Abstract: Shortness of breath is a common complaint associated with a number of conditions. Although the results of the history and physical examination, chest radiography, and spirometry frequently identify the diagnosis, dyspnea that remains unexplained after the initial evaluation can be problematic. A stepwise approach that focuses further testing on the most likely diagnoses is most effective in younger patients. Early bronchoprovocation challenge testing is warranted in younger patients because of the high prevalence of asthma in this population. Older patients require more complete evaluation because of their increased risk of multiple cardiopulmonary abnormalities. For patients who have multiple contributing factors or no clear diagnosis, cardiopulmonary exercise testing can help prioritize treatment and focus further evaluation. (J Respir Dis. 2006;27(1):10-24)
Dyspnea, the experience of breathing discomfort, is a common and complex problem that can be caused by multiple organic and psychosocial factors.1 Patients with chronic dyspnea have symptoms that last at least 3 weeks and are generally considered to have unexplained dyspnea if the cause cannot be identified after the initial history, physical examination, and screening tests.
In this article, we will provide a systematic, timely, and cost-effective approach to the assessment of dyspnea.
A STEPWISE APPROACH
A summary of the conditions associated with chronic dyspnea is displayed in Table 1.2-5 Multiple causes have been identified in up to one third of patients.6 The evaluation of dyspnea starts with a clinical assessment that guides the stepwise selection of tests that can accurately detect or exclude common associated conditions. An approach that combines strategies outlined by previous authors is summarized in Table 2.7-10
Step 1: Initial assessment
The initial clinical assessment includes a thorough history and physical examination. Although few would argue with this approach, it is important to recognize that history and physical examination findings alone have a limited predictive value in the diagnosis of chronic dyspnea.2 Isolated findings should therefore be interpreted with caution.
The addition of a chest radiograph to the initial clinical assessment has been shown to provide reasonable diagnostic accuracy for common conditions, including chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), and congestive heart failure.2 Chest radiographic abnormalities are relatively uncommon in otherwise healthy young adults with dyspnea; sarcoidosis is the most common cause of abnormal findings in this setting.5 The diagnostic yield of a chest radiograph increases with age, as the prevalence of obstructive and interstitial lung diseases, cancer, and their complications increases.
If available, screening spirometry can rapidly identify the presence of obstructive lung disease in young adults in whom asthma is clinically suspected and in older persons who have risk factors for COPD. Examination of the flow-volume loop for evidence of variable or fixed airway obstruction is an important part of this assessment, because conditions associated with these abnormalities can otherwise go undiagnosed despite extensive subsequent testing.
Pulse oximetry at rest or during ambulation can be included in the initial assessment to rapidly and noninvasively evaluate pulmonary gas exchange. Its major uses are to confirm normal oxygen saturation in patients at low risk for oxygen transport abnormalities and to identify a need for supplemental oxygen in patients with known cardiopulmonary disease.
Step 2: Focused testing
If the initial assessment fails to identify a clear diagnosis, further focused testing must be performed. Tests should be selected based on their ability to confirm or exclude common conditions and other possible diagnoses identified through the initial assessment. A focused approach is most effective in younger patients, in whom the possible causes of dyspnea are generally limited. As patients age, the differential diagnosis broadens, with cardiovascular disease becoming a more significant concern. Because of the increased risk, the approach to the older patient who has dyspnea must be more systematic and complete.
