoptysis. Clin Chest Med 20:89–105, 1999. Edell ES, Cortese DA: Photodynamic therapy. Its use in the management of bronchogenic carcinoma. Clin Chest Med 16:455–463, 1995. Fagon JY, Chastre J, Wolff M, et al: Invasive and noninvasive strategies for management of suspected ventilatorassociated pneumonia. A randomized trial. Ann Intern Med 132:621–630, 2000. Guidelines for the management of adults with hospitalacquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171:388–416, 2005. Herth F, Becker HD, Ernst A: Conventional vs endobronchial ultrasound-guided transbronchial needle aspiration: A randomized trial. Chest 125:322–325, 2004. Jackson C, Jackson CL: Bronchoscopy, in Bronchoesophagology. Philadelphia, WB Saunders, 1950, pp 68–109. Klein JS: Interventional techniques in the thorax. Clin Chest Med 20:805–826, ix, 1999. Laforet EG, Berger RL, Vaughan CW: Carcinoma obstructing the trachea. Treatment by laser resection. N Engl J Med 294:941, 1976. Lam S, MacAulay C, Hung J, et al: Detection of dysplasia and carcinoma in situ with a lung imaging fluorescence endoscope device. J Thorac Cardiovasc Surg 105:1035–1040, 1993. LoCicero J 3rd, Metzdorff M, Almgren C: Photodynamic therapy in the palliation of late stage obstructing non-small cell lung cancer. Chest 98:97–100, 1990.

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Mehta AC, Dasgupta A: Airway stents. Clin Chest Med 20:139– 151, 1999. Mendiondo OA, Dillon M, Beach JL: Endobronchial irradiation in the treatment of recurrent non-oat cell bronchogenic carcinoma. J Ky Med Assoc 81:287–290, 1983. Montgomery WW: T-tube tracheal stent. Arch Otolaryngol 82:320–321, 1965. Rafanan AL, Mehta AC: Adult airway foreign body removal. What’s new? Clin Chest Med 22:319–330, 2001. Seijo LM, Sterman DH: Interventional pulmonology. N Engl J Med 344:740–749, 2001.

Sheski FD, Mathur PN: Cryotherapy, electrocautery, and brachytherapy. Clin Chest Med 20:123–138, 1999. Tanaka M, Satoh M, Kawanami O, et al: A new bronchofiberscope for the study of diseases of very peripheral airways. Chest 85:590–594, 1984. Villanueva AG, Lo TC, Beamis JF Jr: Endobronchial brachytherapy. Clin Chest Med 16:445–454, 1995. Wang KP, Brower R, Haponik EF, et al: Flexible transbronchial needle aspiration for staging of bronchogenic carcinoma. Chest 84:571–576, 1983.

37 Thoracoscopy Larry R. Kaiser

I. HISTORICAL PERSPECTIVE

V. MEDIASTINAL PROCEDURES

II. CURRENT TECHNIQUES

VI. OTHER PROCEDURES Pericardial Drainage Sympathectomy

III. SPECIFIC PROCEDURES Pleural Disease Parenchymal Disease

VII. COMPLICATIONS

IV. PULMONARY NODULES

VIII. CONCLUSIONS

Thoracoscopy is a type of surgery in which a motivated medical specialist can develop a level of expertise that puts certain procedures well within his or her reach. These procedures are complementary to bronchoscopy in many instances and aid greatly in the diagnostic evaluation and potentially in therapy for a number of patients, especially those with pleural disease. Within the past several years, videothoracoscopy has, in many ways, changed the way pulmonary medicine and thoracic surgery are practiced, allowing us to alter the approach to a number of clinical problems.

HISTORICAL PERSPECTIVE In the early 1920s, Jacobaeus, a Swedish physician, used a cystoscope in the pleural space to lyse pleural adhesions as an adjunct to collapse therapy in the treatment of pulmonary tuberculosis. He subsequently used this technique of thoracoscopy to localize and diagnose benign and malignant lesions of the pleura and pulmonary parenchyma. Despite the work of Jacobaeus, the procedure was performed only on a limited basis in the United States and was never truly endorsed. In one of the early textbooks of thoracic surgery, Lilienthal mentioned thoracoscopy but warned against its routine use in patients with tuberculosis because of the risk of significant This chapter has been slightly modified from the version that appeared in the third edition of Fishman’s Pulmonary Diseases and Disorders.

bleeding and the perceived possibility of spreading infection within the pleural space. Thoracoscopy evolved mainly as “pleuroscopy,” which was used as an adjunct to other procedures in the diagnosis of pleural pathology—specifically in cases of an effusion of unknown cause, in which the thoracentesis was negative and a closed pleural biopsy was nondiagnostic. In many of these cases, the presence of malignancy was proved at the time of pleuroscopic examination. A number of instruments were used for thoracoscopic examination, including rigid bronchoscopes, mediastinoscopes, and flexible bronchoscopes, as well as rigid fiberoptic thoracoscopes. A mediastinoscope offered a large working channel and excellent visualization of the pleural space; an effusion could be drained, biopsies taken, and pleurodesis effected with talc. The procedure was mainly of diagnostic utility and, other than pleurodesis, offered little in the way of therapeutic applications. It was possible to biopsy the lung, but only small pieces could be removed, and the area that was amenable to biopsy was limited. The availability of the charged coupling device, a silicon chip that is light sensitive, led to the sufficient miniaturization of a video camera so that, when coupled to a fiberoptic telescope, it was practical for use in the operating room by providing a magnified image projected on a video monitor that allowed the operating surgeon to work with an assistant (Fig. 37-1). Previously, it was possible only for a single operator to work with the thoracoscope, but the videothoracoscope frees up the surgeon’s hands and allows more complex procedures to be performed. The power of this technique has

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Figure 37-1 Surgeons carrying out a videothoracoscopic procedure. Note the video monitors, which allow the surgeon and assistants to view the surgical field. The work area is kept between the surgeon and the monitor.

been amply demonstrated by the rapid rise of laparoscopic cholecystectomy, a procedure that changed the specialty of general surgery in a remarkably short time. It was not long before a number of thoracic surgeons began to adapt this new technique for work in the chest, even though thoracoscopy had never been a mainstay in the practice of most such surgeons.

Entry into the chest is made with the index finger, to assure safety. Occasionally, the lung is adherent to the chest wall, and these adhesions must be broken up with the index finger to allow for placement of the trocar sheath. Additional incisions are made as needed—usually arrayed in a triangular fashion, which facilitates instrument placement and allows one to work in coordination with an assistant (Fig. 37-2). It

CURRENT TECHNIQUES The term video-assisted thoracic surgery (VATS) encompasses all procedures performed with the thoracoscope, including those that are purely “thoracoscopic.” The bony thorax provides its own space once the lung is collapsed, so that insufflation of gas, used in the abdomen to create a working space, is unnecessary and even slightly dangerous. The space in the chest is created simply by placing an endobronchial tube and collapsing the ipsilateral lung. This requires a general anesthetic, but certain procedures— namely, those involving the parietal pleura—may be performed with only regional anesthesia and intravenous sedation, since the lung collapses in the spontaneously breathing patient once the negative, intrathoracic pressure is lost. The patient is placed on the operating table in the lateral decubitus position, and the chest is prepared and draped as for a thoracotomy. Incision placement depends somewhat on the procedure to be performed, but the location of the incision for insertion of the videothoracoscope remains constant in the seventh or eighth intercostal space aligned with the anterior superior iliac spine. A 1-cm incision is made, deepened to the intercostal muscles, as if one were inserting a chest tube. Indeed, it is through this incision that the chest tube is placed at the conclusion of the surgical procedure.

Figure 37-2 For most cases three incisions are used, as shown. The thoracoscope most commonly is placed through the inferior incision, allowing other instruments to be placed through the two opposed incisions. Inset: A view within the chest, as would be seen on the monitor, of a biopsy forceps in place to take a specimen of parietal pleura.

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is best to work with two video monitors, which are placed at the head of the table on each side, so that both the operator and the assistant may have an unobstructed view of the surgical field. As long as one maintains the surgical field between oneself and the video monitor, the image is as it seems—that is, forward is forward, backward is backward, etc. It takes some adjustment to become accustomed to working in three dimensions while being able to see in only two. The instrumentation available for thoracoscopy has been slowly improving. Instruments designed specifically for laparoscopy proved to be poor for this new application. Grasping the lung without teating the parenchyma proved to be especially difficult with these instruments. The most significant development in instrumentation, one that markedly expanded the utility of thoracoscopy, was the introduction of the endoscopic linear stapler. This instrument, more than any other, propelled thoracoscopy out of an almost purely diagnostic realm into the mainstream of therapeutic applications.

SPECIFIC PROCEDURES Pleural Disease For many physicians, closed pleural biopsy has become a dying art—and perhaps it should be—with the emergence of videothoracoscopic techniques that allow one to biopsy specific areas of the parietal pleura under direct vision. The major, but certainly not the only, indication for thoracoscopy in the management of pleural disease remains the undiagnosed

Thoracoscopy

pleural effusion. In the past, the patient with an empyema often was forced to undergo thoracotomy for débridement and decortication to rid the space of infection and allow the lung to reexpand. With thoracoscopic techniques, many of these patients may now avoid thoracotomy, especially if they are seen early in the course of the empyema. Thoracoscopic débridement and decortication are indicated in the febrile patient with a pleural effusion in whom tube thoracostomy provides incomplete drainage. The fibrinous nature of the exudate precludes complete drainage with a tube alone, and mechanical débridement is required. Likewise, videothoracoscopic techniques have proved useful in the management of the organized posttraumatic hemothorax, in which a chest tube is unable to effectively drain the organized clot and debris. Benign pleural tumors, specifically solitary fibrous tumors, do occur; most commonly they arise from the visceral pleural surface and are ideal lesions for thoracoscopic resection (Fig. 37-3). Videothoracoscopy has also increased our ability to deal successfully with malignant pleural effusions, especially those in which loculations are present. When tube thoracostomy results in incomplete drainage or one attempt at chest tube pleurodesis has failed, thoracoscopy—whereby the chest is evacuated under direct vision and talc is insufflated—is the procedure of choice. Hartman and colleagues compared the thoracoscopic insufflation of talc in patients who underwent tube thoracostomy and sclerosis with either tetracycline or bleomycin. Talc pleurodesis was performed under local anesthesia supplemented with intravenous sedation. For patients

Figure 37-3 A benign schwannoma arising from the parietal pleural surface–-a lesion that is easily amenable to thoracoscopic excision.

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in the talc group, there was a 97 percent rate of successful pleurodesis at 30 days and 95 percent at 90 days. This is significantly better than results seen in patients treated with the tube thoracotomy, only 33 percent of whom had achieved a successful pleurodesis at 30 days. The results were slightly better when bleomycin was used in the tube thoracostomy group. Patients sclerosed with talc seemed to have less pain following the procedure. The ability to perform thoracoscopic talc pleurodesis under local anesthesia may make the technique attractive for most patients with malignant effusions. In a randomized, prospective trial, Dresler and colleagues examined the outcomes of treating malignant pleural effusions with talc poudrage administered by thoracoscopy versus an instillation of talc slurry through a chest tube.Overall, there was no significant difference in the primary outcome of malignant effusion recurrence at day 30. However, subgroups of patients, including those with breast cancer and lung cancer, were significantly more likely to be effusion free at 30 days when treated by thoracoscopy. Morbidity and mortality were similar in both groups, although there were more respiratory complications in the thoracoscopy group.

Parenchymal Disease Transbronchial lung biopsy is often successful in providing diagnostic material in patients with diffuse pulmonary infiltrates. In situations in which a transbronchial biopsy fails to provide diagnostic material, a VATS procedure is indicated. Before the advent of videothoracoscopy, many of these patients were treated empirically, usually with steroids. Lung biopsy, which required a thoracotomy, albeit a “mini” one, was reserved for patients who either failed empiric therapy or were desperately ill and in intensive care. The empiric approach probably is warranted and may, in fact, be preferred in the non-neutropenic cancer patient with acute pneumonitis, for whom broad-spectrum antibiotic therapy usually is the treatment of choice. In the nonimmunocompromised patient, usually with a chronic interstitial process, serious consideration must be given to obtaining a piece of lung tissue. The pulmonologist must make a judgment as to whether a transbronchial lung biopsy is indicated—a decision that must take into account the most likely diagnostic possibility and whether a transbronchial specimen will be adequate to establish that diagnosis and the small but very real risks of bleeding and pneumothorax. VATS lung biopsy consistantly provides diagnostic material. Burt and colleagues found a 94 percent diagnostic yield from open lung biopsy versus 59 percent for transbronchial biopsy in a series of 20 patients subjected to both procedures. Before the introduction of videothoracoscopy, a thoracotomy was required solely for the purpose of obtaining a piece of lung tissue. The thoracotomy usually consisted of a small inframammary incision into the chest through the fourth or fifth intercostal space, a procedure that can be done expeditiously and allows one to obtain enough lung parenchyma to make a diagnosis. There should be minimal morbidity with this approach, and it still represents the best

approach to lung biopsy in the critically ill, hemodynamically fragile patient who is ventilator dependent (requiring high peak airway pressures and high inspired oxygen concentration), for whom transport to the operating room represents a substantial risk. The “mini” anterior thoracotomy does not require single-lung ventilation and thus avoids the potential morbidity and mortality associated with exchange of the endotracheal tube for an endobronchial tube in these high-risk patients. However, the surgical exposure achieved by this approach can significantly limit the area of lung that may be accessible for biopsy. It is also difficult to obtain tissue from more than one site of the lung with this approach. In most patients, however, VATS wedge lung biopsy, which we and others have referred to as “closed lung biopsy,” represents the best alternative to the “mini” thoracotomy. It offers the advantage of excellent visualization of the entire lung so that suspect areas can be biopsied under direct vision and all areas of the lung can be reached with relative ease. The technique avoids spreading of the ribs, which seems to be one of the factors responsible for the pain that results following thoracotomy, including anterior thoracotomy. It may be that thoracoscopic biopsy causes less postoperative pain, which may be important in weaning patients from a ventilator in the immediate postoperative period, and results in a shorter hospital stay. In a nonrandomized, retrospective study using historical controls, Ferson and colleagues from two other centers compared a group of 47 patients undergoing thoracoscopic lung biopsy with a group of 28 patients who had had open wedge resection via limited thoracotomy. Adequate tissue for diagnosis was obtained for all patients in both groups. Mean surgical time was significantly longer in the thoracoscopic group (69 vs. 93 minutes), but, as would be expected, the time decreased as additional experience was gained. The authors excluded from the study patients requiring mechanical ventilation and still found that hospital stay was significantly shorter in the group undergoing thoracoscopic biopsy (4.9 vs. 12.2 days). There were significantly more complications in the open group (50 percent incidence) than in the VATS group (19 percent), a finding that no doubt explains the variation in duration of hospital stay. All surgeons engaged in the study believed that thoracoscopic biopsy provided better visualization of the entire lung than a “mini” thoracotomy. Our own experience with 80 thoracoscopic lung biopsies in non–ventilator-dependent patients confirms the above-mentioned findings. Diagnostic tissue was obtained in all cases, and in several our ability to provide tissue from different areas of the lung greatly aided in establishing a diagnosis. The mean hospital stay in our series was 1.9 days, significantly shorter than that of Ferson and colleagues. There was no mortality and no significant morbidity, including no prolonged air leaks. When lung biopsy is indicated, thoracoscopic biopsy is our procedure of choice for nonventilated patients. For patients requiring mechanical ventilation, in most cases we prefer a limited anterior thoracotomy with minimal rib spreading—a simple procedure that can be

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performed expeditiously and avoids the need for single-lung ventilation. Thoracoscopic lung biopsies were reported before the advent of VATS techniques and before the linear stapler was available. With a cup biopsy forceps, pieces of lung parenchyma were obtained, and an insulated electrocautery provided the only means of hemostasis. Daniel and colleagues compared results obtained in the era before the advent of video technology with those obtained by current methods. In 30 patients undergoing thoracoscopic cup biopsy, there were 10 deaths and one prolonged air leak that required a thoracotomy for repair. Mean hospital stay was 16.6 days. In contrast, 11 patients underwent videothoracoscopic biopsy with one death and a mean hospital stay of 8.2 days. The significantly better hemostatic as well as aerostatic qualities of the linear stapler than those of a cup biopsy forceps and the larger amount of tissue obtained using a stapler clearly are advantageous. These authors also noted no advantage to either endoscopic approach over limited thoracotomy in patients requiring mechanical ventilation. The availability of VATS lung biopsy should prompt earlier referral for lung biopsy of patients with interstitial disease who either would be treated empirically and not referred for biopsy or would be referred in desperation at the time of marked decompensation, usually after being intubated and ventilated. Utilizing these techniques to obtain an earlier tissue diagnosis in patients with interstitial lung disease should improve management and, it is hoped, improve the long-term outlook. VATS techniques have also had a major impact on the management of spontaneous pneumothorax in the two major groups of patients who present with this problem: young patients with apical blebs and older patients with bullous emphysema. Primary spontaneous pneumothorax in a young person typically can be managed nonsurgically, with the likelihood of recurrence being approximately 30 percent. Surgical treatment for a first-time pneumothorax classically has been reserved for patients with persistent air leaks (longer than 1 week), those whose occupations require them to experience extremes in atmospheric pressure, and those who live in isolated areas without access to medical care. Otherwise, surgery is indicated after a first recurrence or for the patient who has experienced bilateral pneumothoraxes. Surgery for a spontaneous pneumothorax has required either a thoracotomy with stapling of apical blebs and, at times, a pleurectomy or, more recently, a transaxillary thoracotomy with excision of blebs and pleural ablation or pleurectomy to create pleural symphysis. These are both substantial procedures for what is really a trivial problem in terms of what needs to be done intraoperatively. An alternative approach to management, mentioned here only to be dismissed, involves installation of talc or other sclerosant via tube thoracostomy. VATS management of spontaneous pneumothorax provides a simple surgical alternative that is associated with minimal morbidity. With recognition that in young patients the pneumothorax usually results from rupture of a bleb located at the lung apex or occasionally in the apical portion

Thoracoscopy

Figure 37-4 Thoracoscopic appearance of a typical apical bleb responsible for a spontaneous pneumothorax, usually in a young person. These are most commonly found at the lung apex, but they can also occur at the apex of the superior segment of the lower lobe.

