Concise Review for Primary-Care Physicians

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1 Concise Review for Primary-Care Physicians This month, we initiate a new feature entitled "Concise Review for Primary-Care Physicians. " These brief reviews on common subjects are intended to be time-saving summaries directed to the entire readership but particularly to primary-care physicians. The goals are to provide practical material and to encourage application of the information by presenting questions that highlight important facts from each review. We welcome suggestions for topics that may be of interest to you. Udaya B. S. Prakash, M.D. Editor-in-Chief Unexplained Dyspnea DELMAR J. GILLESPIE, M.D., PH.D., AND BRUCE A. STAATS, M.D. Dyspnea is a common symptom that is difficult to define and can result from a wide variety of causes. This complex sensation that arises from multiple stimuli involves both subjective perceptions and objective reactions. In the assessment of patients with dyspnea, use of a systematic approach to determine the precipitating factors and the degree of breathlessness is important. Although many diseases may produce dyspnea, two thirds of the cases result from a pulmonary or cardiac disorder. Neuromuscular and psychogenic causes should also be considered. A comprehensive history, physical examination, and basic laboratory tests are important in the initial assessment; however, the diagnosis may depend on specialized testing, the results of which may differ from the initial clinical impression. Initial testing should include electrocardiography, chest roentgenography, hemoglobin determination, thyroid function, and spirometry with use of a bronchodilator. More specialized evaluation includes detailed pulmonary function testing and echocardiography. As shown in our illustrative case, cardiopulmonary exercise testing is important for evaluation of unexplained dyspnea when initial test results are nondiagnostic. Accurate diagnostic data are critical for choosing appropriate treatment. (Mayo Clin Proc 1994; 69: ) IVC = inferior vena cava; Po2 = partial pressure of oxygen The common complaint of dyspnea can be attributable to a wide spectrum of causes. Although dyspnea has no specific definition, it is best described as a subjective sensation of difficult, labored, uncomfortable breathing.1 Most affected patients have a pulmonary or cardiac disorder, but neuromuscular disease is also an important cause. In addition, hyperventilation syndrome due to organic or, more commonly, psychogenic factors is frequently noted in patients with dyspnea. The cause of dyspnea may be evident on the basis of the initial symptoms, findings on physical examination, or abnormalities on screening tests. In some cases, however, a diagnostic dilemma results when symptoms are unexplained after initial assessment. Therefore, a systematic evaluation is necessary to determine the correct diagnosis From the Division of Thoracic Diseases and Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota. Address reprint requests to Dr. D. J. Gillespie, Division of Thoracic Diseases, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN without undue, expensive testing. In this article, we discuss a systematic approach to the evaluation of unexplained dyspnea. REPORT OF CASE A 38-year-old woman had a 5-year history of rest-related tachycardia. She had had episodes of paroxysmal atrial tachycardia without syncope, which were treated with a ß- blocking agent. After a hysterectomy 2 years previously, her symptoms had intensified. Approximately 1 year previously, she had noted exertional anterior chest and back pressure. Currently, because of dyspnea on exertion, she was able to walk only on level ground and do light housework. Echocardiography and pulmonary function studies performed by her local physician showed findings within normal limits. Cardiac disease was considered, and a treadmill exercise study revealed inappropriate tachycardia and decreased maximal oxygen uptake. Right heart catheterization was then performed, and pulmonary artery and pulmonary Mayo Clin Proc 1994;69: / 994 Mayo Foundation for Medical Education and Research