Dyspnea in young patients is commonly caused by asthma, vocal cord dysfunction, deconditioning, or psychiatric disorders.3,5 We favor bronchoprovocation challenge (BPC) testing as the next diagnostic step in young persons, because of the high prevalence of asthma in this population. Methacholine is a cholinergic agent commonly used in this setting, and it has a well-established safety profile.11
BPC results must be carefully interpreted based on patient response-specifically, the dose of methacholine required to decrease the forced expiratory volume in 1 second by 20% or more, or PC20. The advantage of BPC using methacholine lies in its negative predictive value (over 90% with a PC20 greater than 8 to 25 mg/mL and a pretest probability of 30% to 70%) and its ability to diagnose asthma in a population in whom the prevalence of this disease is high. A low PC20 has a high post-test certainty (90% to 98% with a pretest probability of 20% to 80% and a PC20 less than 1 mg/mL). The clinical interpretation of borderline airway hyperreactivity (PC20 of 4 to 16 mg/mL), however, must be approached with caution because of the high frequency of false positives that occur in this range.11
Vocal cord dysfunction is characterized by paradoxical adduction of the vocal cords during inspiration. This condition has been demonstrated in 10% to 15% of young patients evaluated for exertional dyspnea and in 40% of patients who sought evaluation for asthma that was unresponsive to aggressive therapy.5,12 In the largest published series to date, 56% of patients with vocal cord dysfunction were found to have objective evidence of asthma, underscoring the fact that these conditions are not mutually exclusive.13 Vocal cord dysfunction has been characterized as a form of conversion disorder and is commonly associated with a variety of psychiatric conditions, postnasal drip, and gastroesophageal reflux disease; it is most likely to occur in young, single women.13
Truncation of the inspiratory limb of the flow-volume loop is a characteristic finding in vocal cord dysfunction, but it is present in only 23% of patients who do not have acute symptoms.13 Flow-volume abnormalities can be precipitated by BPC testing in 60% of patients with vocal cord dysfunction14 or by exposure to inciting activities or triggers (such as perfumes, cold air, exercise).15 The gold standard for diagnosis is observation of anterior vocal cord adduction during inspiration alone or during both inspiration and expiration accompanied by a residual posterior glottic "chink" during laryngoscopy (Figure 1).
Since older patients are at increased risk for multiple cardiopulmonary abnormalities, they should undergo screening electrocardiography and more complete pulmonary function testing if the results of screening spirometry are abnormal. Resting ECG changes in patients with clinical risk factors for coronary artery disease have been shown to be of predictive value.16 A stress test or echocardiogram is a reasonable next step in this setting, especially if the patient's symptoms are out of proportion to pulmonary findings.
The aging process causes a gradual deterioration of lung function throughout adult life.17 Decreased lung elasticity, increased chest wall stiffness, and decreased respiratory muscle strength can result in significant changes in pulmonary function.18 These changes may be accelerated by tobacco use or other exposures.
Asthma remains an underdiagnosed and undertreated condition in patients older than 65 years, and it is important to consider this disease in older persons with suggestive symptoms. In one large cohort study, more than 15% of older persons reported symptoms of possible or probable untreated asthma,19 resulting in reduced quality of life and increased morbidity.
Pulmonary function testing in older patients with dyspnea therefore must be more complete. In our pulmonary function laboratory, these patients undergo pre- and post-bronchodilator spirometry and measurement of lung volumes, carbon monoxide-diffusing capacity, and arterial blood gases (ABGs) as part of a standard dyspnea evaluation.
Maximum voluntary ventilation, maximum inspiratory pressure, and maximum expiratory pressure can be measured in patients with a clinical history or pulmonary function test results that suggest neuromuscular weakness. A recent comprehensive review of pulmonary function testing provides an excellent reference for a more detailed discussion on this topic.20
Screening hemoglobin/hematocrit should be considered in high-risk populations. African Americans, Native Americans, immigrants from developing countries, pregnant women, and persons of low socioeconomic status are at highest risk for iron deficiency anemia in the United States.21 The risk of anemia in older persons is largely based on comorbid conditions, such as chronic kidney disease and occult colon cancer.
Although current guidelines do not support screening asymptomatic persons for thyroid disease, some authors continue to suggest that thyroid-stimulating hormone screening in persons at high risk for mild thyroid failure is cost-effective, based on computer decision models. Thyroid disease is most common in older and postpartum women; patients in geriatric units, acute hospital medical wards, and psychiatric wards; and patients with autoimmune antibodies.22
A renal panel can identify metabolic acidosis and volume overload from chronic kidney disease, which are well-documented causes of chronic dyspnea. Hypertension, diabetes, and older age are major risk factors for chronic kidney disease; these risk factors are also more prevalent in the African American population.23
Step 3: Cardiopulmonary exercise testing
There are several limitations to the initial and focused evaluations outlined above. Resting cardiopulmonary measurements have been shown to correlate poorly with symptoms during exertion, and they cannot reliably predict exercise performance and functional capacity. Cardiopulmonary exercise testing (CPET) provides an objective and reproducible measurement of functional capacity (oxygen consumption, or V.O2max) and can identify the main cause(s) of symptoms in patients with multiple contributing conditions.