of the superior segment of the lower lobe, the surgical procedures include resection of the apical blebs and mechanical pleural abrasion to effect a pleural symphysis (Fig. 37-4). The blebs are easily visualized with the thoracoscope and excised with several applications of the linear stapler. The parietal pleural surface is mechanically abraded with a gauze sponge, which creates enough inflammation to cause pleurodesis. Talc or other sclerosing agents are not recommended for these young patients. Obliteration of the apical blebs alone probably would be sufficient, and the contribution of the pleurodesis is probably minimal. A very low recurrence rate is expected (less than 5 percent) following this procedure, similar to that achieved after a transaxillary procedure or formal thoracotomy; the handling of the blebs is identical no matter which approach is used. Cannon and associates performed thoracoscopic excision of apical blebs in nine patients with primary spontaneous pneumothorax and noted one recurrent small apical pneumothorax that resolved without treatment. We performed 70 thoracoscopic procedures for primary spontaneous pneumothorax over a 4-year period. We noted three recurrences, two in patients with catamenial pneumothorax, at the time of their first menstrual period following the procedure, and one in a patient with routine apical blebs. The lesion responsible for catamenial pneumothorax is unknown, and we were unable to detect any pathology at the time of the procedure. These patients experienced recurrence despite the performance of what was believed to be adequate pleurodesis, but the recurrences were early, probably before the development of pleural adhesions. Allenâ&#x20AC;&#x2122;s team reported on 46 patients who underwent wedge excision and pleurodesis for spontaneous pneumothorax. Only one patient required conversion to an open procedure. Seven patients had persistent air leaks (more than 10 days), and two of these required thoracotomy for correction. No recurrences have been seen with

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a median follow-up time of 25 months. Median hospital stay was 5 days. Our own experience, along with that of other groups, suggests that hospital stay after VATS operation for spontaneous pneumothorax is closer to 2 days; prolonged air leaks following the procedure, causing longer hospital stays, are rare. Indications for surgery for spontaneous pneumothorax have not changed significantly despite the availability of the VATS technique, which allows most patients to leave the hospital on the first or second postoperative day. Patients with primary pneumothorax are managed with either aspiration of the pneumothorax or chest tube placement. We used to wait 7 days for an air leak to seal before proceeding with surgery. We now wait only 48 to 72 hours before recommending the thoracoscopic procedure, which allows the patient to leave the hospital sooner than if treated in the conventional fashion. The decision for earlier surgery is justified by the decreased morbidity associated with the VATS procedure when compared with an open procedure, even the transaxillary approach. In a patient treated conservatively for a first-time pneumothorax, recurrence on the same side or a pneumothorax on the opposite side is an indication for surgery. If the pneumothorax occurs on the same side as the first one, we operate only on that side. With a contralateral pneumothorax, both sides should be operated on, since the consequences of spontaneous bilateral pneumothoraxes may be devastating. Bilateral VATS procedures conducted with a single anesthetic may be performed without significant additional morbidity, especially in young patients. If necessary, thoracic epidural analgesia may be used in the early postoperative period. VATS excision of apical blebs and mechanical pleural abrasion constitute the procedure of choice when surgery is indicated in a patient with spontaneous pneumothorax. Pneumothorax occurring secondarily to a process other than the apical blebs seen in young people can also be managed with a VATS approach. In these situations, the pathology may be somewhat more complex, and one needs to search for the air leak and repair it, usually by stapling; but fibrin glue, the neodynium-YAG laser, and the argon beam coagulator have also been used with success. Over a recent 2-year period, we performed 13 procedures for so-called secondary pneumothoraxâ&#x20AC;&#x201D;seven in patients with emphysema who presented in respiratory distress after developing a pneumothorax, two for persistent air leaks following thoracotomy and lobectomy, one in a patient with AIDS and bilateral pneumothoraxes secondary to Pneumocystis carinii infection causing necrotic parenchymal cavitary lesions, and three in patients with metastatic sarcomas. We were successful in managing the air leak in 12 patients; one patient was converted to open thoracotomy. Cannon and colleagues operated on six patients with secondary pneumothorax, two of whom subsequently required a thoracotomy to deal with persistent air leaks following the thoracoscopic procedure. Although recognizing that some patients may still require thoracotomy, we prefer to attempt a VATS approach for an air leak because these patients often have significantly com-

Figure 37-5 A giant bulla occurring as an isolated finding, resulting in compression of adjacent lung parenchyma. Excision usually offers significant relief of symptoms.

promised pulmonary function and avoidance of a thoracotomy is advantageous. If a surgeon develops an interest and gains experience with VATS techniques, the frequency of conversion to an open procedure should remain low. It requires a commitment on the part of the surgeon, however, especially early in oneâ&#x20AC;&#x2122;s experience, to take the extra time that may be required to complete some of the more complex procedures rather than quickly converting to an open operation. The management of bullous lung disease has also changed with the introduction of VATS techniques. The standard indication for surgery in patients with bullous emphysema is the presence of a giant bulla causing significant compression of adjacent, relatively normal lung parenchyma (Fig. 37-5). These giant bullae are readily recognizable on a plain chest radiograph, and a computed tomography (CT) scan helps to define the presence and extent of compressed lung tissue. The major factor that enters into a decision on whether bullectomy is likely to result in improvement in a patientâ&#x20AC;&#x2122;s condition relates to the compressed lung parenchyma and whether there is significant compressed parenchyma to expand and fill the pleural space after bullectomy. A residual space after bullectomy promotes the development of a persistent air leak and, in a small percentage of cases, an empyema, with resultant devastating consequences and usually a prolonged hospital stay. Reviewing a series of chest radiographs performed over the preceding several years to determine the progression in the size of the bullae allows for an assessment of the amount of compressed adjacent lung tissue. Pulmonary function studies should document a decrease in function, and the patient should note a decrease in exercise tolerance. Patients who fulfill these criteria are ideal candidates for VATS bullectomy. The procedure itself requires obliteration of the bulla with the avoidance of air leaks, if possible. We prefer to use the argon beam coagulator, which, when applied at a low power

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setting, causes the wall of the bulla to shrivel although the bulla is not entered. Once the bulla has shrunk, the base may be delineated and then stapled in an attempt to minimize air leak. The walls of the bulla may be used as a buttress for the staple line. Alternatively, a piece of prosthetic material, specifically bovine pericardium (PeriGuard, Biovascular Medical, St. Paul, MN), may be used to reinforce the staple line to prevent air leaks. Performing a VATS procedure rather than open thoracotomy in these markedly compromised patients, most of whom are oxygen dependent and have FEV1 well under 1 L, seems to be preferable. Still, in the early postoperative period these patients are most at risk of secretion retention and pneumonia—which, for many, would be a terminal event. Thus, postoperative pain management and aggressive chest physiotherapy are of major importance. We use thoracic epidural analgesia provided by a continuous infusion of narcotic for pain management in the early postoperative period so that patients may cough more effectively. Patients are extubated as soon as possible, ideally at the completion of the surgical procedure. Unfortunately, giant bullae do occur in some patients with bullous emphysema. Wakabayashi identified 17 cases of giant bullous disease among more than 500 cases of bullous emphysema seen over a 3-year period. Of more than 2000 thoracoscopic cases reported to the Video Assisted Thoracic Surgical Study Group (VATSSG) Registry, only 33 (1.8 percent) were for excision of giant bullae. Diffuse emphysema, with or without a bullous component, is a significantly greater clinical problem in terms of numbers of patients affected. Until recently, the therapeutic options of these patients were extremely limited, with oxygen therapy and bronchodilators being the mainstay for those with a reversible airway component. The reintroduction of a surgical procedure, volume reduction, which has been shown to be efficacious in some cases, may offer many of these desperate patients some relief from their symptoms. Although the initial procedure of volume reduction for diffuse emphysema, as described by Cooper and colleagues, entailed a median sternotomy and bilateral excision of lung parenchyma, other authors have reported on either unilateral or bilateral VATS procedures to accomplish essentially the same outcome. Kotloff and associates compared a series of patients from the University of Pennsylvania who underwent volume reduction via sternotomy with a group undergoing the procedure via a VATS approach. Patients who underwent a bilateral VATS procedure fared as well as those undergoing sternotomy in terms of functional improvement. There were fewer postoperative deaths in the VATS group, but the difference was not statistically significant. The National Emphysema Treatment Trial (NETT), a multi-center NIH-sponsored trial designed to evaluate the efficacy of lung volume reduction surgery as a treatment for chronic obstructive pulmonary disease, compared outcomes in patients undergoing lung volume reduction by a video-assisted approach versus a sternotomy approach. Median hospital stay was recduced by use of the thoracoscopy approach, whereas complication rates were not signicantly different.

Thoracoscopy

PULMONARY NODULES The solitary indeterminate pulmonary nodule is a problem confronted routinely by pulmonologists. In light of the emergence of VATS as a minimally invasive procedure that can be performed with low morbidity even in compromised patients, we must examine closely the current management of a patient who presents with an indeterminate nodule. Whereas in the past definitive management required open thoracotomy, with its attendant morbidity, this no longer is the case. Thoracoscopy offers the opportunity both to definitively make the diagnosis and to treat many of these lesions and, therefore, causes a refocus in our thinking. The salient question posed by the presence of a pulmonary nodule is a very simple one: Is it malignant? If a previous radiograph demonstrates a lesion that has not changed in size over several years, one can be reasonably certain of the benign nature of that lesion. Depending on the series, approximately 40 percent of resected nodules are malignant, and primary carcinoma of the lung accounts for the majority of malignant nodules. A number of factors point to a benign diagnosis, although none are absolute. We may be far less suspicious of a nodule occurring in a nonsmoker, especially if the person is 35 years of age or younger. Lesions larger than 3 cm in diameter are likely to be malignant. Specific patterns of calcification may also be associated with benign lesions, and CT comparison with a phantom of known density may further support a benign diagnosis. Even when all these factors have been taken into consideration, a histologic diagnosis is required in most cases. If benignity cannot be proved, malignancy must be assumed. The diagnostic procedures available to the pulmonary physician are very good at establishing a diagnosis of malignancy but fall short in obtaining a “positive” diagnosis of benign disease. The diagnostic yield from fiberoptic bronchoscopy varies from 20 to 80 percent, but a specific benign diagnosis is made only 10 percent of the time. With these figures, it is hard to justify the performance of a bronchoscopy if one is looking to make a diagnosis of benign disease. Unfortunately, percutaneous needle aspiration biopsy does not fare much better. Although its sensitivity in making the diagnosis of malignancy is high (64 to 97 percent), a specific benign diagnosis can be made only about as often as the rate achieved bronchoscopically. A “negative” needle biopsy is of no help and necessitates a further diagnostic procedure, whereas a diagnosis of malignancy essentially tells us what we already know: The lesion has to be excised. Mack and colleagues, in a multicenter study, have looked closely at the role of thoracoscopy in the diagnosis of the indeterminate solitary pulmonary nodule. Over an 18month period, 242 patients with solitary nodules were treated. A wedge excision of the lesion that included some surrounding normal lung parenchyma was accomplished with an endoscopic stapler alone in most cases. A definite diagnosis was obtained in all cases; there was no mortality or major morbidity, and minor complications (atelectasis, pneumonia, prolonged

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air leak) occurred in only nine patients (3.6 percent). In two patients, the nodule could not be located and a thoracotomy was required; otherwise, a benign diagnosis was obtained in 127 patients (52 percent), while malignancy was found in 115 (48 percent). When a primary lung cancer was identified, formal open thoracotomy and anatomic resection were carried out in patients with adequate pulmonary reserve. The average hospital stay for patients undergoing thoracoscopy alone was 2.4 days. In a series of 771 VATS procedures at the Mayo Clinic, wedge excision of a pulmonary nodule was performed in 234 patients. There were no deaths in this group of patients, and the most common complication was a prolonged air leak, which occurred in 3.0 percent of patients. The median hospital stay was 3 days. The lesion was found to be malignant in 107 patients, and all patients found to have bronchogenic carcinoma underwent an open thoracotomy for anatomic pulmonary resection and lymph node sampling. It is hard to argue against a technique that has a sensitivity and specificity of 100 percent and can be done with no mortality and minimal morbidity. But is it necessary to excise so many benign lesions? If we could be certain of the benignity of a lesion, there would be no reason to excise it. It is the uncertainty of the benign diagnosis in most cases that presents the most compelling argument for thoracoscopic excision of most solitary pulmonary nodules. All questions are answered and the uncertainty disappears with one procedure. Certain lesions are not considered for VATS excision. For lesions greater than 3 cm in diameter, the likelihood of malignancy is so high (greater than 90 percent) that in the absence of metastatic disease, thoracotomy and anatomic resection—i.e., lobectomy—should be the first procedure undertaken. The CT scan aids greatly in localizing the nodule, and we have found it to be the only localizing study that is required. Even deep-seated lesions may be palpated and located, a technique that becomes easier with experience. In our experience with 400 thoracoscopic excisions of pulmonary nodules, we have failed to locate the nodule in only four cases, all early in our experience. Our technique relies heavily on instruments, specifically designed for thoracoscopy, that greatly facilitate the procedure, especially in grasping or moving the lung to the palpating finger (Fig. 37-6). Centrally located lesions, which lie in close proximity to hilar structures, are not suitable for VATS wedge excision and require open thoracotomy. There is some controversy regarding the optimal management of the solitary nodule that proves to be a carcinoma. Is a VATS wedge excision sufficient treatment for a T1 (less than 3 cm) primary lung carcinoma? Based on current knowledge, we believe that wedge excision is not optimal treatment for primary lung cancer, even a small T1 lesion. A wedge excision is a compromise procedure that is acceptable only for the patient who otherwise cannot tolerate a thoracotomy and anatomic resection. Among other factors, a wedge excision removes no regional lymph nodes and thus staging is inadequate. Local recurrence is significantly higher after wedge excision than after lobectomy. Several authors have

Figure 37-6 A modified ring forceps grasping the lung and moving the lung into position either for wedge excision of a nodule or for palpation of the area to identify the nodule. The forceps is able to grasp the lung without tearing the pulmonary parenchyma, a situation that commonly occurs if the lung is grasped with an instrument with a small surface area.

performed large series of nonanatomic resections for patients with marginal pulmonary function, and VATS excision, with its low morbidity, may offer another alternative. The Lung Cancer Study group addressed the question of limited resection versus lobectomy for T1 N0 lesions in a prospective, randomized trial. In this study of carefully staged patients proven conclusively to have N0 disease, there was a significantly higher incidence of local recurrence in those who underwent limited resection, but at 3 years there was no survival difference between the two groups. However, a reexamination of the data at 5 years showed a statistically significant survival advantage for the lobectomy group. Wedge excision for bronchogenic carcinoma as a definitive procedure, whether carried out via a VATS approach or open thoracotomy, must be considered a compromise and should be reserved for patients whose pulmonary function is so marginal as to preclude lobectomy. Anatomic resections (mainly lobectomy) have been performed using a VATS technique that requires a small (6 cm) “utility” incision, but usually without the need for rib spreading—which, theoretically, should minimize postoperative pain (Fig. 37-7). A randomized trial comparing VATS lobectomy with standard muscle-sparing thoracotomy and lobectomy failed to show significant enough differences to justify the routine use of the VATS approach—which probably subjects the patient to a slightly greater risk of intraoperative catastrophe, although no intraoperative deaths have been reported. Roviaro and colleagues performed 52 VATS lobectomies and four pneumonectomies in patients with T1 N0 or T2 N0 lesions. In seven patients it was necessary to convert to an open procedure, three for bleeding during the dissection. There were no deaths related to the procedure. Others have reported the feasibility of performing VATS lobectomy or segmentectomy. A large randomized trial demonstrating

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Thoracoscopy

Figure 37-7 View of a video-assisted lobectomy showing the pulmonary artery in the fissure of the left lung. Note the basilar segmental trunk and the branch to the superior segment of the lower lobe. The procedure is performed with visualization provided by the video camera and access via a small utility incision through which regular instruments are inserted but without spreading the ribs.

Figure 37-8 The aortopulmonary window, a common site for lymph node involvement when the primary tumor is in the left upper lobe (level 5, subaortic, and level 6, para-aortic). These lymph node locations cannot be reached by standard cervical mediastinoscopy, and videothoracoscopy provides an ideal way both to visualize this area and, when appropriate, to take biopsies.

the superiority of a VATS approach over an open procedure is lacking. VATS lobectomy has not found widespread acceptance, nor is the public demanding it. A few centers continue to perform the procedure regularly.

Many primary lesions of the mediastinum prove to be ideal for VATS management. Lesions in all compartments of the mediastinum are easily accessible, and whether biopsy only or complete excision is the intent, VATS techniques save many patients from having to undergo thoracotomy. To approach a lesion in the anterior mediastinum, the patient is positioned with the side to be operated on tilted up at approximately 30 degrees instead of in the full lateral position. Often a small inframammary incision is employed. We have utilized a VATS approach to accomplish 15 thymectomies, nine of them for encapsulated thymomas (Fig. 37-9).

MEDIASTINAL PROCEDURES VATS has proved useful as an adjunct to more conventional procedures used in the invasive staging of lung cancer. Mediastinoscopy remains the gold standard for invasive staging of the mediastinum, but lymph nodes in the posterior subcarinal space (level 7) and in the aortopulmonary window (level 5) are not accessible. VATS offers an unmatched ability to visualize the aortopulmonary window and sample lymph nodes in this region (Fig. 37-8). The same is true for the subcarinal space when it is approached from the right side. A VATS staging procedure is not a substitute for mediastinoscopy, but in certain situations directed by findings on the chest CT scan, it may add valuable staging information. This is particularly important because of the interest in preoperative therapy (neoadjuvant) for patients proved to have N2 (mediastinal) lymph node disease. The utility of VATS is limited for assessing resectability, especially if one is trying to document direct invasion of mediastinal structures (either T3 or T4), but it is of use occasionally. Dissection often proves difficult and potentially hazardous, and there is no substitute for putting oneâ&#x20AC;&#x2122;s hand on a lesion of questionable resectability. VATS proves extremely useful, however, in documenting the absence of diffuse pleural metastatic disease if this possibility has been raised (usually by the presence of a pleural effusion).

Figure 37-9 A well-encapsulated thymoma being dissected off the pericardium. The cervical portions of the thymus gland have been mobilized by a transcervical approach so that a total thymectomyâ&#x20AC;&#x201C;-the goal of the operation in patients with myasthenia gravisâ&#x20AC;&#x201C;-could be carried out.

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difficult, because of the need to extend the dissection well up into the neck. The patient with a large, diffuse mediastinal mass from which tissue is required for diagnosis may also, at times, benefit from a VATS approach. Many of these lesions are more readily accessed for biopsy through an extrapleural, parasternal approach by excision of the costal cartilage (usually the second). Lesions that are not close to the anterior chest wall may be approached and readily sampled with a VATS approach. The posterior mediastinum is also the site of either solid or cystic lesions that are amenable to VATS resection. We have resected eight posterior mediastinal lesions, including schwannomas (four) and bronchogenic cysts (four) (Fig. 3710). Incisions used to approach these posterior or mediastinal lesions differ slightly from those used for access to the anterior mediastinum. Overall, we have performed a total of 85 VATS procedures for mediastinal pathology without mortality and with minimal morbidity. A

OTHER PROCEDURES Pericardial Drainage

Figure 37-10 A. MRI scan showing a posterior mediastinal mass sitting in a paravertebral location. Lesions in this location usually are neurogenic, and this lesion proved to be a ganglioneuroma. B. View at the time of the videothoracoscopy showing the lesion seen in (A). This lesion was able to be completely excised with a videothoracoscopic approach.