2 658 DYSPNEA Mayo Clin Proc, July 1994, Vol 69 Table 1. Results of Exercise Tests in 38-Year-Old Woman With Unexplained Dyspnea* Factor Load (W) Heart rate (beats/min) Blood pressure (mm Hg) Cardiac output (L/min) Stroke volume (ml/beat) 0 2 uptake (ml/min) Ventilation (L/min) Tidal volume (ml) Po 2 (mm Hg) Pco 2 (mm Hg) Lactate (mmol/l) Rest / Max / , Pred max , %pred max *Max = maximum; Pco 2 = partial pressure of carbon dioxide; Po 2 = partial pressure of oxygen; pred max = predicted maximum capillary wedge pressures were normal. She was referred to our medical center for further assessment. On physical examination, the blood pressure was 125/90 mm Hg, and the pulse was 90 beats/min and regular. Auscultation of the heart showed no remarkable findings, and no abdominal bruits were detected. Results of pulmonary function tests were within normal limits. Echocardiography revealed no evidence of a shunt; the ejection fraction was 70%. A magnetic resonance imaging scan of the chest and abdomen disclosed an enlarged azygos vein. Hepatic venous drainage was abnormal. Diagnostic exercise testing was performed (Table 1). Both the maximal oxygen uptake and the cardiac output response to exercise were profoundly decreased. Because of the normal pulmonary function, normal left ventricular function, and reduced cardiac output, an obstruction of venous inflow to the heart was suspected. A venacavogram demonstrated nonthrombotic obstructed venous return at the level of the proximal inferior vena cava (IVC). A complete workup for thrombosis did not reveal a hypercoagulable state. Dilation of the IVC was attempted by balloon venoplasty. The IVC cross-sectional diameter increased from 4 to 8 mm, and the pressure gradient declined from 24 to 14 mm Hg. Therapy with warfarin was initiated. On follow-up examination, exercise tolerance had improved; the patient was able to walk 3 miles daily without severe dyspnea. Exercise studies were repeated on several occasions, and the cardiac output response increased to a maximum of 9.1 L/min. The maximal oxygen uptake increased to 1,160 ml/min. COMMENT This case, although rare, emphasizes the utility of using specialized testing, such as diagnostic exercise tests, to ascertain the cause of dyspnea. Specifically, the decreased cardiac output was a useful finding that provided direction for treatment of the dyspnea. This type of exercise response has been reported in patients with thrombosed vena caval filters and clips who have complained of dyspnea. 2 Dyspnea is a complex sensation that arises from afferent impulses from various peripheral sensory receptors and higher centers. Therefore, it involves both measurable (objective) stimuli and perceptual (subjective) reactions to these stimuli. Receptors that may contribute to dyspnea are listed in Table Afferent impulses travel diffusely in the spinal nerves and in the sympathetic and parasympathetic nervous systems. Many stimuli are vagally mediated. Although the Table 2. Receptors Hypothesized to Contribute to Dyspnea 3 4 Mechanoreceptors (vagal afferent) Lung Stretch receptors J receptors Respiratory muscles Muscle spindle (intercostal) Golgi tendon organ (diaphragm) Airway (irritant receptors) Chemoreceptors Carotid bodies Aortic bodies Central medullary chemoreceptors Central nervous system Efferent signals to respiratory muscles Vascular receptors Right atrial mechanoreceptors Left atrial mechanoreceptors Pulmonary artery baroreceptors Right ventricular strain receptors

3 Mayo Clin Proc, July 1994, Vol 69 DYSPNEA 659 chemoreceptor responses may be the most thoroughly studied, their effects are not necessarily the most important. The mechanoreceptor effects are difficult to quantify but undoubtedly important, especially in patients with pulmonary disease. Although a wide variety of diseases can result in dyspnea (Table 3), approximately two thirds of patients will have a pulmonary or cardiac cause. 5 In general, pulmonary processes that can cause dyspnea are classified into obstructive airways disease, restrictive disease, or pulmonary vascular disease. Cardiac conditions that are associated with dyspnea are valvular disease, cardiomyopathy, ventricular dysfunction, and pericardial disease. Accurate diagnosis, however, depends on specific results from specialized testing; the final diagnosis may differ from the initial clinical impression. In a study of 100 consecutive patients with chronic dyspnea who were examined in a pulmonary outpatient clinic, 75% had respiratory disorders; the other patients had cardiovascular diseases, gastroesophageal reflux, deconditioning, and psychogenic dyspnea. 