For patients whose dyspnea remains unexplained after Steps 1 and 2, incorporating CPET into the decision-making process can be a cost-effective and useful way to identify the exercise response pattern, focus further diagnostic testing, and provide objective measurements that can be used to assess clinical outcomes of therapy.24
A cycle ergometer is generally preferred for CPET, to minimize motion artifact and provide a direct measurement of work rate. Commercially available CPET systems process 4 primary signals-airflow, oxygen, carbon dioxide, and heart rate. These signals form the basis for all measured and derived CPET variables, including V.O2, carbon dioxide output, and minute ventilation (VE). Pulse oximetry, standard-interval 12-lead electrocardiography, and blood pressure are also monitored during a standard symptom-limited CPET. ABG measurements can be added to provide more accurate information on pulmonary gas exchange.
The patient's symptoms during exercise coupled with objective measurements using a standardized dyspnea rating scale also provide vital information. Exercise flow-volume loop analysis is an evolving technology that can give important insight into breathing strategies when it is correlated with symptoms of dyspnea during exercise. A summary of important CPET variables is provided in Table 3.
CPET can be performed using a symptom-limited incremental or constant work protocol. An incremental exercise test consists of 3 minutes of rest, 3 minutes of unloaded pedaling, an 8- to 12-minute exercise phase in which work rate is continuously increased until peak exercise is reached, and 10 minutes of recovery.
The constant work protocol is commonly performed about 1 hour after incremental testing and consists of 6 to 10 minutes of continuous exercise using 70% to 80% of the previously achieved maximum work rate; ABGs are measured at rest and at 5 minutes. Constant work exercise can provide valuable information regarding gas exchange and has been demonstrated to be more sensitive than a 6-minute walk test in determining therapeutic efficacy of pharmacologic interventions.24
CPET interpretation requires a systematic approach that reviews the reason(s) for and overall quality of the test, identifies key variables and graphic relationships to determine normal and abnormal exercise response patterns, and considers conditions that may be associated with these patterns.24,25
Step 4: Specialized testing based on exercise response patterns
CPET is a sensitive method of identifying the mechanisms and severity of the patient's exercise limitation. The observed exercise response pattern allows the interpreting clinician to focus on a limited differential diagnosis for further testing and treatment.9
• Normal exercise response: Normal CPET demonstrates a normal exercise capacity with normal cardiac and respiratory responses to exercise. At peak exercise, healthy persons approach their maximum predicted heart rate and oxygen pulse and have significant physiologic breathing reserve. Gas exchange tends to improve with exercise, and oxygen saturation remains stable throughout the test. A normal exercise response provides reassurance that no significant functional abnormalities exist and frequently obviates the need for further testing.
Patients who have psychogenic causes of dyspnea may have normal CPET findings; these findings should not discourage psychiatric referral if the patient provides a suggestive clinical history. Patients who have gastroesophageal reflux disease may also have a normal exercise response pattern. These patients may be treated with an empiric trial of acid suppression therapy, with referral for further gastroenterologic evaluation and endoscopy if symptoms persist.
• Hyperventilation/psychogenic disorders: As noted above, patients with psychogenic causes of dyspnea often have normal or near-normal exercise tolerance. Abnormal breathing patterns at rest and during exercise should increase clinical suspicion and, in some circumstances, can be diagnostic. In contrast to the gradual increase in respiratory frequency during progressive exercise in healthy persons, patients who have hyperventilation syndrome may have an abrupt onset of regular, rapid, shallow breathing that is disproportionate to the level of metabolic stress (Figure 2).