A VATS procedure is contraindicated for presumed invasive thymomas. In patients with myasthenia gravis and a thymoma, a total thymectomy is mandatory and may be facilitated by combining a transcervical approach with the VATS exposure. The thymus gland is initially mobilized in the neck, and branches to the innominate vein are divided. The mobilized gland is then tucked down into the mediastinum, the neck closed, and the patient positioned for VATS. The thymoma is mobilized and the dissection completed with the removal of the gland and tumor through one of the chest incisions. Attempting to excise the tumor and perform a total thymectomy with a VATS approach alone is possible but more

A pericardial drainage procedure, so-called pericardial window, may be accomplished through either the right or left chest with a VATS procedure. It is, in fact, often easier to perform this procedure from the right side, where a larger area of pericardium is visible and there is more space in which to work. That being said, a subxiphoid approach to pericardial window usually is simpler, less invasive, and more expeditious, and accomplishes the same goals without the need to insert a double-lumen endobronchial tube and place the patient in the lateral decubitus position. If a large window is believed necessary, there may be an advantage to the VATS approach.

Sympathectomy The sympathetic chain is easily visualized, as it lies along the vertebral bodies (Fig. 37-11). The magnification provided by VATS facilitates the performance of a sympathectomy. Either dorsal or lumbar sympathectomy may be performed, and bilateral procedures may be accomplished under the same anesthetic, with minimal morbidity. Dorsal sympathectomy may be indicated for palmar hyperhidrosis, reflex sympathetic dystrophy, or other upper-extremity pain syndromes. The superior cervical (stellate) ganglion is readily visualized and preserved, in order to avoid producing a Hornerâ&#x20AC;&#x2122;s syndrome. Lumbar sympathectomy may be useful for the management of pancreatic pain, particularly when caused by malignant disease. This requires a bilateral procedure to achieve maximal symptom relief. In the treatment of chylothorax, VATS may be employed to ligate the thoracic duct. The thoracic duct is most readily identified in the right chest just as it courses through the aortic

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a death as a result. There appears to be a slightly higher incidence, although still around 3 percent, of recurrent pneumothorax following VATS procedures for spontaneous pneumothorax. Whether this is simply a function of the “learning curve” remains to be determined. The fact that VATS procedures in general have been performed with minimal major morbidity is commendable, since the technology and skills are relatively new to most surgeons.

CONCLUSIONS

Figure 37-11 The sympathetic chain being mobilized off the vertebral bodies. Ganglia are easily seen as are the various branches of the nerve.

hiatus. In most patients, at this level it is still a single trunk running along the vertebral bodies between the aorta and the esophagus. We have performed 10 thoracic duct ligations for chyle leaks; in two patients, it was necessary to convert to an open procedure to successfully ligate the duct. VATS provides excellent exposure to the thoracic spine, and procedures such as drainage of abscesses, biopsy of vertebral bodies, discectomy, and anterior releases for kyphoscoliosis have all been carried out successfully, thereby avoiding thoracotomy. Because of the early success and significantly less morbidity in these patients, this technique is becoming the approach of choice in many centers.

COMPLICATIONS We reviewed the complications that resulted from our initial 266 VATS procedures. There were no deaths, and complications were not life threatening. Ten patients had air leaks lasting longer than 7 days. Eleven patients were electively converted to an open procedure when the intended VATS procedure could not be completed successfully. Bleeding requiring blood transfusion occurred in five patients, and five patients developed superficial wound infections. Data collected on 1358 patients from the VATSG Registry show a similar spectrum of complications, along with 2 percent mortality. As in our series, prolonged air leakage was the most frequent complication; significant bleeding requiring transfusion occurred in only 15 cases (1 percent). To date, no consistent pattern of major complications resulting from VATS has been reported. DeCamp and coauthors list 127 complications occurring in 121 of 595 patients undergoing videothoracoscopy at Brigham and Women’s Hospital. Most of the complications were either prolonged air leakage or supraventricular dysrhythmias. We are aware of at least 10 instances of tumor seeding of VATS incisions, and there is at least one report of

Video-assisted thoracic surgical procedures have proved to be extremely useful in the diagnosis and treatment of various thoracic problems. Improvements in video technology have made it feasible for a surgeon and an assistant to work together, and developments in instrumentation, especially staplers, have made many procedures commonplace that previously seemed impossible. Cost issues still need to be carefully examined. Are the more sophisticated techniques and more expensive equipment saving money or expending more resources? If we are expending more resources, is there enough significant benefit to the patient to justify the added expense in this time of cost consciousness? In at least one study, the cost of a thoracoscopic wedge excision (n = 45) was less than that of a wedge excision done via thoracotomy (n = 31), but the difference was not statistically significant. Disposable instrument costs were significantly higher in the thoracoscopy group. There was no significant difference in the length of hospital stay for the two groups, but in the thoracoscopy group the length of stay was longer than expected. Cost savings potentially should come from a shorter length of stay, and, ultimately, if patients return to work sooner, the overall cost to society should be less, although admittedly this is difficult to measure. With the tremendous strides made in the development of equipment for videothoracoscopy, there was a great rush on the part of thoracic surgeons to perform as many types of procedures as possible with this new technique. Now that the initial rush is over, we are beginning to appreciate just where these techniques have the greatest application. Some procedures for which there was tremendous early enthusiasm are being performed with less frequency; others have withstood the early shakedown period and have proved their worth over the conventional open procedure, resulting in a benefit to patients.

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Boutin C, Viallat JR, Cargnino P, Rey F: Thoracoscopic lung biopsy: Experimental and clinical preliminary study. Chest 82:44–48, 1982. Brooks JW: Open thoracotomy in the management of spontaneous pneumothorax. Ann Surg 177:798–805, 1973. Burt ME, Flye MW, Webber BL, et al: Prospective evaluation of aspiration needle, cutting needle, transbronchial, and open lung biopsy in patients with pulmonary infiltrates. Ann Thorac Surg 32:146–151, 1981. Cannon WB, Vierra MA, Cannon A: Thoracoscopy for spontaneous pneumothorax. Ann Thorac Surg 56:686–687, 1993. Clark TA, Hutchinson DE, Deaner RM, et al: Spontaneous pneumothorax. Am J Surg 124:728–731, 1972. Collard J-M, Lengele B, Otte J-B, et al: En-bloc and standard esophagectomies by thoracoscopy. Ann Thorac Surg 56:675–679, 1993. Cooper JD: Perspectives on thoracoscopy in general thoracic surgery. Ann Thorac Surg 56:697–700, 1993. Cooper JD, Trulock EP, Triantafillou AN, et al: Bilateral pneumectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 109:106–119, 1995. Cortese DA, McDougall JC: Biopsy and brushing of peripheral lung cancer with fluoroscopic guidance. Chest 75:141–145, 1979. Daniel TM, Kern JA, Cargnino P, et al: Thoracoscopic surgery for diseases of the lung and pleura. Ann Surg 217:566–575, 1993. DeCamp MM, Jaklitsch MT, Harpole DH, et al: An improved video-thoracoscopic technique proves superior to axillary thoracotomy in the surgical management of spontaneous pneumothorax (abstract). Am J Respir Crit Care Med 4:A511, 1994. DeCamp MM Jr, Jaklitsch MT, Mentzer SJ, et al: The safety and versatility of video-thoracoscopy: A prospective analysis of 895 consecutive cases. J Am Coll Surg 181:113–120, 1995. Deslauriers J, Beaulieu M, Depres JP, et al: Transaxillary pleurectomy for treatment of spontaneous pneumothorax. Ann Thorac Surg 30:569–574, 1980. Deslauriers J, LeBlanc P, McClish A: Bullous and bleb diseases of the lung, in Shield TW (ed), General Thoracic Surgery. Philadelphia, Lea and Febiger, 1989, pp 744–747. Dijkman JH, van der Meer JWM, Bakker W, et al: Transpleural lung biopsy by the thoracoscopic route in patients with diffuse interstitial pulmonary disease. Chest 82:76–83, 1982. Dresler CM, Olak J, Herndon JE, et al: Phase III Intergroup Study of Talc Poudrage vs Talc Slurry Sclerosis for Malignant Pleural Effusion. Chest 127:909–915, 2005. Erret LE, Wilson J, Chiu RC, et al: Wedge resection as an alternative procedure for peripheral bronchogenic carcinoma in poor-risk patients. J Thorac Cardiovasc Surg 90:656–661, 1985. Ferson PF, Landreneau RJ, Dowling RD, et al: Comparison of open versus thoracoscopic lung biopsy for diffuse infiltrative pulmonary disease. J Thorac Cardiovasc Surg 106:194– 199, 1993.

Fletcher EC, Levin DC: Flexible fiberoptic bronchoscopy and fluoroscopically guided transbronchial biopsy in the management of solitary pulmonary nodules. West J Med 136:477–483, 1982. Fry WA, Siddiqui A, Pensler JM, et al: Thoracoscopic implantation of cancer with a fatal outcome. Ann Thorac Surg 59:42–45, 1995. Gaensler EA, Carrington CB: Open biopsy for chronic diffuse infiltrative lung disease: Clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 30:411–426, 1980. Georghiou GP, Stamler A, Sharoni E, et al: Video-assisted thoracoscopic pericardial window for diagnosis and management of pericardial effusions. Ann Thorac Surg 80:607– 610, 2005. Ginsberg RJ, Rubinstein L: A randomized comparative trial of lobectomy vs limited resection for patients with T1 N0 non-small cell lung cancer. Lung Cancer 7:304–309, 1991. Ginsberg RJ, Rubinstein LV, and the Lung Cancer Study Group: Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Ann Thorac Surg 60:615–622, 1995. Gossot D, Fourquier P, Celerier M: Thoracoscopic esophagectomy: Technique and initial results. Ann Thorac Surg 56:667–670, 1993. Hartman DL, Gaither JM, Kesler KA, et al: Comparison of insufflated talc under thoracoscopic guidance with standard tetracycline and bleomycin pleurodesis for control of malignant pleural effusions. J Thorac Cardiovasc Surg 105:743–748, 1993. Hazelrigg SR, Nunchuck SK, Landreneau RJ, et al: Cost analysis for thoracoscopy: Thoracoscopic wedge resection. Ann Thorac Surg 56:633–635, 1993. Hazelrigg SR, Nunchuck SK, LoCicero J, et al: Video-assisted thoracic surgery study group data. Ann Thorac Surg 56:1039–1044, 1993. Jacobaeus HC: Possibility of the use of the cystoscope for investigation of serous cavities. Munch Med Wochenschr 57:2090–2092, 1910. Jacobaeus HC: The cauterization of adhesions in pneumothorax treatment of tuberculosis. Surg Gynecol Obstet 32:493– 500, 1921. Jacobaeus HC: The practical importance of thoracoscopy in surgery of the chest. Surg Gynecol Obstet 34:289–296, 1922. Kaiser LR: Diagnostic and therapeutic uses of pleuroscopy (thoracoscopy) in lung cancer. Surg Clin North Am 67:1081–1086, 1987. Kaiser LR: Thoracoscopic resection of mediastinal tumors and the thymus. Chest Surg Clin North Am 6:41–52, 1996. Kaiser LR, Bavaria JE: Complications of thoracoscopy. Ann Thorac Surg 56:796–798, 1993. Keenan RJ, Landreneau RJ, Sciurba F, et al: Unilateral thoracoscopic surgical approach for diffuse emphysema. J Thorac Cardiovasc Surg 111:308–316, 1996. Khouri NF, Mezisne MA, Zerhouni EA, et al: The solitary pulmonary nodule: Assessment, diagnosis and management. Chest 91:128–133, 1987.

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Kirby TJ, Mack MJ, Landreneau RJ, et al: Initial experience with video-assisted thoracoscopic lobectomy. Ann Thorac Surg 56:1248–1253, 1993. Kirby TJ, Mack MJ, Landreneau RJ, et al: Lobectomy: Videoassisted thoracic surgery versus muscle-sparing thoracotomy: A randomized trial. J Thorac Cardiovasc Surg 109:997–1001, 1995. Kotloff RM, Tino G, Bavaria JE, et al: Bilateral lung volume reduction surgery for advanced emphysema: A comparison of median sternotomy and thoracoscopic approaches. Chest 110:1399–1406, 1996. Krasna MJ, McLaughlin JS: Thoracoscopic lymph node staging for esophageal cancer. Ann Thorac Surg 56:671–674, 1993. Larrieu AJ, Tyers GFO, Williams EH, et al: Intrapleural instillation of quinacrine for treatment of recurrent spontaneous pneumothorax. Ann Thorac Surg 28:146–150, 1979. Lewis RJ, Kunderman PJ, Sisler GE, et al: Direct diagnostic thoracoscopy. Ann Thorac Surg 21:536–539, 1975. Lilienthal H: Thoracic Surgery. Philadelphia, WB Saunders, 1925. Lillington GA: Management of solitary pulmonary nodules. Dis Mon 37:271–318, 1991. Lillington GA, Mitchell SP, Wood GA: Catamenial pneumothorax. JAMA 219:1328–1331, 1972. Mack MJ, Hazelrigg SR, Landreneau RJ, et al: Thoracoscopy for the diagnosis of the indeterminate solitary pulmonary nodule. Ann Thorac Surg 56:825–832, 1993. Mack MJ, Regan JJ, Bobechko WP, et al: Application for thoracoscopy for diseases of the spine. Ann Thorac Surg 56:736– 738, 1993. McKenna RJ, Benditt JO, DeCamp M, et al: Safety and efficacy of median sternotomy versus video-assisted thoracic surgery for lung volume reduction surgery. J Thorac Cardiovasc Surg 127:1350–1360, 2004. Meyer DM, Jessen ME, Wait MA, et al: Early evacuation of traumatic retained hemothoraces using thoracoscopy: A prospective, randomized trial Ann Thorac Surg 64:1396– 1401, 1997. Miller JI, Hatcher CR: Limited resection of bronchogenic carcinoma in the patient with marked impairment of pulmonary function. Ann Thorac Surg 44:340–343, 1987. Naumheim KS, Keller CA, Krucylak PE, et al: Unilateral video-assisted thoracic surgical lung reduction. Ann Thorac Surg 61:1092–1098, 1996. Ng CSH, Lee TW, Wan S, et al: Video assisted thoracic surgery in the management of spontaneous pneumothorax: the current status. Postgrad Med J 82:179–185, 2006.

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Oakes DD, Sherck JP, Brodsky JB, et al: Therapeutic thoracoscopy. J Thorac Cardiovasc Surg 87:269–273, 1984. Pellegrini CA, Leichter R, Patti M, et al: Thoracoscopic esophageal myotomy in the treatment of achalasia. Ann Thorac Surg 56:680–682, 1993. Potter D, Pass HI, Brower S, et al: Prospective randomized study of open lung biopsy versus empirical antibiotic therapy for acute pneumonitis in nonneutropenic cancer patients. Ann Thorac Surg 40:422–428, 1985. Read RC, Yoder G, Schaeffer RC: Survival after conservative resection for T1 N0 M0 non-small cell lung cancer. Ann Thorac Surg 49:391–400, 1990. Rice TW, Boyce GA, Siall MV: Esophageal ultrasound and the preoperative staging of carcinoma of the esophagus. J Thorac Cardiovasc Surg 101:536–543, 1991. Roviaro G, Varoli F, Rebuffat C, et al: Videothoracoscopic staging and treatment of lung cancer. Ann Thorac Surg 59:971–974, 1995. Rusch VW, Mountain C: Thoracoscopy under regional anesthesia for the diagnosis and management of pleural disease. Am J Surg 154:274–278, 1987. Santillan-Doherty P, Argote-Greene LM, Guzman-Sanchez M: Thoracoscopic management of primary spontaneous pneumothorax. Am Surg 72:145–149, 2006. Shulkin AN: Management of the indeterminate solitary pulmonary nodule: A pulmonologist’s view. Ann Thorac Surg 56:743–744, 1993. Solaini L, Prusciano F, Bagioni P: Video-assisted thoracic surgery in the treatment of pleural empyema Surgical Endoscopy 21:280–284, 2007. Wakabayashi A: Thoracoscopic technique for management of giant bullous lung disease. Ann Thorac Surg 56:708–712, 1993. Wakabayashi A, Brenner M, Kayalek RA, et al: Thoracoscopic carbon dioxide laser treatment of bullous emphysema. Lancet 337:881–883, 1991. Wall CP, Gaensler EA, Carrington CB, et al: Comparison of transbronchial and open biopsies in chronic infiltrative lung diseases. Am Rev Respir Dis 123:280–285, 1981. Wallace JM, Deutsch AI: Flexible fiberoptic bronchoscopy and percutaneous needle lung aspiration for evaluating the solitary pulmonary nodule. Chest 81:665–671, 1982. Westcott JL: Percutaneous transthoracic needle biopsy. Radiology 169:593–601, 1988. Zerhouni EA, Stitik FP, Siegelman SS, et al: CT of the pulmonary nodule: A cooperative study. Radiology 160:319– 327, 1986.

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38 Perioperative Respiratory Considerations Horace M. Delisser Michael A. Grippi

I. CHANGES IN PULMONARY FUNCTION WITH SURGERY Lung Volumes Diaphragm Function Gas Exchange Control of Breathing Lung Defense Mechanisms II. PULMONARY COMPLICATIONS III. PREOPERATIVE RISK FACTORS Chronic Lung Disease Smoking History General State of Health Age Obesity Nutritional Status Antecedent Respiratory Tract Infection IV. INTRAOPERATIVE RISK FACTORS Type of Anesthesia Duration of Anesthesia

Postoperative pulmonary complications constitute a significant cause of morbidity and mortality following surgery. Managing patients at risk for postoperative pulmonary problems requires an understanding of the predictable changes in pulmonary physiology that occur with surgery and anesthesia, as well as knowledge of factors associated with development of postsurgical respiratory compromise. Despite the availability of several screening tests, a careful history and physical examination continue to be the cornerstone of preoperative pulmonary evaluation. Although a number of measures can be employed before and after surgery to minimize the risk of respiratory complications, close patient monitoring and early detection are essential. This chapter focuses initially on changes in pulmonary function with surgery. Pulmonary risk factors before, during, and after surgery are reviewed prior to discussion of preop-

Surgical Site Type of Surgical Incision V. POSTOPERATIVE RISK FACTORS Inadequate Postoperative Analgesia Immobilization VI. PREOPERATIVE EVALUATION History and Physical Examination Chest Radiograph Arterial Blood-Gas Analysis Pulmonary Function Tests VII. EVALUATION FOR LUNG RESECTION Pulmonary Function Tests, Lung Scans, and Arterial Blood-Gas Analyses Additional Tests for Evaluating Patients for Lung Resection Recommended Approach VIII. PREOPERATIVE PREPARATION IX. POSTOPERATIVE PROPHYLACTIC MEASURES

erative evaluation of the patient for surgery, including lung resectional surgery. Finally, recommendations are made regarding preoperative preparation and postoperative prophylactic measures.