5 In many patients, the history and physical examination were nonspecific in suggesting a cause. The most useful diagnostic procedures were chest roentgenography, pulmonary function studies, and bronchoprovocation challenges for interstitial or airway disease and cardiopulmonary exercise testing for psychogenic dyspnea and deconditioning. When dyspnea is unexplained on the basis of the history, physical examination, chest roentgenography, and spirometry, the diagnosis is considerably more difficult. In a study of 72 consecutive patients referred because unexplained dyspnea had been present for more than 1 month, a definite diagnosis could be established in only 81%. 6 Of the 22 conditions associated with the dyspnea, pulmonary disease (36%), psychogenic hyperventilation (19%), and cardiac disease (14%) were the most common. In patients younger than 40 years of age, intermittent symptoms and a normal alveolar-arterial gradient for partial pressure of oxygen (Po 2 ) were related to reactive airways or hyperventilation syndrome. For subjective rating of dyspnea or breathlessness, various methods have been used. These classifications are based on psychophysical testing or clinically perceived grades of breathing difficulty after the patient has been subjected to a respiratory load. Various clinical rating scales have been Table 3. Some Disorders That Cause Dyspnea Pulmonary Airway Airway mass Asthma Bronchiolitis obliterans Chronic bronchitis Laryngeal disease Trachéal stenosis Tracheomalacia Parenchymal Acute alveolitis Drug-induced conditions Emphysema Lymphangitic carcinomatosis Metastatic disease Pneumonitis Pulmonary edema Pulmonary fibrosis Pleural or chest wall Abdominal distention Chest wall injury Effusion Fibrothorax Kyphoscoliosis Pleural mass Pneumothorax Vascular Pulmonary hypertension Thromboembolic disease Vasculitis Veno-occlusive disease Neuromuscular Central nervous system disorders Myopathy and neuropathy Phrenic nerve and diaphragmatic disorders Spinal cord disorders Systemic neuromuscular disorders Cardiac Arrhythmia Coronary artery disease Intracardiac shunt Left ventricular failure Myxoma Pericardial disease Valvular disease Other Anemia Deconditioning Gastroesophageal reflux Hyperthyroidism or hypothyroidism Metabolic acidosis Psychogenic

4 660 DYSPNEA Mayo Clin Proc, July 1994, Vol 69 developed: the Medical Research Council scale, which uses a 5-point intensity rating (Table 4); the Oxygen-Cost Diagram, which is a vertical 100-mm line that represents graded activity levels; and the Baseline Dyspnea Index, which uses three categories based on functional impairment, magnitude of task, and magnitude of effort. 7 Psychophysical testing includes the Borg scale (a 15-grade and a revised 10-grade scale) 8 (Table 4) and the Visual Analogue Scale, which consists of a 100- to 150-mm horizontal scale, ranging from no breathlessness to maximal breathlessness. In addition, the American Thoracic Society has composed a questionnaire for rating breathlessness. 3 In general, clinical rating scales correlate with cardiopulmonary function. An excellent use of these scales is in assessing a change in dyspnea after a therapeutic intervention. INITIAL ASSESSMENT For assessing a patient with dyspnea, the physician should ascertain the specific activities that cause breathlessness for example, washing walls, vacuuming, shoveling, or walking. Simply asking whether a patient is ever short of breath is insufficient; the precipitating activities and the degree of dyspnea are important. The diagnosis may be evident from the history, physical examination, or basic laboratory testing. The initial assessment should include eliciting a comprehensive history, documenting exposures (workplace, farm, hobbies, animals, and birds), reviewing the medication history (including drug-induced pulmonary conditions), and inquiring about past medical diseases, trauma, and surgical procedures. A detailed physical examination is helpful in distinguishing pulmonary dysfunction from cardiac conditions. Neuromuscular diseases and chest wall disorders also should be considered. Screening laboratory studies should include electrocardiography (arrhythmias, ischemia), chest roentgenography (pulmonary, cardiac, and chest wall abnormalities; position of diaphragm), hemoglobin concentration (anemia), thyroid function (hyperthyroidism and hypothyroidism), and spirometry with use of a bronchodilator, including maximal voluntary ventilation (airways disease). If no cause of dyspnea is disclosed by these initial tests, more specific testing is indicated, depending on the suspected cause (Table 5). SPECIFIC TESTING Obstructive Disease. If bronchospasm is suspected and findings on spirometry are normal, bronchoprovocation testing can be done by performing spirometry before and after a challenge with methacholine, cold air, or exercise. In unusual cases of dyspnea accompanied by stridor, the flowvolume curve may also be helpful. In a variable extra- Table 4. Examples of Classification of Dyspnea 7 8 Grade Definition Modified Medical Research Council dyspnea scale 0 Not troubled with breathlessness except during strenuous exercise 1 Troubled by shortness of breath when hurrying on the level or walking up a slight hill 2 Because of breathlessness, walks slower on the level than other people of the same age, or must stop for breath when walking at own pace on the level 3 Stops for breath after walking approximately 100 yards (91.5 m) or after a few minutes of walking on the level 4 Too breathless to leave the house or breathless when dressing or undressing Revised Borg scale* Very severe Nothing at all Very, very slight (just noticeable) Very slight Slight Moderate Somewhat severe Severe Very, very severe (almost maximal) Maximal Definitions for Borg scale describe degree of dyspnea. thoracic obstruction, the peak on the inspiratory curve will be flattened; a variable intrathoracic obstruction produces a flattened peak on the expiratory curve, and a fixed airway obstruction produces flattened inspiratory and expiratory curves. When measured at mid-vital capacity, the ratio of maximal expiratory and maximal inspiratory flow averages 2.3 for variable extrathoracic, 0.3 for variable intrathoracic, and 0.9 for fixed airway lesions. 9 Restrictive Disease. A restrictive disorder is characterized by decreased total lung capacity (preferably determined by body plethysmography) and suggests a parenchymal process, chest wall restriction, or diaphragmatic dysfunction. The carbon monoxide diffusing capacity of the lungs is useful for determining whether a parenchymal or vascular abnormality is present. This value must be corrected for hemoglobin concentration because anemia may be present. Pulse oximetry during rest and exercise can be used for screening for disorders of gas exchange. Occasionally, the pulse oximeter can be inaccurate; 10 thus, arterial blood gases remain the standard determinations for substantiating abnormal gas exchange. Generally, a widened alveolar-arterial Po 2 gradient is an indicator of lung disease. Although maxi-

5 Mayo Clin Proc, July 1994, Vol 69 DYSPNEA 661 Table 5. Specific Testing for Unexplained Dyspnea common finding. Angina may limit the duration of the exercise test. Deconditioning, a potentially reversible process, results in a decreased maximal oxygen uptake but normal gas exchange and breathing reserve. During exercise, the heart rate, cardiac output, and blood pressure response should increase normally. Occasionally, distinguishing decondiruimunary Flow-volume curves Total lung capacity Carbon monoxide diffusing capacity of the lungs Oximetry or arterial blood gases during exercise Bronchoprovocation testing Maximal inspiratory and expiratory respiratory pressures Vascular Ventilation-perfusion lung scanning Venous studies of the legs Cardiac Echocardiography Additional procedures for difficult cases Cardiopulmonary exercise testing Monitoring of cardiac rhythm Radionuclide cardiac studies Right or left heart catheterization (or both) Pulmonary angiography High-resolution computed tomographic scanning of chest Lung biopsy (transbronchoscopic, thoracoscopic, or open) Monitoring of esophageal ph (24-hour study) mal inspiratory and expiratory respiratory pressures can be used to diagnose a restrictive process due to a neuromuscular disorder, these values must be interpreted with caution because submaximal effort can also yield low values." When a major obstructing airway lesion has been excluded, a clue to neuromuscular weakness on spirometry is reduction of the maximal voluntary ventilation out of proportion to the forced expiratory volume in 1 second; however, this measurement is also effort dependent. 