Matthew J. Hegewald, MD, FCCP

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.

Unexplained dyspnea is a common complaint among patients seen in pulmonary clinics, and can be difficult to define, quantify, and determine the etiology. The ATS official statement defined dyspnea as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity” (Am J Respir Crit Care Med. 2012; 185:435). A myriad of diseases can cause dyspnea, including cardiac, pulmonary, neuromuscular, psychological, and hematologic disorders; obesity, deconditioning, and the normal aging process may also contribute to dyspnea. Adding further diagnostic confusion, multiple causes may exist in a given patient.

Finding the cause or causes of dyspnea can be difficult and may require extensive testing, time, and cost. Initially, a history and physical exam are performed with more focused testing undertaken depending on most likely causes. For most patients, initial evaluation includes a CBC, TSH, pulmonary function tests, chest radiograph, and, often, a transthoracic echocardiogram. If these tests are unrevealing, or if clinical suspicion is high, more costly, invasive, and time-consuming tests are obtained. These may include bronchoprovocation testing, cardiac stress tests, chest CT scan, and, if warranted, right- and/or left-sided heart catheterization. Ideally, these tests are utilized appropriately based on the patient’s clinical presentation and the results of initial evaluation. In addition to high cost, invasive testing risks injury.

Cardiopulmonary exercise testing (CPET) has been called the “gold standard” test for evaluation of unexplained dyspnea (Palange P, et al. Eur Respir J. 2007;29:185).

Symptom-limited CPET measures multiple physiological variables during stress, potentially identifying the cause of dyspnea that is not evident by measurements made at rest. CPET may also differentiate the limiting factor in patients with multiple diseases that each could be contributing to dyspnea. CPET provides an objective measurement of cardiorespiratory fitness and may provide prognostic information. CPET typically consists of a symptom-limited maximal incremental exercise test using either a treadmill or cycle ergometer. The primary measurements include oxygen uptake (Vo₂), carbon dioxide output (Vco₂), minute ventilation (VE), ECG, blood pressure, oxygen saturation (Spo₂) and, depending on the indication, arterial blood gases at rest and peak exercise. An invasive CPET includes the above measurements and the addition of a pulmonary artery catheter and radial artery catheter allowing the assessment of ventricular filling pressures, pulmonary arterial pressures, cardiac output, and measures of oxygen transport. Invasive CPET is less commonly performed in clinical practice due to cost, high resource utilization, and greater risk of complications.

What is the evidence that CPET is the gold standard for evaluating dyspnea? Limited evidence supports this claim. Martinez and colleagues (Chest. 1994;105[1]:168) evaluated 50 patients presenting with unexplained dyspnea with normal CBC, thyroid studies, chest radiograph, and spirometry with no-invasive CPET. CPET was used to make an initial diagnosis, and this was compared with a definitive diagnosis based on additional testing guided by CPET findings and response to targeted therapy. Most patients (68%) eventually received a diagnossis of normal, deconditioned, hyperactive airway disease, or a psychogenic cause of dyspnea. The important findings from this study include: (1) CPET was able to identify cardiac or pulmonary disease, if present; (2) A normal CPET excluded significant cardiac or pulmonary disease in most patients suggesting that a normal CPET is useful in limiting subsequent testing; (3) In some patients, CPET wasn’t able to accurately differentiate cardiac disease from deconditioning as both exhibited an abnormal CPET pattern including low peak Vo₂, low Vo₂ at anaerobic threshold, decreased O₂ pulse, and often low peak heart rate. In more than 75% of patients, the CPET, and focused testing based on CPET findings, confidently identified the cause of dyspnea not explained by routine testing.

There is evidence that invasive CPET may provide diagnostic information when the cause of dyspnea is not identified using noninvasive testing. Huang and colleagues (Eur J Prev Cardiol. 2017;24[11]:1190) investigated the use of invasive CPET in 530 patients who had undergone extensive evaluation for dyspnea, including noninvasive CPET in 30% of patients, and the diagnosis remained unclear. The cause of dyspnea was determinedin all patients and included: exercise-induced pulmonary arterial hypertension (17%), heart failure with preserved ejection fraction (18%), dysautonomia or preload failure (21%), oxidative myopathy (25%), primary hyperventilation (8%), and various other conditions (11%). Most patients had been undergoing work up for unexplained dyspnea for a median of 511 days before evaluation in the dyspnea clinic. Huang et al’s study demonstrates some of the limitations of noninvasive CPET, including distinguishing cardiac limitation from dysautonomia or preload failure, deconditioning, oxidative myopathies, and mild pulmonary vascular disease. This study didn’t answer how many patients having noninvasive CPET would need an invasive study to get their diagnosis.

A limitation of both the Martinez et al and Huang et al studies is that they were conducted at subspecialty dyspnea clinics located in large referral centers and may not be representative of patients seen in general pulmonary clinics for the evaluation of dyspnea. This may result in over-representation of less common diseases, such as oxidative myopathies and dysautonomia or preload failure. Even with this limitation, these two studies showed that CPETs have the potential to expedite diagnoses and treatment in patients with unexplained dyspnea.

More investigation is needed to understand the clinical utility, and potential cost savings, of CPET for patients referred to general pulmonary clinics with unexplained dyspnea. We retrospectively reviewed 89 patients who underwent CPET for unexplained dyspnea from 2017 to 2019 at Intermountain Medical Center (Cook CP. Eur Respir J. 2022; 60: Suppl. 66, 1939). Nearly 50% of the patients undergoing CPET were diagnosed with obesity, deconditioning, or normal. In patients under the age of 60 years, 64% were diagnosed with obesity, deconditioning, or a normal study. Conversely, 70% of patients over the age of 60 years had an abnormal cardiac or pulmonary limitation.

We also evaluated whether CPET affected diagnostic testing patterns in the 6 months following testing. We determined that potentially inappropriate testing was performed in only 13% of patients after obtaining a CPET diagnosis. These data suggest that CPET results affect ordering provider behavior. Also, in younger patients, in whom initial evaluation is unrevealing of cardiopulmonary disease, a CPET could be performed early in the evaluation process. This may result in decreased health care cost and time to diagnosis. At our institution, CPET is less expensive than a transthoracic echocardiogram.

So, is CPET worthy of its status as the gold standard for determining the etiology of unexplained dysp-nea? The answer for noninvasive CPET is a definite “maybe.” There is evidence that some CPET patterns support a specific diagnosis. However, referring providers may be disappointed by CPET reports that do not provide a definitive cause for a patient’s dyspnea. An abnormal cardiac limitation may be caused by systolic or diastolic dysfunction, myocardial ischemia, preload failure or dysautonomia, deconditioning, and oxidative myopathy. Even in these situations, a specific CPET pattern may limit the differential diagnosis and facilitate a more focused and cost-effective evaluation. A normal CPET provides reassurance that significant disease is not causing the patient’s dyspnea and prevent further unnecessary and costly evaluation.