CHANGES IN PULMONARY FUNCTION WITH SURGERY Many postoperative respiratory complications relate to exaggerations of the expected postoperative changes in pulmonary function that occur as a result of the surgery itself, anesthesia, or various pharmacologic interventions. Hence, an appreciation of normal postoperative pulmonary physiology is useful in understanding a number of pulmonary problems

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Table 38-1 Changes in Pulmonary Function with Surgery Reduction in lung volumes Diaphragm dysfunction Impaired gas exchange Respiratory depression due to residual effects of anesthesia or postoperative narcotics Impaired cough and mucociliary clearance Source: From Goldmann DR, Brown FH, Guarnieri DM (eds), Perioperative Medicine. New York, McGraw-Hill, 1994, with permission.

seen following surgery. Five principal categories of change in pulmonary function with surgery may be considered: (1) lung volumes, (2) diaphragm function, (3) gas exchange, (4) control of breathing, and (5) lung defense mechanisms (Table 38-1).

Lung Volumes The pattern of pulmonary function abnormalities following thoracic and abdominal surgery is restrictive, characterized by moderate to severe reductions in vital capacity (VC) and smaller, but more important, reductions in functional residual capacity (FRC). The degree of impairment is similar after upper abdominal and thoracic surgery. Smaller changes in VC and FRC are noted with lower abdominal surgery; superficial or extremity surgery is usually unassociated with any significant or persistent changes in lung volumes. During the first 24 h following upper abdominal surgery, VC and FRC may be reduced by more than 70 percent and 50 percent, respectively, and they may remain depressed for more than a week. Consequently, it is not surprising that pulmonary complications are seen more often with thoracic and upper abdominal procedures than with surgery involving the lower abdomen or extremities (see “Intraoperative Risk Factors” below). Reductions in other lung volumes, including total lung capacity (TLC), inspiratory capacity (IC), expiratory reserve volume (ERV), and residual volume (RV) have been noted. While the forced expiratory volume in 1 second (FEV1 ) is decreased, the ratio of FEV1 to the forced vital capacity (FEV1 /FVC%) remains unchanged, indicating that major airway obstruction does not occur. Since patients undergoing superficial or extremity surgery do not experience major changes in lung volumes, residual or carryover effects from general anesthesia do not appear to play a primary role in this regard. In fact, studies show that in many patients, FRC in the early postoperative

period is unchanged from baseline. An alternative proposal for the reduction is that postsurgical pain and associated muscle splinting may impair lung mechanics. However, since effective pain control using epidural anesthesia or intercostal nerve block fails to fully restore VC or FRC to preoperative levels, other causes must be operative. A growing consensus is that diaphragm dysfunction is an important contributing factor (see below). The reduced FRC is of major physiological significance postoperatively. Its importance can be understood when the phenomenon of airway closure and the concept of closing capacity (CC) are considered. FRC is the lung volume at the end of a normal tidal expiration. CC is the lung volume at which small airways in the lung bases begin to close during expiration because of a reduction in airway radial traction. The relationship between the two is a key factor in the development of postoperative changes in lung function (Fig. 38-1). In a normal lung, FRC is always greater than CC, and the airways remain open throughout a tidal breath. However, when CC is greater than FRC, lung volume fails to increase sufficiently during tidal breathing to open all the airways and, consequently, some alveolar units remain closed during a breath. Such regions constitute areas of atelectasis. An intermediate state exists when CC exceeds lung volume for part of the time during each tidal breath. Under these circumstances, the airways open for only a portion of the respiratory cycle, creating areas of low ventilation relative to perfusion. In summary, any circumstance that reduces FRC below CC or that increases CC above FRC produces regions of reduced ventilation and atelectasis (Table 38-2).

Diaphragm Function Diaphragm dysfunction has been recognized as an important factor contributing to the postoperative reduction in lung volumes. In patients undergoing cholecystectomy, the diaphragm’s contribution to quiet tidal breathing after surgery is reduced. This impairment is not due to postoperative pain. Measurements of transdiaphragmatic pressure during maximal phrenic nerve stimulation following upper abdominal surgery indicate that decreased central nervous system output to the phrenic nerves, possibly as a result of inhibitory reflexes arising from sympathetic, vagal, or splanchnic receptors, may be the important etiological factor.

Gas Exchange Postoperative hypoxemia occurs commonly. There are two phases in its development. The initial phase occurs in the first several hours following anesthesia and surgery. The underlying mechanisms are related largely to the residual effects of the anesthesia and include ventilation-perfusion mismatch, anesthetic-induced inhibition of hypoxic pulmonary vasoconstriction, right-to-left shunting, alveolar hypoventilation, depressed cardiac output, and increased oxygen consumption

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Figure 38-1 The relationship between functional residual capacity (FRC) and closing capacity (CC). See text. (From Goldmann DR, Brown FH, Guarnieri DM (eds): Perioperative Medicine. New York, McGraw-Hill, 1994, with permission.)

by peripheral muscle. This phase resolves within 24 h following superficial surgery. A second phase of hypoxemia that may persist for several days or weeks is seen after thoracic and upper abdominal surgery. This phase correlates with reductions in FRC and changes in the FRC-CC relationship. Although alterations in the FRC-CC relationship predominate, other processes may contribute to late postoperative hypoxemia: (1) alveolar hypoventilation (see “Control of Breathing” below); (2) increased dead space ventilation due to rapid, shallow breathing; and (3) decreased mixed venous oxygen tension due to

Table 38-2 Conditions That Alter the Relationship between Functional Residual Capacity (FRC) and Closing Capacity (CC) Decrease FRC

Increase CC

Supine position

Advanced age

Obesity

Smoking

Pregnancy

Chronic obstructive pulmonary disease (COPD)

General anesthesia

Pulmonary edema

Abdominal pain Source: From Goldmann DR, Brown FH, Guarnieri DM (eds), Perioperative Medicine. New York, McGraw-Hill, 1994, with permission.

increased oxygen consumption, impaired cardiac output, and reduced oxygen carrying capacity.

Control of Breathing Respiratory depression is a common feature of the postoperative period. Two factors are responsible. First, residual effects of preanesthetic or anesthetic agents inhibit respiratory drive and reduce the ventilatory response to hypercapnia, hypoxia, and acidemia. Second, narcotics given for postoperative analgesia depress both hypercapnic and hypoxic ventilatory drives, resulting in decreased tidal volume, reduced minute ventilation, and increased PaCO2 . Narcotics also alter the pattern of breathing, reducing the frequency of sighs or eliminating them entirely; in susceptible patients, narcotics may precipitate sleep apnea.

Lung Defense Mechanisms Several mechanisms protect the lung from environmental and infectious insults. Two of the most important—cough and mucociliary transport—are compromised after surgery, contributing to an increased risk of pulmonary infection. Postoperative pain or the excessive use of narcotics may inhibit coughing; in addition, altered lung mechanics decrease the expulsive force generated with each cough. Mucociliary clearance is impaired for up to a week following upper abdominal surgery. Although an ineffective cough reflex contributes significantly to reduced mucociliary clearance, several additional mechanisms are involved. These include: (1) cilia damage from endotracheal intubation and inhalation of dry, hyperoxic gas mixtures; (2) reduced tracheal mucus velocity due to the presence of an endotracheal tube; (3) anesthetic-induced inhibition of mucociliary transport; and (4) atelectasis.

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Table 38-3 Pulmonary Complications Associated with Thoracic Surgery Procedure

Complication

Incidence

Coronary artery bypass grafting

Phrenic nerve damage

10%

Late pleural effusions (arising after discharge)

Not reported in literature

Thoracotomy with lung resection

Bronchopleural fistula or empyema∗

5–20%

Median sternotomy

Sternal wound infection (mediastinitis or osteomyelitis)

1–2%

Esophagectomy, gastrectomy

Anastamotic leak

3–6%

∗ Higher for patients with sarcoidosis and aspergilloma. Source: From Goldmann DR, Brown FH, Guarnieri DM (eds), Perioperative Medicine. New York, McGraw-Hill, 1994, with permission.

PULMONARY COMPLICATIONS The criteria used for defining postoperative pulmonary morbidity have varied considerably in published reports, although it is clear that, from a broad perspective, five major categories of complications may be considered: (1) atelectasis; (2) infection, including acute tracheobronchitis and pneumonia; (3) exacerbation of underlying chronic lung disease; (4) prolonged mechanical ventilation and respiratory failure; and (5) thromboembolic disease. With thoracic surgery, several additional unique problems have been noted (Table 38-3). The variability in defining postoperative pulmonary complications has resulted in reported incidences in the literature ranging from 5 to 90 percent. In general, a healthy, young nonsmoker of normal weight has a very low risk of

postoperative pulmonary complications (1 percent or less). However, a number of factors have been identified that are associated with the development of postoperative pulmonary complications (Table 38-4). They include preoperative factors (chronic lung disease, smoking, general state of health, age, obesity, nutritional status, and antecedent respiratory tract infection), intraoperative factors (type and duration of anesthesia, surgical site of operation, and type of surgical incision), and postoperative factors (immobilization and inadequate pain control).

PREOPERATIVE RISK FACTORS A number of patient-related factors have been implicated in the development of postoperative respiratory complications.

Table 38-4 Factors Associated with Development of Postoperative Pulmonary Complications Preoperative

Intraoperative

Postoperative

Chronic lung disease

Type of anesthesia

Immobilization

Smoking

Duration of anesthesia

Inadequate pain control

General state of health

Surgical site

Age

Type of surgical incision

Obesity Nutritional status Antecedent respiratory tract infection

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Chronic lung disease (particularly obstructive airway disease), cigarette smoking, and the patientâ&#x20AC;&#x2122;s overall state of health are the most important preoperative risk factors. In addition, age and obesity are relatively minor factors. The precise risks associated with malnutrition and recent viral infections are unknown.

Chronic Lung Disease The following discussion focuses on the operative risks in patients with three common categories of chronic lung disease: (1) chronic obstructive pulmonary disease, (2) restrictive lung diseases, and (3) pulmonary vascular diseases. Chronic Obstructive Pulmonary Disease Since chronic obstructive pulmonary disease (COPD) is the most common chronic pulmonary disorder, most studies addressing the impact of preexisting lung disease on surgical risk have focused on this entity. The reported incidence of postoperative pulmonary complications in patients with COPD varies from 25 to 100 percent and is influenced by type of surgery, magnitude of preexisting respiratory impairment, and criteria used to define complications. Although not precisely quantified in the literature, the risk for postoperative respiratory complications appears to increase significantly (greater than 50 percent) when the FEV1 is below 65 percent of predicted. The risk is also increased in patients who are hypercapnic. In patients with severe disease, an important issue is whether a critical level of lung function exists below which the risk of developing a major, potentially life-threatening pulmonary complication is so high as to make anesthesia and surgery too dangerous. In the 1950s, such a prohibitive threshold or level was proposed. Subsequent studies, however, have failed to support this hypothesis. Patients with an FEV1 as low as 450 ml have been found to tolerate surgery safely. Hence, patients should not be denied necessary operative procedures solely on the basis of marginal lung function. As with all medical interventions, the potential benefits of the operative procedure must be weighed against the operative risk. The increased incidence of postoperative pulmonary complications in patients with COPD is due, in part, to an increase in the CC, favoring the development of areas of low ventilation-to-perfusion ratios and atelectasis. In addition, in patients who continue to smoke, impaired ciliary function and chronic tracheobronchitis may be contributing factors. Restrictive Lung Diseases The risk of pulmonary complications in patients with restrictive lung diseases who undergo surgery is unknown. Although some experience has been reported with patients undergoing thoracic and corrective orthopedic surgery (see below), very little data exist with regard to abdominal and extremity surgery. One might expect a higher incidence of postoperative respiratory complications in these patients for two reasons: (1) FRC is reduced, favoring the formation of areas of poor

Perioperative Respiratory Considerations

ventilation and atelectasis; and (2) coughing, and thus the ability to clear respiratory secretions, is impaired. Experience with postoperative pulmonary complications has been reported in three relatively common situations for patients with restrictive disorders: (1) sarcoidosis complicated by aspergilloma and hemoptysis; (2) corrective surgery for kyphoscoliosis; and (3) myasthenia gravis with associated thymoma. Sarcoidosis may progress to diffuse interstitial fibrosis and cavitary changes, primarily involving the upper lobes (see Chapter 67). These cavities are prone to infection with Aspergillus species and aspergilloma formation, with subsequent development of recurrent and, at times, life-threatening hemoptysis. These patients generally have very poor lung function and, hence, are managed conservatively. However, if supportive medical therapy fails, patients may require thoracotomy and lung resection. Unfortunately, the postoperative course is rarely problem-free and is often complicated by the development of a bronchopleural fistula or empyema. Corrective surgery in patients with kyphoscoliosis may involve anterior or posterior spinal fusion procedures or a combination of the two. In addition to correction of the primary orthopedic abnormality, an important indication for performing these procedures is progressive deterioration of pulmonary function. Postoperative respiratory complications have been reported in up to 20 percent of these patients, with pleural space-related processes (e.g., pneumothorax, pleural effusion, bronchopleural fistula, and empyema) among the most common. Important risk factors include: (1) nonidiopathic scoliosis, (2) open anterior spinal fusion procedures, (3) age greater than 20 years, (4) mental retardation, (5) preoperative hypoxemia, and (6) obstructive pulmonary function tests. Video-assisted thorascopic (VAT) approaches have emerged as alternatives to open thoracotomy, and initial studies indicate that outcomes of anterior fusion by a VAT procedure and thoracotomy are similar. Most patients with myasthenia gravis will, during the course of their disease, undergo thymectomy. Risk factors for postoperative pulmonary complications include chronic myasthenia gravis (greater than 6 years), severe bulbar weakness, preexisting respiratory illness, need for large doses of pyridostigmine, and reduced maximal static expiratory pressure (less than 50 cm H2 O or 66 percent of predicted). The preoperative VC has not been found consistently to be a significant predictor of respiratory morbidity following thymectomy. Historically, up to 30 percent of these patients required mechanical ventilation for more than 3 days following the surgery. However, more recent routine use of plasma exchange in patients with bulbar or generalized myasthenia gravis has significantly reduced the duration of postoperative ventilatory support and time in the intensive care unit. Virtually all patients with the disorder are treated with anticholinesterases, which are usually discontinued prior to surgery in order to minimize tracheobronchial secretions. However, controversy exists regarding whether these agents should be restarted immediately after surgery or withheld for 24 to 48 h following thymectomy.

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Pulmonary Vascular Diseases The risk of postoperative pulmonary complications in patients with underlying pulmonary vascular disease and intact respiratory mechanics is not known. However, one might anticipate an exaggeration of, or prolongation in, the hypoxemia seen postoperatively (see “Gas Exchange” above). In addition, pulmonary reserve in these patients is usually reduced; hence, additional pulmonary insults are less likely to be tolerated.

Table 38-5 American Society of Anesthesiologists’ (ASA) Clinical Classification ASA I:

Otherwise healthy patient undergoing elective surgery

ASA II:

Patient with single system or well-controlled disease which does not affect daily life

ASA III:

Patient with multisystem or well-controlled major system disease which limits daily activity

ASA IV:

Patient with severe, incapacitating disease which is poorly controlled or end-stage

ASA V:

Patient who is in imminent danger of death and is not expected to survive 24 h

Smoking History Smoking increases the risk of postoperative respiratory complications, independent of the association of smoking with COPD. Given the well-documented adverse changes in respiratory epithelium and pulmonary function that correlate with the degree of tobacco consumption, such an association is not surprising. In individuals undergoing coronary artery bypass graft surgery, the risk of smoking becomes significant when tobacco use exceeds 20 pack-years. A statistically significant reduction in complications occurs only when patients discontinue smoking for at least 8 weeks prior to surgery. This finding is consistent with studies showing that abnormalities in pulmonary function may persist up to several months after smoking cessation. Although smoking cessation of more than 2 months is associated with a decreased risk of postoperative respiratory complications, some initial retrospective studies actually showed a paradoxical increase in pulmonary complications in patients who stopped smoking only a few weeks or days prior to surgery. However, a more recent prospective analysis found no evidence for increased pulmonary complications in patients who quit smoking within 2 months prior to a thoracotomy.

General State of Health Overall clinical status, as categorized by the American Society of Anesthesiologists’ (ASA) classification (Table 38-5), correlates with development of postoperative pulmonary complications. For patients undergoing abdominal surgery, an ASA classification of II or higher is a powerful predictor of increased risk of respiratory problems after surgery.

Age Based primarily on retrospective data from the 1950s and 1960s, advanced age has long been considered a major risk factor for postoperative pulmonary complications. However, recent work suggests that age may not be as significant as originally believed, once other confounding variables are controlled. For example, in a study of 520 patients undergoing elective thoracic or abdominal surgery, no association between age and postoperative pneumonia was found. These findings appear to hold true even when lung tissue is resected. In addition, in a study of patients undergoing thoracotomy for lung cancer, despite a somewhat higher 30-day postoperative mortality in patients over age 70 years, the incidences

of postoperative pulmonary complications and hospital stay were not increased, and actual survival was not decreased in the older group.

Obesity A number of changes in respiratory mechanics and pulmonary function occur with obesity. The accumulation of fat in the chest wall, diaphragm, and abdomen may reduce total respiratory compliance by more than 60 percent—a change that is amplified when the patient assumes the supine position. The reduced compliance, in turn, increases the work of breathing. Consequently, minute ventilation, oxygen consumption, and carbon dioxide production are further increased beyond baseline values, which are already elevated as a result of increased metabolic demands imposed by the obese state. Normally, spirometry in obese patients does not indicate airway obstruction. However, a reduction in ERV is found consistently. The magnitude of the reduction correlates with the degree of obesity. Areas of low ventilation relative to perfusion and atelectasis are seen (see “Lung Volumes” above). In addition to these mechanical changes, obese patients appear to have a larger gastric volume and lower pH than do non-obese patients and may be predisposed to aspiration. Despite what might be predicted based on the changes in lung function described above, retrospective reviews of obese patients undergoing abdominal surgery do not show an increased incidence of pneumonia or atelectasis compared to non-obese patients undergoing similar procedures. The few prospective studies on the risk in obesity of postoperative pulmonary complications have yielded conflicting results. However, in these studies, small numbers of patients have been

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studied, liberal definitions of obesity have been employed, patient height has not been routinely considered, and the degree of obesity has not been noted precisely. In studies showing a correlation between obesity and postoperative respiratory morbidity, the principal complication has been atelectasis. Thus, although obesity may increase the risk of some postoperative pulmonary complications, the precise magnitude and significance of the risk are unknown. However, since respiratory complications (e.g., bacterial pneumonia, acute respiratory failure, or prolonged mechanical ventilation) occur in only 4 to 7 percent of morbidly obese patients undergoing gastric bypass surgery, in the absence of other cardiopulmonary disease, the risk of postoperative pulmonary complications associated with obesity appears not to be excessive. Obesity is, however, clearly a risk factor for obstructive sleep apnea syndrome, which may be unmasked or exacerbated because of use of postoperative analgesics or narcotics. Since sleep apnea occurs in individuals of normal weight, all patients should be questioned about symptoms of the disorder (see Chapter 97).