Patients with hyperventilation syndrome can have a variety of psychogenic disorders. They commonly complain of "asthma-like" symptoms of dyspnea, chest pain, and light-headedness with exertion and may have a history of substance abuse or multiple somatic complaints. Anxiety and stress are among the several postulated mechanisms for hyperventilation, and both treatment of the underlying psychiatric disorder and behavioral modification techniques can be very successful in this otherwise challenging disorder.26,27
• Obesity: A spectrum of exercise responses can be seen in obese patients. Exercise capacity may be normal or low, and it will be even lower with significant obesity when expressed per kilogram of actual body weight (V.O2max/kg). The increased metabolic requirements of moving the excess weight during exercise results in a disproportionately increased V.O2, heart rate, and VE at any given level of work. Coronary ischemia and diastolic dysfunction are commonly associated with obesity and must be carefully excluded during CPET evaluation. Once other causes of dyspnea are excluded, obese patients should be enrolled in a weight reduction/aerobic training program and monitored for symptom improvement.
• Cardiac/ischemia: Patients with a cardiac/ischemia response pattern on CPET may have problems with the heart or the pulmonary or systemic circulation, or reduced oxygen delivery resulting from significant anemia. Exercise capacity is reduced, and anaerobic threshold is low as a result of the early onset of lactic acidosis. During exercise, heart rate is elevated and oxygen pulse is low, which is a surrogate marker of inadequate stroke volume augmentation during exercise.
An ECG may show evidence of cardiac ischemia if coronary artery disease is present. Ample ventilatory reserve is generally present, although gas exchange abnormalities may be observed if significant pulmonary hypertension is present.
Patients with suspected cardiac ischemia should be given empiric -blocker and aspirin therapy while further cardiac evaluation is performed. Monitoring response to therapy after risk stratification and coronary intervention is important, because continued symptoms may suggest additional diagnoses that require further evaluation.
Patients with a cardiac/ischemia response pattern and gas exchange abnormalities need to be assessed for pulmonary hypertension. Treatment of the underlying condition is generally the only management necessary for secondary pulmonary hypertension associated with such conditions as lung disease, obstructive sleep apnea, or left ventricular dysfunction.
Patients without such conditions need further assessment to exclude pulmonary arterial hypertension (PAH), including evaluation for connective-tissue disease, chronic venous thromboembolism, congenital heart abnormalities, cirrhosis, cocaine or methamphetamine use, and HIV infection. Echocardiography remains an effective screening tool for these patients, but individuals with clinically significant PAH and/or progressive symptoms need invasive studies, including a right heart catheterization and vasodilator study, before being considered for medical treatment.
• Cardiac/deconditioning/mitochondrial myopathy: An exercise response pattern associated with deconditioning has many similarities to early or mild heart disease. The similarities between deconditioning and early heart disease make this exercise response pattern particularly challenging to distinguish. Because diastolic dysfunction and electrically silent coronary disease are common, we recommend an echocardiogram as the next step to evaluate for left ventricular dysfunction or focal wall motion abnormalities. Patients with a normal echocardiogram should be given an exercise prescription based on CPET results and monitored for clinical response.
If the patient's exercise capacity remains significantly limited following the completion of an intensive exercise program, a mitochondrial myopathy should be considered. Although uncommon, the prevalence of metabolic myopathy was found to be 8.5% in one series of unexplained dyspnea referrals to a tertiary care specialty clinic. The observed exercise pattern is the result of abnormal peripheral muscle oxygen use, although concomitant deconditioning is commonly present and can confound the diagnosis. A muscle biopsy can confirm the diagnosis.28
• Respiratory disease: Patients with evidence of respiratory disease on CPET can demonstrate a wide variety of exercise patterns depending on the predominant mechanism of exercise limitation and disease severity. In early obstructive lung disease, CPET responses may be normal, but exercise flow-volume loops can demonstrate expiratory flow limitation. Postexercise spirometry after CPET can identify postexercise bronchospasm in patients who have occult asthma or are receiving inadequate asthma therapy.
Patients with moderate to severe COPD demonstrate reduced exercise tolerance with decreased breathing reserve, suggesting a ventilatory limitation to exercise. Anaerobic threshold may be normal or low if deconditioning and skeletal muscle dysfunction are present; there usually is significant cardiovascular reserve. Exercise flow-volume loops demonstrate dynamic hyperinflation, reduced inspiratory capacity, and expiratory flow limitation (Figure 3). Gas exchange abnormalities are generally present because of increased dead space and ventilation/perfusion mismatch.