12 Pulmonary Vascular Disease. Pulmonary hypertension, often due to chronic pulmonary emboli, must be considered in patients with dyspnea. Frequently, pulmonary hypertension is associated with subtle clinical signs, including an increased pulmonary second sound, right ventricular lift, and right ventricular gallop. Although a decrease in the diffusing capacity for carbon monoxide is usually noted, normal values have been reported. 13 The alveolar-arterial Po 2 gradient during exercise is usually increased. If pulmonary emboli are suspected, a ventilation-perfusion scan of the lungs and venous studies of the legs (impedance plethysmography, ultrasonography, or venography) should be considered. Ultimately, right heart catheterization for measuring pulmonary pressures and pulmonary angiography may be necessary. Cardiac Disease. Echocardiography is useful for assessing most cardiac diseases that cause dyspnea. Common abnormalities that can be diagnosed include mitral and aortic valve disease, "restrictive" physiologic processes, pericardial disease (effusion and tamponade), ventricular dysfunction, and, rarely, atrial myxoma or cor triatriatum. Occasionally, radionuclide studies of left ventricular function or monitoring of cardiac rhythm is worthwhile. At times, cardiac catheterization and coronary angiography are needed to confirm cardiac dysfunction. In some patients, dyspnea may be an anginal equivalent. ADDITIONAL TESTING Cardiopulmonary Exercise Testing. If the diagnosis remains unclear and the dyspnea is disproportionate to findings, cardiopulmonary exercise testing is useful. It will help determine whether a cardiac or pulmonary abnormality exists and, if not, whether the symptoms relate to deconditioning or psychogenic factors. Exercise testing will reveal the level of fitness and, if decreased, which organ system is predominantly responsible. Variables routinely assessed are the blood pressure, electrocardiographic tracing, heart rate, ventilation, oxygen saturation, oxygen uptake, and carbon dioxide output. If previous abnormalities in gas exchange were confirmed or suspected, arterial blood gases should be determined at intervals during the study. In addition, if cardiac dysfunction is a consideration, cardiac output can be measured by the acetylene method or the carbon dioxide rebreathing technique. 14 The expected responses to exercise in patients with various conditions are summarized in Figure 1. In general, patients with obstructive pulmonary disease have a decrease in maximal oxygen uptake and an increase in the ratio of maximal exercise ventilation to maximal voluntary ventilation. Exercise limitation results because the ventilatory requirement is increased while the ventilatory capacity is reduced. Patients with interstitial restrictive lung disease have abnormalities of both gas exchange and pulmonary mechanics, increased ventilation above expected workload requirements, increased dead space, and progressive hypoxemia. Patients with cardiac diseases (valvular and cardiomyopathies) have a lower maximal heart rate than expected. Diminished cardiac output results in decreased maximal oxygen uptake and anaerobic metabolism at low workloads. Ventilation is usually higher than expected, but breathing reserve is normal. In addition, the blood pressure response may be blunted during exercise, and electrocardiographic abnormalities may occur. Hypoxemia, however, is an un-

6 662 DYSPNEA Mayo Clin Proc, July 1994, Vol 69 Variable Normal Mild Mod Severe Fibrosis Vas Cardiac Decond Max heart rate N N N { j N lo { N VQ 2 max N N { j\ \\ \ to {{ \ to Cardiac output N N N N N I I to H N Ventilation/work N f tt tt tt tt t Anaer threshold N N???? to { { V E max/mw < > <0.6 <0.6 <0.6 PaQ 2 N { U H U N N A-a DO 2 N f ff ff ff f N VD/VT N f f ff ff ff t N N Fig. 1. Classic responses to exercise in normal subjects and in patients with various diseases or conditions. A-a D0 2 = alveolar-arterial difference in partial pressure of oxygen; Anaer = anaerobic; COPD = chronic obstructive pulmonary disease; Decond = deconditioning; Max = maximal; Mod = moderate; MW = maximal voluntary ventilation; N = normal; Pa0 2 = partial pressure of oxygen; Pulm vas = pulmonary vascular disease; VD/VT = ratio of volume of dead space to tidal volume; V E max = maximal expired volume per unit time; Vo 2 max = maximal oxygen consumption per unit time. tioning from mild cardiac disease is difficult, and further cardiac evaluation may be considered. High-Resolution Computed Tomography. Computed tomographic scanning of the chest with use of maximal spatial resolution techniques can show specific details of lung disease. 