Nutritional Status The effects of malnutrition and severe starvation on the respiratory system include a reduced ventilatory response to hypoxia, decreased diaphragmatic muscle function, impaired cell-mediated and humoral immunity, and alterations in the elastic properties of the lung (see Chapter 154). Some evidence of malnutrition can be found in many hospitalized patients, but it is unclear whether the degree of malnutrition usually noted produces clinically significant changes in pulmonary function. In addition, although patients whose nutritional status is compromised may be at higher risk for developing postoperative pulmonary complications, aggressive preoperative nutritional support has not been shown to decrease postsurgical pulmonary morbidity.

Antecedent Respiratory Tract Infection Enhanced airway reactivity and increased airway resistance may persist for several weeks beyond resolution of the acute symptoms of a viral respiratory tract infection. In addition, diaphragmatic dysfunction has been shown to be impaired during viral infections. Although no published studies have addressed the effect of concurrent viral infections on postoperative pulmonary morbidity, a delay in elective surgery is generally advised, given the changes in airway reactivity and diaphragm function in this setting.

Perioperative Respiratory Considerations

Type of Anesthesia The pulmonary effects of general anesthesia are addressed in detail elsewhere (see Chapter 147). They include impairment of oxygenation and carbon dioxide elimination. These effects result from anesthetic-induced changes in the shape and motion of the chest wall and diaphragm, which, in turn, lead to increases in alveolar dead space, shunt fraction, and ventilation-perfusion mismatching. The alterations in lung function may contribute to pulmonary morbidity. Because of the effects of general anesthesia on gas exchange, regional anesthesia has been used as an alternative in patients with underlying pulmonary disease. Indeed, epidural anesthesia to a T4 sensory level does not appear to alter FRC, VC, FEV1 , the alveolar-arterial oxygen gradient, shunt fraction, or cardiac output. Many clinicians have the impression that these strategies lower the incidence of postoperative respiratory complications. However, with the exception of several reports showing a reduced risk of postoperative thromboembolism, studies to date have not been well designed and have not consistently demonstrated that regional anesthesia results in a lower incidence of other postoperative pulmonary complications.

Duration of Anesthesia The incidence of pulmonary complications increases significantly for procedures lasting longer than 3 to 4 h. Patients whose procedure lasts 4 h or more are five times more likely to suffer postoperative pneumonia than those whose procedures last less than 2 h.

Surgical Site The development of postoperative pulmonary complications correlates strongly with the anatomic site of operation. The complication rate (excluding thromboembolic disease) is less than 1 percent for non-thoracoabdominal procedures, less than 5 percent for lower abdominal surgery, and greater than 5 percent for upper abdominal surgery (with reported complication rates ranging from 7 to 76 percent). For thoracotomy with lung resection, the complication rate also depends on a number of other factors, including: (1) the presence of underlying lung disease, (2) the amount of functional lung removed, and (3) the extent to which the “bellows” function of the lung is impaired (see “Evaluation for Lung Resection” below).

Type of Surgical Incision INTRAOPERATIVE RISK FACTORS Several intraoperative factors have been associated with the development of pulmonary complications after surgery. These include the type of anesthesia, the length of the procedure (as determined by the duration of anesthesia), the surgical site, and the type of surgical incision.

For abdominal procedures, vertical laparotomy incisions carry a higher incidence of postoperative complications than do horizontal incisions. Abdominal laparoscopic procedures and thoracoscopic lung resection have gained widespread acceptance because of reduced patient discomfort, shortened length of hospitalization, and faster patient return to full activity. Since the magnitude of incisional pain is usually less, and since patients typically ambulate sooner, the incidence

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of postoperative respiratory problems associated with these less invasive procedures is likely to be reduced. Thus, not surprisingly, laparoscopic cholecystectomy, compared with open cholecystectomy, demonstrates better preservation and faster recovery of lung volumes, less postoperative pain and analgesia use, and higher arterial oxygen saturations.

POSTOPERATIVE RISK FACTORS Inadequate pain control, prolonged bed rest, and inactivity contribute to the development of respiratory complications following surgery.

Chest Radiograph The preoperative chest radiograph is usually unrevealing if risk factors and abnormal physical findings are absent. Although the admission or screening chest radiograph is more likely to show an abnormality in individuals with known cardiopulmonary disease, the study usually simply confirms the presence of previously known abnormalities; only occasionally does it result in an alteration in management. Thus, a preoperative chest radiograph is indicated when there are new or unexplained symptoms or signs, when there is a history of underlying lung disease and no recent chest radiograph, or when thoracic surgery is planned.

Arterial Blood-Gas Analysis Inadequate Postoperative Analgesia Effective pain control is vital in the early postoperative period, since pain inhibits coughing and deep breathing and discourages early mobilization—factors that contribute to an increased risk of pulmonary complications. Obstacles to good postoperative analgesia include hesitancy of the patient to report pain for fear of being labeled a “bad” patient and anxiety of caregivers in administering narcotics because of side effects.

Since an elevated PaCO2 is associated with an increased incidence of postoperative respiratory morbidity in patients with significant chronic lung disease, an arterial blood-gas analysis should be done preoperatively in these patients. It is also recommended that an arterial blood-gas specimen be obtained in patients who, by either history or physical examination, have a new significant pulmonary process or who are undergoing lung resection. Data do not support use of arterial blood-gas analysis as a routine preoperative screening test.

Immobilization

Pulmonary Function Tests

Prolonged bed rest and inactivity following surgery impact the risk of postoperative respiratory complications in several ways. FRC decreases by 500 to 1000 ml in moving from the upright to the supine position, favoring the development of atelectasis. Increased ambulation is associated with better patient mobilization and clearance of secretions. As discussed elsewhere (see Chapter 82), lack of patient movement in the postsurgical period is a major risk factor for deep venous thrombosis and pulmonary embolism.

An increased risk of respiratory complications has been demonstrated only in the obstructive category of pulmonary disorders. Although there are theoretical reasons to expect a higher incidence of postoperative respiratory problems in patients with restrictive lung diseases (see “Preoperative Risk Factors” above), currently, no data correlate the degree of restriction (as assessed by lung volumes) with subsequent pulmonary morbidity. Hence, although a complete battery of pulmonary function tests is useful in evaluating suspected restrictive lung disease, spirometry to evaluate for airway obstruction is all that is required to screen patients at risk. Indications for preoperative pulmonary function testing include the presence of cough or unexplained dyspnea, a history of chronic lung disease, a history of cigarette smoking (greater than 20 pack-years), and planned lung resection (discussed below). Current data do not support the routine use of these studies to evaluate the pulmonary risks of advanced age, obesity, malnutrition, or abdominal surgery. Finally, normal pulmonary function tests do not guarantee a complicationfree postoperative course and do not lessen the need for diligent and attentive respiratory care following surgery.

PREOPERATIVE EVALUATION The principal elements in preoperative evaluation of the surgical patient are: (1) the history and physical examination, (2) the chest radiograph, (3) arterial blood-gas analysis, and (4) pulmonary function tests (Fig. 38-2).

History and Physical Examination A careful history is an essential component of the preoperative evaluation. The following issues should be reviewed: (1) smoking history; (2) history of respiratory symptoms (e.g., cough, chest pain, dyspnea), including symptoms of sleep apnea; (3) extent of preexisting lung disease; and (4) history of recent respiratory tract infection. The physical examination is rarely helpful in identifying pulmonary risk factors. When the history is negative, the physical examination is typically unremarkable. However, the initial physical examination supplements the history and provides a baseline for future comparisons.

EVALUATION FOR LUNG RESECTION In evaluating patients for lung resection, the clinician must consider two issues: (1) What are the surgical morbidity and mortality for the patient with significant underlying chronic lung disease? (2) Will postoperative lung function be adequate? A number of approaches have been used over the years

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Figure 38-2 Algorithm for preoperative pulmonary evaluation. See text for discussion.

to address these questions. Several, including pulmonary function tests, lung scans, and arterial blood-gas analyses are used routinely; others are used less commonly.

Pulmonary Function Tests, Lung Scans, and Arterial Blood-Gas Analyses Studies have shown that the risk of postoperative respiratory complications following lung resection (especially pneumonectomy) increases significantly when the FEV1 is less than 2 L or when the FVC or maximal voluntary ventilation (MVV) is less than 50 percent predicted. For these “high risk” patients, a number of additional tests have been used to estimate postoperative pulmonary function. The most helpful have been quantitative perfusion and ventilation scintigraphy. Ventilation and perfusion lung scans are equally accurate in calculating the postoperative FEV1 , although perfusion scanning is more commonly used because it is technically easier to perform. These scans measure the relative blood flow or ventilation to one lung or lung region and can be used to predict postoperative FEV1 . For pneumonectomy, the predicted postoperative FEV1 is calculated as: Predicted postoperative FEV1

preoperative FEV1 × percent perfusion to remaining lung (1)

For lobectomy, regional quantitative perfusion scans may be used. Alternatively, the postoperative FEV1 may be predicted using the following equation: Preoperative FEV1 × (number of lung Predicted postsegments remaining after resection operative FEV1 = divided by total number of segments in both lungs) (2) Equation (2) appears to provide information as accurate as that obtained from perfusion studies. When these calculations are inaccurate, they tend to underestimate the predicted postoperative FEV1 . A predicted postoperative FEV1 of 800 ml has been used as a cutoff for withholding resectional lung surgery, based on the clinical impression that below 800 ml many patients are

disabled and develop carbon dioxide retention. Indeed, studies employing this threshold report “acceptable” surgical and postoperative morbidity and mortality. However, no prospective studies have confirmed the significance of this value. Furthermore, the physiological implications of an FEV1 of 800 ml depend upon a number of factors, including the patient’s body size. Therefore, calculation of percent predicted FEV1 might be of greater value in determining operability. A predicted postoperative FEV1 of greater than 40 percent predicted has been proposed as a safe criterion in patients undergoing pulmonary resection. Finally, recognizing that most patients who undergo resectional lung surgery have lung cancer and that this malignancy has virtually a 100 percent mortality without surgery (for non–small-cell tumors), caution must be exercised in applying exclusionary criteria. Finally, as noted previously, hypercapnia in the setting of chronic lung disease is associated with a higher incidence of postoperative respiratory morbidity. Hypoxemia is, however, not as good a predictor of subsequent pulmonary morbidity. In fact, resection of areas of the lung having significant ventilation-perfusion mismatch may improve the level of oxygenation postoperatively. A preoperative arterial bloodgas analysis should be obtained in all patients with preexisting lung disease undergoing pulmonary resection. Although supportive data are lacking, it is common practice to obtain an arterial blood-gas sample in all patients undergoing resectional surgery, even those without significant underlying lung disease. This determination serves as a basis for comparison with subsequent intra- and postoperative measurements.

Additional Tests for Evaluating Patients for Lung Resection Several additional tests, including measurement of diffusing capacity, assessment of exercise capacity, bronchospirometry, the lateral position test, and unilateral pulmonary artery occlusion have been advocated in preoperative evaluation of the candidate for lung resection. Studies on the predictive value of the preoperative diffusing capacity in assessing operative risk have yielded conflicting results. However, determination of predicted

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postoperative DlCO using a formula similar in concept to Eq. (1) may be useful. A predicted postoperative DlCO less than 40 percent of the predicted normal value appears to be associated with a high risk of operative morbidity and mortality. A number of investigators have found measurement of maximal oxygen consumption during cardiopulmonary ˙ 2 max) to be useful in predicting postexercise testing (VO ˙ 2 max less than 15 operative morbidity and mortality. A VO to 20 ml/kg/min is associated with an increased incidence of postoperative complications. In addition, exercise-induced arterial oxygen desaturation (greater than 2 percent decline) appears to predict postoperative complications, including death and respiratory failure. The 6-minute walk test and stair climbing are technologically simpler approaches than cardiopulmonary exercise testing and have been used clinically to evaluate the exercise capacity of patients undergoing lung resection. Studies in patients evaluated for lung volume reduction surgery indicate that those unable to complete a 6-minute walk of more than 500 feet are unacceptable candidates for lung resection. However, for those who maintain an oxygen saturation greater than 90 percent on 2 L of supplemental oxygen while exceeding 700 to 900 feet during a 6-minute walk, morbidity and mortality with lung resectional surgery are less than 10 percent and 1 percent, respectively.

Retrospective studies have demonstrated a significant risk of postoperative pulmonary complications in patients who are unable to climb two flights (where one flight is the equivalent of 12 steps). Bronchospirometry (the measurement of oxygen uptake in each lung, individually), the so-called lateral position test, and measurement of pulmonary artery pressure during temporary, unilateral pulmonary artery occlusion are techniques used in the past to assess the risk of thoracotomy in borderline patients. These tests are now of historical interest because of technical problems and concerns over reproducibility of results.

Recommended Approach In evaluating patients for lung resection, the following approach should be considered (Fig. 38-3). Operability for pneumonectomy is determined in the event that this procedure should become necessary, either to remove the tumor completely or because of an intraoperative complication. If the preoperative FEV1 is 2 L or greater, or at least 80 percent of the predicted normal value, the patient is “cleared” for pneumonectomy; no further testing is required. If the preoperative FEV1 is less than these values, the predicted post-pneumonectomy FEV1 should be determined. The patient is cleared for pneumonectomy if the predicted

Figure 38-3 Algorithm for preoperative evaluation for lung resection. See text for discussion.

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postoperative FEV1 is at least 40 percent of the predicted value. The patient is considered borderline if this number is between 30 and 40 percent of the predicted value; the patient is considered to be at high risk for pneumonectomy if the value is below 30 percent. For the borderline patient, or for the patient with radiographic evidence of interstitial lung disease or significant dyspnea despite an “operable” FEV1 or predicted postoperative FEV1 , the predicted post-pneumonectomy DlCO should be determined. The patient is cleared for pneumonectomy if this value is at least 40 percent of the predicted value. If confirmatory evidence of operability is required, particularly for the borderline patient, an exercise test should be performed. The patient is cleared for pneumonectomy if the ˙ 2 max is at least 15 to 20 ml/kg/min and arterial oxygen VO saturation declines less than 2 percent. If the patient cannot tolerate a pneumonectomy but, from a technical standpoint, appears to be a good candidate for lobectomy, the appropriate steps in Fig. 38-3 should be followed for calculation of the predicted post-lobectomy FEV1 and DlCO . Importantly, for selected borderline patients with emphysema and potentially resectable lung cancer, consideration should be given to combined cancer resection and lung volume reduction. This is particularly worth considering if the emphysema is heterogeneous and primarily involves the lobe to be resected. When respiratory insufficiency occurs as a result of pulmonary resection, it is manifest early (i.e., within the first several weeks following operation). After 3 months, respiratory insufficiency directly attributable to the surgery is rare.

PREOPERATIVE PREPARATION Surprisingly, few studies have specifically addressed the question of whether aggressive, preoperative pulmonary preparation decreases postoperative pulmonary morbidity and mortality. Although data on preoperative preparation are limited, for patients with significant obstructive airway disease, intensive preoperative respiratory therapy (bronchodilators, corticosteroids, antibiotics, and chest physiotherapy) does appear to reduce the incidence of postoperative respiratory complications by more than 50 percent. Several preoperative prophylactic measures should be considered in patients undergoing elective surgery (Table 38-6). Pulmonary function in patients with obstructive airway disease should be optimized. Therapy may include any or all of the following: bronchodilators, corticosteroids, antibiotics (when there is evidence of infection), and chest physiotherapy (if excessive secretions are present). When possible, these interventions should be implemented 48 to 72 h prior to surgery. Ideally, for at least 8 weeks prior to surgery, smoking should be discontinued. As noted previously, recent data

Perioperative Respiratory Considerations

Table 38-6 Preoperative Pulmonary Preparation Optimization of airway function in patients with obstructive lung disease (bronchodilators; corticosteroids, antibiotics, and chest physiotherapy, when indicated) Smoking cessation (ideally, a minimum of 8 weeks prior to surgery) Weight reduction for severely obese individuals Patient education (deep breathing exercises, importance of coughing and pain control, use of incentive spirometry) Source: From Goldmann DR, Brown FH, Guarnieri DM (eds), Perioperative Medicine. New York, McGraw-Hill, 1994, with permission.

indicate that complication rates are not increased by shorter periods of abstinence; therefore, even when 8 weeks of abstinence is not possible, patients should still be advised to quit smoking prior to surgery. In severely obese patients, if patient compliance can be achieved, weight reduction should be attempted. Finally, patient education on the importance of coughing and pain control, proper use of an incentive spirometer, and deep breathing exercises should take place preoperatively.

POSTOPERATIVE PROPHYLACTIC MEASURES Several postoperative measures may be employed in an attempt to prevent respiratory complications (Table 38-7).

Table 38-7 Postoperative Measures for the Prevention of Respiratory Complications Early patient mobilization and ambulation Prophylatic lung expansion maneuvers (incentive spirometry, deep-breathing exercises, continuous positive airway pressure [CPAP] Provision of adequate analgesia (including patient-controlled analgesia, intercostal nerve blocks, and epidural anesthesia) Prophylaxis against thromboembolism

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Early patient mobilization and ambulation should be encouraged. As noted previously, these measures are important postoperatively in reducing the incidence of atelectasis, in promoting the clearance of secretions, and in decreasing the risk of thromboembolic disease. Prophylactic lung expansion maneuvers should be initiated. Two equally effective measures are deep breathing exercises and incentive spirometry. Intermittent positive pressure breathing (IPPB) is generally ineffective and costly and is associated with several adverse effects. Reports of intermittent continuous positive airway pressure (CPAP) applied by face mask indicate that it is at least equivalent to deep breathing exercises and incentive spirometry in preventing and treating atelectasis. However, while CPAP may be useful in the patient who cannot cooperate with inspiratory maneuvers, its role in the management of patients capable of taking deep breaths is unclear. Adequate analgesia should be provided. Traditionally, parenteral narcotics have been used for postoperative analgesia, despite the risk of respiratory depression. Unfortunately, concerns over adverse respiratory effects may lead to inadequate dosing and inadequate pain relief. To overcome this problem, alternative approaches, including use of patient-controlled analgesia, epidural analgesia, and intercostal nerve blocks, have been employed. These alternative techniques provide analgesia equivalent or superior to parenteral narcotics, but published data conflict as to how effective they are in reducing postoperative pulmonary complications. Prophylaxis for thromboembolism is an important consideration, as discussed in Chapter 82. Finally, careful monitoring for postoperative complications constitutes a key element in all surgical patients. Several postoperative interventions have been shown to be ineffective, including the use of “blow bottles,” carbondioxide–induced hyperventilation, chest physiotherapy in the absence of excessive secretions or sputum production, and routine application of positive end-expiratory pressure in mechanically ventilated patients.