Patients with exercise-limiting obstructive lung disease should be treated according to current practice guidelines. Patients with post-exercise bronchospasm should have their asthma regimen intensified, with regular administration of a short-acting bronchodilator before exercise.29,30
In addition to appropriate bronchodilator therapy and oxygen, patients with clinically significant COPD should be considered for referral to a pulmonary rehabilitation program. Deconditioning is common in patients with COPD; combined with new evidence of muscle wasting resulting from systemic oxidative stress and inflammatory mediator release, this emphasizes the fact that exercise limitation in these patients is usually multifactorial. Pulmonary rehabilitation has been shown to improve exercise capacity, reduce health care use, and improve quality of life.31
Patients with ILD generally have reduced exercise capacity and anaerobic threshold. A cardiac response pattern may be more common than previously recognized in diseases such as idiopathic pulmonary fibrosis; however, a ventilatory pattern characterized by a reduced breathing reserve and rapid shallow breathing may also be seen in ILD, accompanied by evidence of inefficient ventilation, increased dead space, and marked gas exchange abnormalities.
The evaluation of ILD requires an integrated approach that includes a careful clinical history, high-resolution CT scanning, bronchoscopy and, frequently, surgical lung biopsy.32
EVALUATING TREATMENT OUTCOMES
Dyspnea is a common problem that consumes significant health care resources, making it an ideal subject for the development of systematic disease management strategies. An important aspect of disease management is the ability to measure and report outcomes.33 However, outcomes measurements in patients with dyspnea have been problematic, because of the complexity of the condition and the diversity of the patients that it affects.
The sensation of dyspnea can be triggered by a variety of different disease states and pathophysiologic mechanisms, several of which can coexist in any given patient. The perception of dyspnea can also vary based on the patient's gender, ethnicity, and physical expectations.
The major goals of dyspnea measurement are to effectively differentiate patients by symptom severity and to objectively evaluate the response to treatment. A variety of methods have been developed to address these goals. The first clinical rating scales, which were developed by the Medical Research Council and American Thoracic Society, focused only on specific physical tasks that provoked breathlessness.34,35
The Baseline and Transition Dyspnea Indexes (BDI/TDI) and the dyspnea component of the Chronic Respiratory Questionnaire are several of the more commonly used multidimensional tools available for clinical assessment, and they include measurements of patient effort and functional impairment.36,37 Although these are validated clinical tools, further investigation is necessary to determine whether the discriminative capacity of these scales is reduced when applied to women and different ethnic populations.
Objective measurements of exercise capacity using CPET and 6-minute walk distance are attractive options for differentiating physiologic impairment and evaluating responses to therapy. Limitations in their discriminative capacity lie in the accuracy of normal reference values between population subgroups and in the effort-dependent nature of these measurements. The visual analog scale and Borg scales are commonly used to assess patient effort during testing, and they have been found to be effective in quantifying changes after specific interventions.24
A variety of health-related quality-of-life measurements have been developed to quantify the impact of disease on a patient's health or well-being. These tools can be generic (Sickness Impact Profile, Nottingham Health Profile) or disease-specific (St. George's Respiratory Questionnaire, Asthma Quality of Life Questionnaire).
Although these tools can provide significant insight into the functional status of patients and populations, their use is limited by their overall poor correlation with objective measures of physiologic impairment and the need for further work to establish thresholds of clinical significance in different populations. More work is clearly needed to further develop effective outcomes measures to use in a global strategy of dyspnea management.38
Dyspnea is a common and complex problem, and its evaluation can consume significant time and resources. Dyspnea that remains unexplained after the initial evaluation requires a stepwise approach that uses diagnostic testing focused on common clinical causes, based on the characteristics of the individual patient. This focused testing can be limited in younger persons, but older patients require more complete evaluation because of their increased risk of multiple cardiopulmonary abnormalities.
CPET can help prioritize treatment and focus further evaluation in patients who have multiple abnormalities or no clear diagnosis found on initial testing. The impact of treatment should be monitored using symptom-based, physiologic and functional outcome measures, although these tools must be further developed and standardized as we devise more effective management strategies for this common clinical problem.
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