15 In selected cases, this procedure may be useful in defining subtle interstitial changes or unsuspected emphysema that may be contributing to dyspnea. Lung Biopsy. Rarely is lung tissue needed to determine the cause of dyspnea. If a biopsy specimen is necessary, tissue should be obtained by transbronchoscopic techniques or by thoracoscopy, and an open thoracotomy should be avoided if possible. Esophageal ph Monitoring. Occasionally, gastroesophageal reflux and aspiration have been shown to be associated with dyspnea. 45 This relationship can be confirmed by performing 24-hour esophageal ph monitoring. CONCLUSION Dyspnea can result from a wide variety of diseases or disorders. Diagnosing the cause of dyspnea can be challenging, but using a logical diagnostic approach, including a thorough history and physical examination, frequently establishes the etiologic mechanism and thus helps direct therapeutic options. REFERENCES 1. Tobin MJ. Dyspnea: pathophysiologic basis, clinical presentation, and management. Arch Intern Med 1990; 150: Miller TD, Staats BA. Impaired exercise tolerance after inferior vena caval interruption. Chest 1988; 93: Altose MD. Assessment and management of breathlessness. Chest 1985; 88(Suppl 2):77S-83S 4. Wasserman K, Casaburi R. Dyspnea: physiological and pathophysiological mechanisms. Annu Rev Med 1988; 39: Pratter MR, Curley FJ, Dubois J, Irwin RS. Cause and evaluation of chronic dyspnea in a pulmonary disease clinic. Arch Intern Med 1989;149: DePaso WJ, Winterbauer RH, Lusk JA, Dreis DF, Springmeyer SC. Chronic dyspnea unexplained by history,

7 Mayo Clin Proc, July 1994, Vol 69 DYSPNEA 663 physical examination, chest roentgenogram, and spirometry: 11. analysis of a seven-year experience. Chest 1991 ; 100: Mahler DA, Rosiello RA, Harver A, Lentine T, McGovern 12. JF, Daubenspeck JA. Comparison of clinical dyspnea ratings and psychophysical measurements of respiratory sensation in obstructive airway disease. Am Rev Respir Dis 1987; : Borg GAV. Psychophysical bases of perceived exertion. Med Sei Sports Exerc 1982;14: Miller RD, Hyatt RE. Evaluation of obstructing lesions of the 14. trachea and larynx by flow-volume loops. Am Rev Respir Dis 1973; 108: Council on Scientific Affairs, American Medical Association. The use of pulse oximetry during conscious sedation. JAMA 1993;270: Black LF, Hyatt RE. Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1969;99: Enright PL, Hyatt RE. Office Spirometry: A Practical Guide to the Selection and Use of Spirometers. Philadelphia: Lea& Febiger, 1987: Kapitän KS, Buchbinder M, Wagner PD, Moser KM. Mechanisms of hypoxemia in chronic thromboembolic pulmonary hypertension. Am Rev Respir Dis 1989; 139: Staats BA. Dyspnea heart or lungs? Int J Cardiol 1988; 19:13-17 Swensen SJ, Aughenbaugh GL, Douglas WW, Myers JL. High-resolution CT of the lungs: findings in various pulmonary diseases. AJR Am J Roentgenol 1992; 158: Questions About Unexplained Dyspnea (See article, pages 657 to 663) Note: One or more answers may be correct. 1. Dyspnea can be rated subjectively by: a. The Medical Research Council scale b. The maximal attainable heart rate c. The Baseline Dyspnea Index d. Results of cardiopulmonary exercise testing e. The distance walked in 6 minutes 2. In patients younger than 40 years of age with intermittent dyspnea and a normal alveolar-arterial Po 2 gradient, the most likely diagnosis is: a. Cardiac valvular disease b. Restrictive lung disease c. Reactive airways d. Pulmonary hypertension e. Diaphragmatic dysfunction 3. Cardiopulmonary exercise testing routinely measures: a. Blood pressure, ventilation b. Nitrogen washout c. Pulmonary dead space d. Oxygen uptake, heart rate e. Arterial blood gases, cardiac output 4. Dyspnea can result from: a. Hypothyroidism b. Drugs c. Abdominal distention d. Coronary artery disease e. Gastroesophageal reflux f. All of the above 5. Dyspnea is best described as: a. Chest tightness or pressure b. Air hunger c. Rapid breathing d. Difficult, labored, or uncomfortable breathing e. Shallow breathing Correct answers: ρς /> p'd 3-z ο'ό\