SUGGESTED READING Alexander JI, Spence AA, Parikh RK, et al: The role of airway closure in postoperative hypoxaemia. Br J Anaesth 45:34– 40, 1973. Ali J, Gana TJ: Lung volumes 24 h after laparoscopic cholecystectomy—justification for early discharge. Can Respir J 5:109–113, 1998. Ali J, Weisel RD, Layug AB, et al: Consequences of postoperative alterations in respiratory mechanisms. Am J Surg 128:376–382, 1974. Arozullah AM, Khuri SF, Henderson WG, et al, for the Participants in the National Veterans Affairs Surgical Quality Improvement Program. Development and validation

of a multifactorial risk index for predicting postoperative pneumonia after major noncardiac surgery. Ann Intern Med 135:847–857, 2001. Barrera R, Shi W, Amar D, et al: Smoking and timing of cessation: Impact on pulmonary complications after thoracotomy. Chest 127:1977–1983, 2005. Bousamra M 2nd, Presberg KW, Chammas JH, et al: Early and late morbidity in patients undergoing pulmonary resection with low diffusion capacity. Ann Thorac Surg 62:968– 974, 1996. Burke JR, Duarte IG, Thourani VH, et al: Preoperative risk assessment for marginal patients requiring pulmonary resection. Ann Thorac Surg 76:1767–1773, 2003. Dureuil B, Vires N, Cantineau J, et al: Diaphragmatic contractility after upper abdominal surgery. J Appl Physiol 61:1775–1780, 1986. Fairshter RD, Williams JH: Pulmonary physiology in the postoperative period. Crit Care Clin 3:287–306, 1987. Ford GT, Rosenal TW, Clergue F, et al: Respiratory physiology in upper abdominal surgery. Clin Chest Med 14:237–252, 1993. Ferguson MK, Little L, Rizzo L, et al: Diffusing capacity predicts morbidity and mortality after pulmonary resection. J Thorac Cardiovasc Surg 96:894–900, 1988. Garibaldi RA, Britt MR, Coleman ML, et al: Risk factors for postoperative pneumonia. Am J Med 70:677–680, 1981. Gass GD, Olsen GN: Preoperative pulmonary function testing to predict postoperative morbidity and mortality. Chest 89:127–135, 1986. Gracey DR, Diverte MB, Didier EP: Preoperative pulmonary preparation of patients with chronic obstructive pulmonary disease. A prospective study. Chest 76:123–129, 1979. Hall JC, Tarala RA, Hall JL, Mander J: A multivariate analysis of the risk of pulmonary complications after laparotomy. Chest 99:923–927, 1991. Latimer RG, Dickman M, Day WC, et al: Ventilatory patterns and pulmonary complications after upper abdominal surgery determined by preoperative and postoperative computerized spirometry and blood gas analysis. Am J Surg 122:622–632, 1971. 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. Marshall MC, Olsen GN: The physiologic evaluation of the lung resection candidate. Clin Chest Med 14:305–320, 1993. Marshall BE, Wyche MQ: Hypoxemia during and after anesthesia. Anesthesiology 37:178–209, 1972. Milledge JS, Nunn JF: Criteria of fitness for anaesthesia in patients with chronic obstructive lung disease. Br Med J 3:670–673, 1975. Pasulka PS, Bistrian BR, Benotti PN, et al: The risk of surgery in obese patients. Ann Intern Med 104:540–546, 1986. Raffin TA: Indications for arterial blood gas analysis. Ann Intern Med 105:390–395, 1986.

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Santry HP, Gillen DL, Lauderdale DS: Trends in bariatric surgical procedures. JAMA 294:1909–1917, 2005. Sherman S, Guidot CE: The feasibility of thoracotomy for lung cancer in the elderly. JAMA 258:927–930, 1987. Simonneau G, Vivien A, Sartene R, et al: Diaphragm dysfunction induced by upper abdominal pain. Role of postoperative pain. Am Rev Respir Dis 128:899–903, 1983.

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The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 325:525–532, 1991. Warner MA, Divertie MB, Tinker JH: Preoperative cessation of smoking and pulmonary complications in coronary artery bypass patients. Anesthesiology 60:380–383, 1984. Wightman JAK: A prospective survey of the incidence of postoperative pulmonary complications. Br J Surg 55:85–91, 1968.

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39 Evaluation of Impairment and Disability Due to Lung Disease Paul E. Epstein

I. METHODS OF EVALUATING IMPAIRMENT Medical History Physical Examination Imaging Studies Pulmonary Function Testing Arterial Blood Gas Analysis Cardiopulmonary Exercise Testing Bronchoprovocation Testing II. AMA GUIDES TO THE EVALUATION OF PERMANENT IMPAIRMENT Asthma Classification of Impairment Resulting from Other Pulmonary Diseases III. AMERICAN THORACIC SOCIETY CRITERIA FOR EVALUATION OF IMPAIRMENT OR DISABILITY IV. DISABILITY EVALUATION UNDER SOCIAL SECURITY V. SOCIAL SECURITY LISTINGS

Evaluation of disability due to pulmonary impairment is performed for a variety of reasons, including assessment of eligibility for government entitlement programs, litigation following a workplace injury, and evaluation of fitness for placement in a specific job. For purposes of the discussion that follows, the term impairment is used to denote a measurable decrease in normal organ function. The term disability is used to indicate the total effect that decreased function has on that person’s ability to carry out activities of daily living, including the ability to work. Most evaluations of pulmonary impairment are initiated when a worker complains that he or she can no longer perform the duties of a particular job that were previously

Chronic Obstructive Pulmonary Disease Asthma Restrictive Lung Disease Abnormalities of Gas Exchange Pneumoconiosis Cystic Fibrosis Cor Pulmonale Due to Chronic Pulmonary Vascular Hypertension Mycobacterial, Mycotic, and Other Chronic Persistent Infections of the Lung VI. STATE WORKERS’ COMPENSATION PROGRAMS VII. FEDERAL WORKERS’ COMPENSATION VIII. BLACK LUNG BENEFITS IX. ENERGY EMPLOYEES’ OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT X. AMERICANS WITH DISABILITIES ACT

accomplished without difficulty. Self-assessment of inability to work is almost always too subjective to be useful to organizations or government agencies that award disability benefits, and the subjective impression of the worker must be verified by a knowledgeable examiner. The worker’s treating physician often provides important information about physical impairment, but it is common practice to seek additional evaluation from a specialist or subspecialist who performs an independent medical examination. The information required for determining the degree of impairment and disability status depends on the purpose of the evaluation. For those seeking benefits under government-sponsored disability programs, the question is

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simply whether or not the individual is able to take part in gainful employment. For litigation purposes, the critical questions are whether an employee has been injured on the job (and, if so, what is the severity and permanence of the injury), whether the injury has been totally disabling or whether another type of work is possible, and whether or not workplace restrictions are needed if work is resumed. For workers attempting to be placed in a particular job, the question is whether or not respiratory function is sufficient to perform the job successfully. Each of these questions should be answered as carefully as possible on the basis of objective data. The need for independent medical assessment arises from a concern that many factors are in play when a claim for disability is filed. Some of these concerns arise because there is a need for standardization of disability criteria in fairness to others who are seeking disability benefits. To deal effectively with this concern, various professional organizations have published standards that are commonly used to estimate an applicant’s degree of impairment and to assess the risks involved in performing a particular job. Another reason for requiring independent assessment is that both the worker and the employer may bear significant financial impact from a determination of disability, and it is the physician’s responsibility to provide an unbiased opinion of the severity of impairment. Finally, claims of disability frequently arise from a workplace injury and evoke anger and other emotions that have little to do with the physical effects of the injury. Legal proceedings that often follow such an injury require that the evaluator identify the portion of the impairment that is attributable to loss of function and separate it from other extraneous issues. The physician must approach the evaluation process as an impartial observer whose primary role is to provide a scientific basis on which disability determination can be made. The physician must avoid taking the role of advocate for one party or another. Pulmonary physicians play an important, but limited, role in disability evaluation that is confined to determining the worker’s degree of pulmonary impairment. Clearly, there are gradations of impairment, and not all impairment leads to disability. In fact, disability determination requires knowledge not only of the impaired person’s physical abilities, but also his or her education, skills, job experience, and the availability of appropriate work. Finally, determination of disability depends on the laws and regulations governing the award of benefits. Physicians are not usually expert in the entirety of this knowledge base. This chapter reviews an approach to the evaluation of pulmonary impairment, the types of information that should be collected in an attempt to answer the pertinent questions, the standards used by various professional organizations to quantify the degree of impairment, and the major programs that use this information in coming to a determination of disability.

METHODS OF EVALUATING IMPAIRMENT While the claimant or worker initiates the process of disability evaluation, the physician sets the framework for assessment of the degree of impairment. The primary goal in evaluating physical impairment is to provide an objective, valid, reliable, repeatable, and reproducible appraisal of the individual’s respiratory condition. In this context, validity means that measurements made in the process of evaluation actually test meaningful aspects of physical capability. Reliability means that changes in the individual’s condition will be accurately reflected in the results of appraisal. Repeatability means that there will be close agreement of results when successive measurements are performed using the same instrument, at the same sitting. Reproducibility means that if the tests are repeated by other observers at other times, the results will be similar (or at least within acceptable limits of variability). The concept that a physician can evaluate an individual in a medical office and perform laboratory tests that provide meaningful information about his or her ability to perform specific tasks in the workplace makes many assumptions that are not strongly evidence-based. Ideally, the physician might achieve the best understanding of the claimant’s physical capability by observing him or her perform the tasks necessary to carry out a particular job. Unfortunately, that type of observation is not practical and can not be standardized. For these reasons and others, it is important to understand that many compromises must be made in the evaluation procedure. While some government entitlement programs prescribe arbitrary criteria for eligibility for benefits, in general, the process of impairment evaluation is at least partially based on judgment that requires concordance of several lines of investigation. In the case of pulmonary evaluation, these include history and symptom review, physical examination, radiographic examination, and pulmonary function testing.

Medical History In addition to documentation of prior medical conditions, an important part of the medical history, in the context of impairment/disability evaluation, is an applicant’s occupational and exposure history. The examiner must carefully collect a chronological history of jobs held, specific job duties, time spent in each position, specific chemical or dust exposures encountered at each job site, and an accounting of accidental exposures or physical injury on the job. Many work-related abnormalities resemble other diseases and cannot be diagnosed correctly without a validated exposure history. Industrial facilities are required by the Occupational Safety and Health Administration (OSHA) to maintain material safety data sheets (MSDSs) on all chemicals used in the manufacturing process and to make them available to the employee upon request. These MSDSs can provide valuable help to the physician in evaluating the cause of pulmonary dysfunction.

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Table 39-1

Table 39-2

Medical Research Council Breathlessness Scale

American Thoracic Society/Division of Lung Diseases Respiratory Symptoms Questionnaire

Grade 1

Are you ever troubled by breathlessness except on strenuous exercise?

Grade 2

If yes: Are you short of breath when hurrying on the level or walking up a slight hill?

Grade 3

If yes: Do you have to walk slower than most people on the level? Do you have to stop after a mile or so (or after 30 min) on the level at your own pace?

Grade 4

Grade 5

If yes to either: Do you have to stop for a breath after walking about 100 yards (or after a few minutes) on the level?

Mild

Do you have to walk more slowly on the level than people of your age because of breathlessness?

Moderate

Do you have to stop for a breath when walking at your own pace on the level?

Severe

Do you ever have to stop for a breath after walking about 100 yards or for a few minutes on the level?

Very Severe

Are you too breathless to leave the house or breathless on dressing or undressing?

If yes: Are you too breathless to leave the house or breathless after undressing?

The most common symptoms that lead to pulmonary impairment/disability evaluation are dyspnea, cough, and wheezing. Dyspnea is entirely subjective and is, therefore, difficult to quantitate. Nonetheless, it is of such importance that a number of dyspnea severity scales have been devised for its evaluation. Measurement of dyspnea is an attempt to discriminate between feelings of breathlessness that are experienced by normal people in performing physical tasks and the heightened feelings of air hunger experienced by people with disordered physiology performing the same tasks. One of the earliest and most useful dyspnea scales is the Medical Research Council Breathlessness Scale, which designates five progressively more severe grades of dyspnea based on the answers to questions about common activities of daily life (Table 39-1). Another instrument that is widely used for evaluating the severity of dyspnea is based on the American Thoracic Society/Division of Lung Diseases Respiratory Symptoms questionnaire, shown in Table 39-2. The usefulness of scales such as these is limited because of their frankly subjective nature, but the intensity of dyspnea should be consistent with other, more objective measures of respiratory impairment. In the context of disability evaluation, cough and sputum production must be viewed as acute, subacute, or chronic, depending on the duration of the symptoms. By definition, acute cough lasts up to 4 weeks; subacute cough lasts between 4 and 12 weeks; and chronic cough lasts more than 12 weeks. Only the chronic forms of cough and sputum production are relevant with regard to disability evaluation.

Recognizing the fact that these symptoms can be important concomitants of disabling disease, two features must be recognized. First, it is difficult to quantitate the severity of cough and sputum production and, therefore, it is not easy to integrate them into a system of progressive gradation of disability. Second, they often accompany objectively quantifiable diseases such as asthma, chronic obstructive pulmonary disease (COPD), interstitial fibrosis, or diseases that are characterized by abnormalities on imaging studies, such as bronchiectasis, suppurative lung disease, or neoplasm. As a result, cough and sputum production should not be used as independent indicators of disability, but rather as signposts that help the physician identify what kind of objective evaluation will most likely lead to appropriate classification. A history of wheezing, on the other hand, can provide important context for the evaluation of impairment. The temporal characteristics of the onset of wheezing, as well as its association with the workplace (or with particular exposures), often helps identify a specific cause of impairment. Wheezing that occurs primarily on workdays and improves during weekends or during vacations is highly suggestive of work-related asthma. The examiner should also be aware that some workplace exposures produce not only wheezing during work but may also cause repetitive nocturnal wheezing after the dayâ&#x20AC;&#x2122;s work has been completed. A history of wheezing that begins immediately after starting a new job implies a different kind of respiratory tract abnormality than a history that is characterized by a latency period between the date of employment and onset of wheezing. Each of these patterns can help the physician identify a particular cause of wheezing and can indicate methods appropriate for protecting the worker from ongoing respiratory tract injury.

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Physical Examination Even though the results of physical examination are less precise and less quantifiable than other techniques used in impairment/disability evaluation, for a variety of reasons this method of assessment retains value even in â&#x20AC;&#x153;high-techâ&#x20AC;? settings. First, the physician has a unique opportunity to assess the applicantâ&#x20AC;&#x2122;s ability (and willingness) to function in normal circumstances and is better able to verify the reasonableness of laboratory findings. Since financial considerations are usually at stake in determinations of disability, physical examination provides an opportunity for the physician to identify malingering as a possible cause of abnormal test results. Second, physical examination often provides clues to alternative explanations for abnormal laboratory results that might be missed if only laboratory test results and imaging studies were considered. For example, a finding of conjunctival pallor on physical examination may lead to reevaluation of the significance of a diminished diffusing capacity on pulmonary function testing. Since pallor suggests anemia (a common, reversible cause of diminished diffusing capacity), as opposed to intrinsic pulmonary disease (commonly due to irreversible causes of decreased diffusing capacity, such as pulmonary fibrosis or emphysema), physical examination may add value to pulmonary function testing. Third, physical examination can help direct attention to additional causes of physical impairment that were previously unrecognized. Careful cardiac assessment often uncovers evidence of extrapulmonary disease that helps explain complaints of dyspnea. On the other hand, pursed-lip breathing, a barrel-shaped chest, inspiratory crackles, expiratory wheezing, and digital clubbing remain valuable diagnostic observations that help verify the pulmonary origin of respiratory complaints and abnormal pulmonary function test results.

Imaging Studies A routine chest radiograph remains the most widely used and universally accepted imaging study in the diagnosis of pulmonary impairment resulting from pneumoconiosis, despite the fact that radiographic findings correlate poorly with physiological abnormalities or functional ability. The International Labor Organization (ILO), a specialized agency of the United Nations, first published the ILO International Classification of Radiograph of Pneumoconioses in 1950 as an epidemiologic tool to standardize radiographic interpretation of dust-related lung diseases. This classification system was subsequently revised in 1980 and in 2000. It has been adopted as a standard for the presence and severity of pneumoconiosis by many government disability programs, both in the United States and in other countries. The National Institute of Occupational Safety and Health (NIOSH) offers a certification examination to practitioners wishing to qualify as experts in the ILO system (B Reader certification). Computed tomography of the chest is generally accepted as more sensitive in detecting both pleural and

pulmonary parenchymal abnormalities than plain films of the chest. However, it is much more expensive and administers a higher radiation dose than plain film radiography. High-resolution computed tomography (HRCT) of the chest has proven to be extremely helpful in the differential diagnosis of interstitial lung disease. Like the plain film, correlation between HRCT findings and functional measures are not strongly evidence-based. Despite its clear-cut diagnostic value, HRCT has not been adopted as a standard for disability evaluation.

Pulmonary Function Testing Most of the standard evaluation schemes for impairment/disability evaluation depend on relatively simple pulmonary function testing. Spirometry and diffusing capacity measurements are generally accepted as appropriate criteria upon which functional judgments are made, since the severity of airways obstruction and abnormalities of gas transfer have been most reliably associated with decreased ability to function in activities of daily living and in the ability to work. Furthermore, these simple tests fulfill requirements that equipment used for testing be widely accessible and that adequate standards for repeatability and reproducibility be met. The American Thoracic Society (ATS) periodically publishes requirements for standardization of equipment and test interpretation. The most recent ATS statements were published in association with the European Respiratory Society (ERS) and have gained worldwide acceptance. In addition to standardization of both the equipment and techniques of test administration, an important issue in pulmonary function interpretation is the choice of an appropriate normal reference population against which the test taker is compared. Many large populations of normal subjects have undergone pulmonary function testing and have been used to develop reference values for this purpose. Current recommendations of the ATS/ ERS task force suggest that prediction values be chosen on the basis that the reference population is of a similar age range and has the same anthropometric, racial, ethnic, socioeconomic, and environmental characteristics as the individuals being tested. The individual being tested should be asked to self-identify his or her own racial or ethnic group. Although it is most desirable to match the person being tested to an ethnically similar reference group, if none is available an adjustment factor, based on published data, may be used for volume measurements. Various adjustment factors have been recommended for use in these circumstances, since African Americans and Asians have been noted in a number of large surveys to have somewhat smaller lung volumes than Caucasians (about 12 percent and 6 percent smaller, respectively). Hence, individuals may be incorrectly classified as having abnormal pulmonary function as a result of the wrong reference values having been chosen. No race adjustment should be made for the ratio of forced expiratory volume in 1 second to the forced vital capacity percent (FEV1 /FVC%) prediction.

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Arterial Blood Gas Analysis Arterial blood gas testing is rarely used by itself as a criterion of impairment since the test is more invasive than other, more common methods of evaluation. Furthermore, abnormalities of pulmonary function are usually present in association with blood gas abnormalities. Resting hypoxia is sometimes used as a modifying factor in adjusting the assessment of severity of impairment. If arterial blood gas analysis is used as a criterion of disability (as in the Black Lung program), the altitude at which the measurements are made must be specified and abnormal studies must be repeated at an interval of at least 3 to 4 weeks.

Cardiopulmonary Exercise Testing Cardiopulmonary exercise testing (CPET) is sometimes helpful in evaluating impairment, particularly in individuals whose pulmonary function is moderately abnormal, but whose symptoms are more severe than would be expected from the results of routine testing. Both the ATS and the American Medical Association (AMA) support use of CPET in selected circumstances and provide criteria for impairment based on the results. CPET is seldom helpful when routine pulmonary function tests are either normal or severely abnormal, since the results do not affect determination of disability. The other circumstance in which CPET is helpful is in assessing the ability of the subject to perform a specific job. Maximum oxygen uptake (V˙ O2 max ) measured during CPET is used to determine the maximum peak exercise level that the individual can achieve. Many experts assume that a worker can perform sustained exertion to a level of approximately 35 to 40 percent of their V˙ O2 max , although this assumption is not firmly evidence-based. A number of investigators have published estimates of the energy requirements for various jobs, and these can be used to judge the likelihood that an individual is able to perform a specific occupational function. A full description of performance techniques and methods of interpretation of CPET is provided in Chapter 35. The ATS and the American College of Chest Physicians have published a joint consensus statement on the subject.

Bronchoprovocation Testing Bronchoprovocation testing is a method of evaluating bronchial hyperreactivity in individuals who are suspected of having asthma. The method is important in impairment/disability evaluation because occupational asthma, the presence of which may have significance in judging ability to continue certain types of employment, may not be apparent on routine pulmonary function testing performed between attacks. Evaluation schemes of both the AMA and the ATS take bronchial hyperreactivity into account in assessing impairment. The ATS has published guidelines for performing methacholine bronchial challenge studies and interpretation of the results (see Chapter 34).

Evaluation of Impairment and Disability Due to Lung Disease

AMA GUIDES TO THE EVALUATION OF PERMANENT IMPAIRMENT The American Medical Association (AMA) has developed guidelines for assessing physical impairment that are widely accepted by governments and legal systems as the standard of evaluation for loss of physical function. These guidelines are continually updated by expert panels that are convened by the AMA and published periodically in book form under the title, “Guides to the Evaluation of Permanent Impairment.” Most state workers’ compensation programs in the United States, as well as the federal governments of many other countries, use the AMA standards in assessing an individual’s ability to work. According to the AMA Guides, impairment is defined as “a loss, loss of use, or derangement of any body part, organ system, or organ function.” It should be obvious from such a broad definition of impairment that not all impairments lead to inability to perform activities of daily living or inability to take part in occupational activities. However, identification of a specific impairment allows the evaluator to initiate an impairment rating that estimates the percentage of loss of function of a particular organ. Varying percentages of lost function are grouped into four severity classes. Class 1 constitutes 0 percent functional loss (for instance, an observable abnormality caused by an anatomic variation); class 2 indicates that there is objective evidence for a 10 to 25 percent impairment of the whole person as result of organ dysfunction; class 3 indicates a 26 to 50 percent impairment of the whole person; and class 4 is 51 to 100 percent impairment of the whole person. In other words, according to the AMA Guides, impairment rating requires that the evaluator first recognize that an abnormality is present, then identify the cause of the abnormality and objectively evaluate the severity of deviation from normal function, and finally, translate the severity of dysfunction into a numerically based classification that estimates how much of an effect the organ dysfunction has on the individual’s ability to carry on the activities of daily living. Evaluation of the severity of impairment is largely based on results of easily obtainable pulmonary function tests that include spirometry and diffusing capacity. Studies must be performed after the individual has achieved maximal medical improvement and is judged to be in stable condition. If possible, respiratory medications are discontinued 24 hours prior to testing. Spirometry is performed initially; if the FEV1 /FVC% is below 70, the test is repeated following administration of an inhaled bronchodilator. The equipment, its calibration, test performance, and methods of interpretation must conform to recommendations of the ATS Statement on Standardization of Spirometry. Diffusing capacity measurement is also performed according to ATS recommendations. Physicians evaluating physical impairment using the AMA Guides may also use cardiopulmonary exercise studies. Levels of oxygen consumption required to perform various intensities of work have been published and are used in

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Table 39-3 Impairment Classification for Respiratory Disorders

Pulmonary Function Test

Class 1 0% Impairment of the Whole Person

Class 2 10%–25% Impairment of the Whole Person

Class 3 26%–50% Impairment of the Whole Person

Class 4 51%–100% Impairment of the Whole Person

FVC

≥ lower limit of normal

≥60% of predicted and < lower limit of normal

≥51% and ≤59% of predicted

≤50% of predicted

FEV1

≥ lower limit of normal

≥60% of predicted and < lower limit of normal

≥41% and ≤59% of predicted

≤40% of predicted

FEV1 /FVC%

≥ lower limit of normal

N/A

DlCO

≥ lower limit of normal

≥60% of predicted and < lower limit of normal

≥41% and ≤59% of predicted

≤40% of predicted

V˙ O2 max

≥ 25 ml/kg/min or >7.1 METS

≥20 and < 25 ml/kg/min or 5.7–7.1 METS

≥15 and < 20 ml/kg/min or 4.3–5.7 METS

<15 ml/kg/min or <1.05 L/min or <4.3 METS

FVC, forced vital capacity, FEV1 , forced expiratory volume in 1s; DlC O ; diffusing capacity of the lung for carbon monoxide; V˙ O2 max , maximum oxygen uptake.

the AMA Guides to classify levels of impairment. Table 39-3 shows the rating impairment method based on AMA Guides. Several specific pulmonary disorders merit special consideration with regard to the Guides.

Asthma Standard criteria for classification of respiratory impairment are most easily developed for diseases that cause a fixed level of lung damage, producing decrements in pulmonary function that can be measured reproducibly by serial pulmonary function testing. However, asthma is a disorder that is defined by variability over time, with airflow obstruction that may revert toward normal, either spontaneously or as a result of medication administration. As a result, individuals with even moderately severe asthma may appear normal by pulmonary function testing during periods between exacerbations. This unique variability in lung function in asthma creates difficulty for the physician attempting to evaluate a particular level of impairment caused by the disease, especially if the evaluation is performed during a period of quiescence. Asthma occupies a unique niche among the disorders which prompt an assessment of respiratory impairment and disability evaluation. Asthma affects about 5 percent of the entire population of the United States and is responsible for substantial amounts of time lost from work and school. The

attendant economic impact is huge. No matter what the underlying cause of asthma, frequent attacks degrade quality of life and are a common cause of inability to work. Workplace exposures frequently exacerbate an underlying asthmatic condition (work-related asthma) or cause sensitization of the respiratory tract to materials found uniquely in the workplace (occupational asthma). Previous attempts to classify the level of impairment caused by asthma have depended on historical assessment of the number of exacerbations per year, as indicated by hospitalizations or unscheduled visits to the physician’s office. Unfortunately, this type of assessment introduces extraneous variability into the objective process of standardization of disease severity that results from differences in the patient’s ability to self-manage exacerbations, the primary care physician’s knowledge, and the emergency room’s guidelines for managing acute asthmatic attacks. In the interest of standardizing evaluation of asthma severity, the AMA Guides incorporate the objective evaluation criteria previously published by the ATS. The AMA Guides assign percentage impairment ratings according to the criteria. In addition to providing more objective standards for judgment, the new AMA classification system for asthma offers the additional advantage that evaluation can be performed during periods of stability, even if spirometry is normal at the time of testing.

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Table 39-4 Impairment Classification for Asthma Severity Postbronchodilator Score FEV1

% FEV1 changes after bronchodilator

PC20 (mg/ml)

Minimum Medication Needed

≥ lower limit of normal

<10%

>8 mg/ml

No medication

≥70% of predicted

10%–19%

8 mg/ml to >0.6 mg/ml

Occasional, but not daily, bronchodilator and/or occasional, but not daily, cromolyn

60%–69% of predicted

20%–29%

0.6 mg/ml to ≥0.125 mg/ml

Daily bronchodilator, and/or daily cromolyn, and/or daily low dose inhaled corticosteroid (≤ 800 µg of beclomethasone or equivalent)

50%–59% of predicted

≥30%

<0.125 mg/ml

Bronchodilator on demand and daily high-dose inhaled corticosteroid (> 800 µg of beclomethasone or equivalent), or occasional course (1–3 courses per year) of systemic corticosteroid

< 50% of predicted

N/A

Bronchodilator on-demand and daily high-dose inhaled corticosteroid (> 1000 µg of beclomethasone or equivalent), and daily or every-other-day systemic corticosteroid

FEV1 , forced expiratory volume in 1 s; PC20 , concentration of methacholine required to decrease FEV1 by at least 20%.

Using the AMA Guides, four types of information are evaluated in assessing impairment from asthma: (1) postbronchodilator FEV1 , (2) percentage change in FEV1 following bronchodilator administration, (3) results of bronchoprovocation testing, and (4) assessment of the minimal amounts of medication required to keep the patient’s asthma under control. Postbronchodilator FEV1 values denoting levels of increasing severity of asthma are shown in Table 39-4 and range from the lower limit of normal to less than 50 percent of predicted. If the FEV1 is less than 70 percent of predicted, additional evaluation is based on the percentage of reversibility of FEV1 following bronchodilator administration. When the FEV1 is greater than the lower limit of normal, bronchoprovocation testing is performed. Both the ATS and AMA methods of evaluating asthma severity take advantage of the fact that even when there is no active bronchospasm, asthmatic airways show nonspecific hyperresponsiveness to irritant materials, including dust, smoke, and certain chemicals (e.g., methacholine and histamine). If the results of spirometry are initially normal, methacholine bronchoprovocation testing is performed and the de-

gree of bronchial hyperresponsiveness classified according to the concentration of methacholine required to decrease the FEV1 by at least 20 percent—a measurement known as the PC20 . A final criterion for asthma severity depends on the minimum amount of medication required to keep the disease under control. Disease requiring higher amounts of medication and systemic corticosteroids is considered more severe. The evaluating physician calculates an asthma impairment score by adding the numerical values assigned to the results of measurements of postbronchodilator % change in FEV1 (or PC20 ), and minimum medication requirement. The total score is used to assign an impairment class, as shown in Table 39-5.

Classification of Impairment Resulting from Other Pulmonary Diseases Special criteria are applied by the AMA Guides to certain pulmonary diseases that are influenced by factors other than decrements in pulmonary function.

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Table 39-5 Impairment Rating for Asthma Total Asthma Score

Impairment Class

% Impairment of the Whole Person

1–5

10–25

6–9

III

26–50

10–11, or asthma not controlled despite maximal treatment (i.e, FEV1 < 50% despite use of prednisone at >20 mg/day)

51–100

Lung Cancer Patients with lung cancer are presumed to be severely impaired (class 4) for at least 1 year following diagnosis, even if surgical resection appears to have been successful in curing the disease. If, 1 year after diagnosis, the patient continues to show no evidence of persistence or recurrence of the disease, reevaluation according to the criteria provided in Table 39-5 may lead to reclassification at a lower level of impairment. Any evidence of recurrence of lung cancer mandates retention of a classification of severe impairment. Hypersensitivity Pneumonitis Hypersensitivity pneumonitis may produce no permanent pulmonary impairment if the disease is recognized early in its course and the affected person is removed from exposure to the causative material (usually a high-molecular-weight organic dust, but occasionally, a low-molecular-weight chemical). Even when there has been timely resolution of the pulmonary function abnormality, individuals with a history of hypersensitivity pneumonitis should be permanently removed from exposure. Subacute and chronic forms of the disease caused by repeated exposures often produce pulmonary fibrosis that results in restrictive lung disease. An obstructive component in the subacute and chronic forms of the disease may also be observed. Abnormalities may become permanent features of impairment and should be assessed according to the criteria provided in Table 39-3. Pneumoconiosis Pneumoconiosis resulting from exposure to a variety of inorganic dusts that produce pulmonary fibrosis (e.g., asbestos,

silica, or coal dust), or those producing granulomatous disease and fibrosis (e.g., beryllium), usually alter pulmonary function in a manner that can be assessed by pulmonary function testing and are classified according to criteria provided in Table 39-3. Although not all cases of pneumoconiosis are associated with physiological impairment, the AMA Guides suggest that recognition of a pneumoconiosis should prompt the physician to recommend limitation of further exposure to the causative material. In the cases of silicosis and coal workers’ pneumoconiosis, development of disease depends on the dust burden in the lung and pathological progression that occurs long after exposure has ceased. In fact, the latency period between exposure and disease manifestation is measured in decades, rather than years, so that failure to remove a worker from further exposure to the responsible dusts may progressively increase the risk of worsening disease. Therefore, in order to avoid further accumulation of dust in lung tissue, recognition of radiologic manifestations of these diseases should prompt removal from mining employment, particularly in relatively young individuals. Berylliosis Chronic beryllium disease causing pulmonary fibrosis is mediated by an immune process and is not necessarily dependent on total dust burden in the lung. Regardless of whether a beryllium worker has abnormalities of pulmonary function that fulfill AMA criteria for impairment, once a diagnosis of chronic beryllium disease is made, the evaluating physician should recommend complete cessation of beryllium exposure, since even small amounts may cause further pulmonary fibrosis. Obstructive Sleep Apnea Although individuals with obstructive sleep apnea characteristically have daytime somnolence and may have cognitive defects that make adequate work performance difficult, welldocumented criteria that provide guidance in determining fitness for employment are lacking. The AMA Guides recommend that impairment determination be left to the judgment of a sleep specialist.

AMERICAN THORACIC SOCIETY CRITERIA FOR EVALUATION OF IMPAIRMENT OR DISABILITY The American Thoracic Society (ATS) has published a series of guidelines and official statements regarding performance and interpretation of pulmonary function testing. The last ATS statement that was specifically devoted to the general subject of impairment/disability criteria was published in 1986. Since that time, several updates of portions of the statement dealing with the evaluation of pulmonary function test interpretation and asthma, partially in the context of the evaluation

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of disability, have been published. In general, the AMA has adopted standards of impairment that have been published by the ATS. The ATS assigns severity ratings to specific results of spirometry and diffusing capacity, but it does not assign percentage impairment ratings. According to ATS criteria, pulmonary impairment is considered mild if the FEV1 is greater than 70 percent predicted (but less than the lower limit of normal, based on 95 percent confidence intervals); moderate if it is 60 to 69 percent predicted; moderately severe if it is 50 to 59 percent predicted; severe if it is 35 to 49 percent predicted; and very severe if it is less than 35 percent predicted. On the other hand, FEV1 % predicted does not correlate well with the severity of upper-airway obstruction and may underestimate the severity of obstruction in very severe COPD. Furthermore, FEV1 % predicted correlates poorly with symptoms. The degree of severity of a decrease in diffusing capacity is judged to be mild if the value obtained is less than the lower limit of normal, but greater than 60 percent predicted; moderate if it is between 40 and 60 percent predicted; and severe if it is less than 40 percent predicted. The ATS acknowledges the fact that, in general, the level of pulmonary function is related to the ability to work and function in daily life. The level of pulmonary function is also recognized as having an association with morbidity and prognosis. Standards of impairment evaluation for asthma published by the ATS in 1993 form the basis for impairment ratings adopted in the AMA Guides in 2000. Since that time, the ATS has updated its own guidelines for assessing and managing asthma.

DISABILITY EVALUATION UNDER SOCIAL SECURITY The United States Social Security Administration has two programs that provide financial and rehabilitative benefits to disabled individuals. Both programs require objective demonstration of disability using medical standards set forth in the Social Security Act. Importantly, the standards for disability required by the Social Security Administration are not necessarily the same as those required by other federal programs. Furthermore, while Social Security criteria for disability are uniform across all states, they differ markedly from the criteria developed by each individual state in regard to workers’ compensation programs. In addition, they are quite different from those endorsed by insurance companies from which many people purchase policies. The Social Security Act provides two pathways by which individuals can access disability benefits. The first is through Title II of the act (known as Social Security disability insurance); this is a program that is available to individuals who are insured as a result of their contributions to the Social Security trust fund (through taxes on employment earnings during their work careers). The second is through Title XVI of the act (known as supplemental security income, or SSI); this

Evaluation of Impairment and Disability Due to Lung Disease

program is available to disabled individuals who have limited income or resources but, who, for one reason or another, are not covered by contributions to the Social Security trust fund. For adults, the definition of disability is the same whether application for benefits is made under Title II or Title XVI of the Social Security Act. The Social Security Administration defines disability as “the inability to engage in any substantial gainful activity by reason of any medically determinable physical or mental impairment(s) which can be expected to result in death or which has lasted or can be expected to last for a continuous period of not less than 12 months.” The methods used for disability evaluation under Social Security are important for the physician to understand for two reasons: first, because it is a common and important source of financial support for many patients who are under the care of pulmonary physicians, and second, because the pulmonary physician often takes an active role in helping determine eligibility. Unlike workers’ compensation programs, the cause of disability is not relevant in awarding benefits. The sole criterion for granting benefits is whether or not the claimant is able to participate in gainful employment. Evaluation of disability under Social Security is a staged process, beginning with application to a local Social Security field office or the Office of Disability Determination Services (DDS). The DDS gathers objective medical information primarily from the treating physician (who is the preferred source of medical evaluation). If the available information is insufficient to make a determination of disability, the DDS may purchase additional testing and examination from a consultative examiner (CE), such as a pulmonary physician. The Social Security Administration has decided that certain specific impairments of each major body system are severe enough to prevent a person from engaging in any gainful employment and, therefore, serve as prima facie evidence that disability exists. These impairments have been codified and are known as the Listings of Impairments. Listings include specific severities of abnormalities for various diseases, including COPD; chronic restrictive ventilatory disease; chronic impairment of gas exchange; asthma; cystic fibrosis; pneumoconiosis; bronchiectasis; mycobacterial, mycotic, and other chronic persistent infections of the lung; and cor pulmonale due to chronic pulmonary vascular hypertension. If a claimant cannot meet the severity criteria of the Listings, he or she may still receive award of benefits by presenting the medical information pertinent to his or her case to the DDS. An initial judgment may then be made by the DDS, but the claimant has the right to challenge an unfavorable decision and to have it reviewed by other members of the DDS staff. If the decision is still unfavorable, the claimant may appeal to the Office of Hearings and Appeals for review by an administrative law judge, who may request expert physician testimony before making a decision. Once again, the claimant can request that an unfavorable decision be reviewed by an appeals council.

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Table 39-6

Table 39-7

Social Security Listings for Severity of COPD According to FEV1

Social Security Listings for Severity of Restrictive Lung Disease According to FVC

Height without Shoes (cm)

Height without Shoes (in)

FEV∗1 ≤

Height without Shoes (cm)

Height without Shoes (in)

FVC∗1 ≤

≤154

≤60

1.05

≤154

≥60

1.25

155–160

61–63

1.15

155–160

61–63

1.35

161–165

64–65

1.25

161–165

64–65

1.45

166–170

66–67

1.35

166–170

66–67

1.55

171–175

68–69

1.45

171–175

68–69

1.65

176–180

70–71

1.55

176–180

70–71

1.75

≥181

≥72

1.65

≥181

≥72

1.85

∗ L,

BTPS (liters, body temperature and pressure standardization).

SOCIAL SECURITY LISTINGS An examination of the criteria that determine eligibility for Social Security benefits according to the Listings is helpful in understanding the process.

Chronic Obstructive Pulmonary Disease In order for COPD to fulfill criteria for the Social Security Listings, the measured FEV1 must fall at or below the values shown in Table 39-6.

Asthma Claimants with asthma can meet the Listings criteria either on the basis that they fulfill the pulmonary function abnormalities noted previously for COPD, or because the severity of their disease is such that it requires physician intervention at least six times a year, despite following a prescribed therapeutic regimen. Inpatient hospital treatment lasting more than 24 hours is viewed as equal to two attacks requiring physician attention.

∗ L,

BTPS (liters, body temperature and pressure standardization).

breath DlCO must be less than 10.5 ml/min/mmHg or less than 40 percent of the predicted normal value. Arterial blood gas abnormalities are also considered valid indicators for Social Security Listings, as long as they are performed in the prescribed manner and indicate the required severity of pulmonary disease. Simultaneously, measurements of PaO2 and PaCO2 using arterial blood gas analysis must be performed with the claimant at rest and in stable condition. He or she must be awake and in a sitting or standing position. Furthermore, arterial blood gas analysis must be performed on two occasions which are at least 3 weeks apart but within 6 months of one other. The arterial blood gas results must also be interpreted with recognition of the altitude at which they were obtained. With these requirements in mind, a claimant will meet the Listings if arterial blood gas findings are equal to or less than those shown in Table 39-8. Of note is the fact that according to the Listings, measurement of pulse oximetry is not accepted as prima facie evidence of severe pulmonary disease.

Pneumoconiosis

For chronic restrictive ventilatory disease, the FVC must be equal to or less than the values shown in Table 39-7.

In order for a person to meet the Listings criteria for pneumoconiosis, a radiographic diagnosis must first be made according to appropriate imaging techniques. The severity of the disease is then judged on the basis of the functional deficits shown in Tables 39-6, 39-7, and 39-8, for obstructive disease, restrictive disease, or abnormal gas exchange.

Abnormalities of Gas Exchange

Cystic Fibrosis

In order to reach the severity required for inclusion under the listings for chronic abnormalities of gas exchange, the single

Patients with cystic fibrosis qualify for benefits under the Listings if they have an FEV1 that is less than or equal to the

Restrictive Lung Disease

687 Chapter 39

Evaluation of Impairment and Disability Due to Lung Disease

Table 39-8

Table 39-9

Social Security Listings for Severity of Gas Exchange Abnormalities According to Arterial Blood Gas Results∗

Social Security Listings for Severity of Cystic Fibrosis According to FEV1 Height without Shoes (cm)

Height without Shoes (in)

FEV∗1 ≤

≤154

≤60

1.45

PaCO2 and PaO2 (mmHg) from Column 2 or 3

At altitude ≤3000 ft, PaO2 (mmHg) ≤

At altitude 3000–6000 ft, PaO2 (mmHg) ≤

≤30

155–159

61–62

1.55

160–164

63–64

1.65

165–169

65–66

1.75

170–174

67–68

1.85

175–179

69–70

1.95

≥180

≥71

2.05

≥40

∗ Fulfillment

of blood gas criteria shown denotes severe impairment and qualifies applicant for disability status.

levels listed in Table 39-9; or if they have episodes of bronchitis, pneumonia, hemoptysis, or respiratory failure that require physician intervention at least six times annually (one hospitalization for more than 24 hours counts as two outpatient visits); or if there is persistent pulmonary infection with symptomatic episodes requiring intravenous or nebulized antibiotic therapy at least every 6 months.

Cor Pulmonale Due to Chronic Pulmonary Vascular Hypertension Qualification for benefits under the listings for patients with cor pulmonale requires clinical evidence of the disease and either a measured mean pulmonary artery pressure greater than 40 mmHg or arterial hypoxemia to the levels shown in Table 39-8.

Mycobacterial, Mycotic, and Other Chronic Persistent Infections of the Lung These diseases meet standards for inclusion under the listings only when the degree of functional abnormality reaches the levels outlined previously for obstructive disease, restrictive

∗

L, BTPS (liters, body temperature and pressure standardization).

disease, or abnormalities in gas exchange (Tables 39-6, 39-7, and 39-8).

STATE WORKERS’ COMPENSATION PROGRAMS Until the early part of the twentieth century, US federal and state-based programs to compensate workers for injuries sustained on the job did not exist. The only legal recourse available to a worker injured on the job was to sue his or her employer through the usual tort system of the courts. Such legal proceedings were often heavily weighted in favor of the employer. Worse still, the legal concept of occupation-related disease (as opposed to occupational injury) was not widely recognized by the courts at that time. As the Industrial Revolution became progressively more established in Europe and the United States during mid- and late nineteenth century, however, the problem of workplace injuries and occupation-related diseases became ever more important as large numbers of workers left the farm for urban employment in factories and other industrial environments where they were frequently adversely affected by working conditions. By the late nineteenth century, Great Britain had passed legislation that afforded some protection to injured workers, and a few decades later the United States followed suit by passing legislation modeled on the British system. However, because the US Supreme Court at that time interpreted the US Constitution as forbidding federal legislation from covering private-sector employers, the federal government kept workers’ compensation legislation at arms’ length, leaving each state to work out its own solution to the

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problem. As a result, significant variations occurred from state to state in the details of coverage and management systems for workers’ compensation, with legislation that was enacted at varying times in a pattern that formed what was essentially a patchwork quilt that eventually covered all 50 states. Despite the history of independent development of legislation in each state, certain unifying concepts emerged in the way state programs were crafted. In each state, concepts of coverage were hotly contested on the one hand by powerful industrial concerns and on the other hand by labor unions which had recently found their voice in the formation of a strong labor movement. One of the concepts, finally accepted by all stakeholders, marked a dramatic change in the way claims were handled. In what amounted to an epiphany of understanding between the parties, the interaction between the employer and the injured employee changed from a frankly adversarial relationship to a no-fault system that focused on providing help to the injured employee without consideration of which party was at fault in causing the injury. Both the employer and the employee had to give up certain rights in order to develop a system that would fairly serve all parties. The employee gave up almost all rights to sue the employer for workplace injuries, but, in return, received automatic acceptance of the right to receive free medical care for the immediate injury, cash benefit payments during the period of disability, and rehabilitation services to facilitate a return to work. These services are commonly provided through insurance carriers that sell workers’ compensation policies to employers. Most states require the employer to purchase insurance coverage for their workers, although some states maintain a workers’ compensation pool (which the employer can purchase from the state), and some states allow large companies to self-insure. The employer usually has the right to maintain a panel of physicians who evaluate injured employees. In most states, the employee has the right to choose his or her treating physician, but the rates of payment to the physician may be set by law. If the employee has lost time from work as a result of injury, cash benefits are paid for temporary disability according to a formula that varies from state to state with regard to payment size and period of time allowed for each type of disability. Benefits may be awarded for temporary total disability, permanent partial disability, or permanent total disability. Some cash payments are known as “scheduled” losses if they involve injuries, such as loss of arms, hands, fingers, legs, feet, toes, eyes, and ears, while others are “nonscheduled,” such as injuries to lungs, heart, back, and so forth. Most states use the classification system of the AMA Guides to the Evaluation of Permanent Impairment (described in detail above) to determine the severity of nonscheduled losses.

FEDERAL WORKERS’ COMPENSATION The first legislation to providing workers’ compensation for civilian federal employees to pass the test of constitutionality

by the US Supreme Court was signed into law by President Theodore Roosevelt in 1908. However, this program was extremely limited in both scope and benefits and was restricted to very hazardous jobs. Not until 1916 was more comprehensive legislation covering civilian government employees passed in the form of the Federal Employees’ Compensation Act. The legislation is administered by the Office of Workers’ Compensation Programs. Subsequently, a few additional federal programs were passed by Congress, including the Merchant Marine Act, Longshore and Harbor Workers’ Compensation Act, Black Lung Benefits Act, and Energy Employees’ Occupational Illness Compensation Program Act. The last two programs are of particular interest to pulmonary physicians because the programs deal specifically with occupational lung diseases, and because the criteria for awarding benefits are radically different from one another.

BLACK LUNG BENEFITS The federal Black Lung program grew out of the federal Coal Mine Health and Safety Act of 1969. This act was modified by the Black Lung Benefits Act in 1972, which set eligibility criteria for the award of benefits; the act since has been amended several times. While providing funding for benefits is primarily the responsibility of the mining company responsible for the injury, it is not unusual in the coal mining industry to find that either the company had gone out of business or that no specific mine can be identified as responsible. The Black Lung Benefits Revenue Act, therefore, set up a trust fund, funded by an excise tax on coal that was mined and sold in the United States. Eventually, management of the Black Lung program became the responsibility of the US Department of Labor, administered through the Office of Workers’ Compensation Programs, Division of Coal Mine Workers’ Compensation. A coal miner applying for Black Lung benefits must supply to the Division of Coal Mine Workers’ Compensation medical evidence of pneumoconiosis, including the following: a chest radiograph, along with a report of the findings using the International Labor Organization (ILO) classification system; a report of physical examination detailing the occupational and medical history as well as all manifestations of chronic respiratory disease; pulmonary function test results; and arterial blood gas results. The submitted chest radiograph should fulfill the ILO criteria for radiographic quality and must be interpreted as showing at least category 1/0 pulmonary parenchymal interstitial abnormalities, indicating pneumoconiosis (according to the ILO International Classification of Pneumoconioses). Preferably, the chest radiograph should be interpreted by a NIOSH-certified B Reader or a board-certified or board-eligible radiologist. Pulmonary function tests, recorded as flow-volume loops, must provide measurements of FVC and FEV1 and calculation of the FEV1 /FVC ratio. Measurements of maximal voluntary ventilation (MVV) may also be used to support a claim for disability. Arterial blood gas analysis is initially performed at

689 Chapter 39

rest, but if the results do not fulfill criteria for disability, the study may be repeated during exercise. The Department of Labor has published detailed tables of spirometric and arterial blood gas values delineating criteria for total disability. For example, according to the tables, a 55-year-old male who is 5’ 10” tall is considered totally disabled if the FVC is less than or equal to 2.71 L, or the FEV1 is less than or equal to 2.14 L. At any age or height, the applicant is considered totally disabled if the FEV1 /FVC% is less than or equal to 55 percent, or the PaO2 is 60 mmHg or less (at sea level, with the PaCO2 between 40 and 49 mmHg). Importantly, for the purposes of the Black Lung Benefit Act, pneumoconiosis is defined as “a chronic dust disease of the lung and its sequelae, including respiratory and pulmonary impairments arising out of coal mine employment.” Included in this definition are not only the diseases that chest physicians usually consider as pneumoconioses (e.g., coal workers’ pneumoconiosis, anthracosis, anthracosilicosis, massive pulmonary fibrosis, silicosis, or silicotuberculosis), but also what the act notes as “legal pneumoconiosis” (i.e., any chronic restrictive or obstructive pulmonary disease arising out of coal mine employment).

ENERGY EMPLOYEES’ OCCUPATIONAL ILLNESS COMPENSATION PROGRAM ACT The Energy Employees’ Occupational Illness Compensation Program Act (EEOICPA) was signed into law in 2000 and provides benefits to workers who have acquired disease in the course of their work in the nuclear defense industry. This includes employees and former employees of the Department of Energy at nuclear weapons factories, as well as private contractors and subcontractors who supplied the facilities. The two major toxic exposures encountered by these workers include beryllium (used in the manufacture of ballistic missile nose cones) and radiation. Chronic beryllium disease, as a result of exposure to beryllium dust, produces a granulomatous disease of the lungs that commonly causes progressive pulmonary fibrosis. Radiation exposure is a major cause of cancer, including lung cancer. In contradistinction to Black Lung evaluation, the EEOICPA has adopted the standards of the AMA Guides to the Evaluation of Permanent Impairment as the method of rating impairment and disability.

AMERICANS WITH DISABILITIES ACT Although many physicians think of impairment assessments as inquiries that follow an injury or are conducted at the end of employment, in reality, some of the most important assessments of physical abilities are made at the start of a job. Until relatively recently, people with any type of physical impairment were excluded from employment because of unreasonable fear that an impaired employee would be a

Evaluation of Impairment and Disability Due to Lung Disease

detriment in the workplace. The Americans with Disabilities Act (ADA), which was enacted in 1992, produced a fundamental change in the way physical impairments are viewed within the business and legal communities. Many of the regulations established by the ADA deal with the removal of physical barriers that prohibit impaired workers from entering and functioning within the workplace. Others are specifically directed at removing bias and prejudice from the opportunity to enter the workforce itself. While the ADA has not altered the methods of impairment evaluation used by physicians, it does have a substantial impact on the timing of evaluations and the way these evaluations are reported and used. For instance, while pre-employment physical examinations were commonly requested by industrial and commercial firms prior to enactment of the ADA, they are no longer allowed, due to the perceived risk that a qualified individual might be excluded from employment because of an impairment that has little or nothing to do with the requirements of the job. Prior to making a job offer, employers are no longer allowed to ask if a prospective employee has a physical impairment, although they may ask if he or she can perform the duties of the job. Once a job offer is made and accepted, physical examination is permissible to confirm that the job can be performed in a safe and acceptable manner. In fact, the employer is legally permitted to make a job offer conditional on the applicant passing a physical examination, as long as the same physical requirements are required for every employee in the same job category. These examinations, known as pre-placement physicals, must deal only with job-related issues and must be consistent with business necessity. The other major change in the determination of workrelated physical fitness is that businesses are required to make reasonable accommodation for physical impairments as long as the impairments do not interfere with the essential requirements of the job. The two concepts of forbidding non–job-related impairment to preclude employment and of making reasonable accommodation for the presence of a non-essential disability can be illustrated in the following scenarios. Consider a prospective employee who has severe COPD, with an FEV1 of 50 percent predicted and DlCO of 59 percent predicted; the individual has no history of recurrent infections or excessive absences from work. On the basis of his physical condition, this individual cannot be excluded from a job as an accountant, but he might legally be denied a physically demanding job, such as a firefighter, who must regularly carry heavy equipment into smoke-filled buildings and climb many flights of stairs. The essential work of an accountant does not involve physical exertion, and the applicant’s physical condition would not adversely affect his performance in the workplace. On the other hand, the work of a firefighter would be dangerous to a person with severe pulmonary disease. As a second example, consider a prospective employee who has the same pulmonary function tests as noted in the first scenario. The individual applies for a position in a factory

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Symptoms and Signs of Respiratory Disease

where the main job responsibility is watching the flow of products on a conveyor belt and pressing a stop button if a malfunction arises. Once a day, the employee is required to lift to shoulder height a 75-pound bag. While it would be difficult for the employee to perform the lifting activity, a reasonable accommodation would be either to provide help from another employee, or to install a hydraulic lifting device. Employers are not, however, required to make unreasonably extensive changes to a work area or to undertake “action requiring significant difficulty or expense” in order to accommodate an otherwise qualified applicant.

SUGGESTED READING ACOEM Position Statement: Spirometry in the Occupational Setting. J Occup Environ Med 42:228–245, 2000. American Medical Association: Guides to the Evaluation of Permanent Impairment, 5th ed. Chicago, American Medical Association, 2000. Americans with Disabilities Act of 1990. 42 USC S 12101 et seq. American Thoracic Society: Dyspnea: Mechanisms, assessment, and management: A consensus statement. Am J Respir Crit Care Med 159: 321–340, 1999. American Thoracic Society: Evaluation of impairment/disability secondary to respiratory disorders. Am Rev Respir Dis 133:1205–1209, 1986. American Thoracic Society: Guidelines for assessing and managing asthma risk at work, school, and recreation. Am J Respir Crit Care Med 169:873–881, 2004. American Thoracic Society: Guidelines for methacholine and exercise challenge testing—1999. Am J Respir Crit Care Med 161:309–329, 2000. American Thoracic Society: Guidelines for the evaluation of impairment/disability in patients with asthma. Am Rev Respir Dis 147:1056–1061, 1993. American Thoracic Society/American College of Chest Physicians: ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 167:211–277, 2003.

Astrand PO, Rodahl K: Textbook of Work Physiology, 3d ed. New York, McGraw-Hill, 1986. Babb TG, Viggiano R, Hurley B, et al: Effects of mild-tomoderate airflow limitation on exercise capacity. J Appl Physiol 70:223–230, 1991. Becklake M: Concepts of normality applied to the measurement of lung function. Am J Med 80:1158–1164, 1986. Chan-Yeung M: ACCP Consensus Statement: Assessment of asthma in the workplace. Chest 108:1084–1117, 1995. Federal Coal Mine Health and Safety Act of 1969 (Pub L91– 173), enacted Dec 30, 1969, as amended by the Black Lung Benefits Act of 1972 (Pub L92–3030), enacted May 19, 1972. 20 C.F.R. 410.101 et seq. HankinsonJL, Odincrantz JR, Fedan KB: Spirometry reference values from a sample of the general U.S. population. Am J Respir Crit Care Med 159:179–187, 1999. Harber P, Fedoruk MJ: Work placement and worker fitness: Implications for the Americans with Disabilities Act for pulmonary medicine. Chest 105:1565–1571, 1994. International Labor Office: Guidelines for the Use of the ILO International Classification of Radiographs of Pneumoconioses. Geneva: International Labour Office, 1980. MacIntyre N, Crapo RO, Viegi G, et al: Standardization of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J 26:720–735, 2005. Mahler DA (ed): Dyspnea. New York, Marcel Decker, Inc., 1998. Medical Research Council: Questionnaire on Respiratory Symptoms. London, Medical Research Council, 1966. Miller MR, Crapo R, Hankinson J, et al: General considerations for lung function testing, Eur Respir J 26:153–161, 2005. Miller MR, Hankinson J, Brusasco V, et al: Standardization of spirometry. Eur Respir J 26:319–338, 2005. Pellegrino R, Viegi G, Brusasco V, et al: Interpretive strategies for lung function tests. Eur Respir J 26:948–968, 2005. Seligman PJ, Bernstein IL: Medicolegal and compensation aspects, in Bernstein IL, Chan-Yeung M, Malo JL, et al (eds): Asthma in the Workplace. New York, Decker, 1993, pp 323–340. Social Security Administration: Disability Evaluation under Social Security. SSA Pub No 64-039, ICN 468600, 2003.