INTRODUCTION — Cardiopulmonary exercise testing (CPET) provides an integrated evaluation of the cardiorespiratory system during exercise. Dyspnea, or shortness of breath, is one of the most common complaints by patients and is characterized by general breathing discomfort that has different meanings to different people. Indeed, the American Thoracic Society and other expert groups recognize dyspnea as a very complex phenomenon that arises from multiple physiologic, psychologic, social, and environmental factors [1].
The evaluation of dyspnea can be complex and generally requires a history (eg, smoking, pattern and triggers of symptoms), complete physical examination, laboratory testing, electrocardiogram, and pulmonary function tests [2]. While the five most common causes of dyspnea are asthma, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), heart disease, and obesity/deconditioning [3], the wide variety of possibilities makes it challenging to develop a diagnostic strategy that is both time and cost effective, as well as complete [4,5]. A CPET can often be helpful in narrowing down the diagnostic possibilities.
The use of CPET in the evaluation of dyspnea will be reviewed here. Other topics, such as an approach to the evaluation of dyspnea, the physiology of exercise, the role of exercise testing in children and adolescents, and exercise testing in the management of heart failure, are discussed separately.
●(See "Approach to the patient with dyspnea".)
●(See "Exercise physiology".)
●(See "Exercise testing in children and adolescents: Principles and clinical application".)
●(See "Cardiopulmonary exercise testing in cardiovascular disease".)
DEFINITIONS
VE – Minute ventilation, volume of air exhaled (L/minute)
VEMAX – Maximum minute ventilation at peak exercise (L/minute)
VO2 – Measurement of oxygen uptake (L/minute)
VCO2 – Measurement of carbon dioxide output from the lungs (L/minute)
VCO2/VO2 – Respiratory exchange ratio (RER; measured at the mouth)
PETO2 – End-tidal oxygen tension
VT – Tidal volume
VD/VT – Proportion of dead space ventilation per tidal volume breath
O2 pulse – VO2/heart rate (HR; mL/beat)
OUES - Oxygen uptake efficiency slope (slope of VO2 versus logVE)
PREPARATION FOR CPET
Indications — CPET can be helpful in a number of settings, most commonly in the evaluation of exercise intolerance.
●Undiagnosed exercise intolerance (eg, dyspnea, fatigue) (see "Approach to the patient with dyspnea")
●Assessment of exercise tolerance in patients with known pulmonary or cardiac disease (see "Cardiopulmonary exercise testing in cardiovascular disease")
●Preoperative evaluation for lung resection (see "Preoperative physiologic pulmonary evaluation for lung resection", section on 'Integrated cardiopulmonary exercise testing')
●Assessment of impairment for disability claim (see "Evaluation of pulmonary disability", section on 'Exercise tests')
Contraindications — The following are considered contraindications to CPET for most patients:
●Uncontrolled hypertension or arrhythmia
●Unstable angina, myocardial infarction in preceding four weeks, or active heart failure
●Pulmonary embolism in preceding four weeks
●Poorly controlled asthma
●Acute myocardial or pericardial inflammatory disease
●Severe cardiac outflow tract obstruction for which surgical intervention is indicated
Pretest evaluation — In addition to obtaining informed consent, a simple pretest evaluation is important to determine baseline patient characteristics that may be important for the final interpretation of CPET results. Such an evaluation should include review of medications (eg, beta-blockers that may affect heart rate response, or inhaled beta-agonists that may affect ventilatory response) and a directed physical exam (eg, baseline cardiac and lung exam) so that any changes with exercise may be detected. Baseline spirometry should be obtained to detect any underlying obstruction or possible restrictive disease, and to establish the maximum voluntary ventilation (MVV) for later calculation of breathing reserve.
Pretest evaluation for coronavirus disease 2019 (COVID-19) through antigen or PCR testing is appropriate as the high minute ventilation of CPET is thought to increase the risk of aerosol generation and COVID-19 (severe acute respiratory syndrome coronavirus 2; SARS-CoV-2) transmission by infected, but asymptomatic patients [6-8].
Exercise testing equipment and protocols — CPETs are typically performed in a specialized testing unit with capability for continuous cardiopulmonary monitoring (ie, electrocardiogram, automated blood pressure monitoring, continuous pulse oximetry); a metabolic unit to measure respiratory rate, tidal volume, oxygen consumption, carbon dioxide production, and work output; and personnel to monitor the test, obtain arterial blood gases, and respond to emergencies.
For infection control purposes, CPET equipment should be fitted with single-use mouthpieces and disposable in-line bacterial and viral filters [6-8]. It is preferred that negative pressure rooms with at least six air exchanges per hour be used for testing.
The cycle ergometer and treadmill are the most common modalities of testing. Different protocols are available to allow the individual to reach their maximal power output within about 8 to 15 minutes with a symptom-limited end to the test. The protocols typically include incremental increases in the power output over predefined time intervals, such as an increase of 25 watts every three minutes (staged) or an increase of 16.5 watts every one minute (incremental), and may occur in a stepped or ramp-up format. Greater increments may be used for testing in extremely fit individuals. Protocols for evaluating patients with heart failure are described separately. (See "Cardiopulmonary exercise testing in cardiovascular disease", section on 'Exercise test protocols'.)
Testing includes measurement of heart rate, blood pressure, electrocardiogram (ECG), ventilation, and concentrations of expired gases (oxygen [O2] and carbon dioxide [CO2]) both at rest (prior to starting exercise) and continuously throughout exercise. These parameters are typically reported at brief intervals (eg, every 30 seconds, or sliding average over every seven breaths) during exercise. Borg ratings of dyspnea and/or fatigue are usually obtained at baseline, and the patient is asked to rate their peak level of dyspnea and/or fatigue at the conclusion of the test (table 1). Patients are also asked to identify the primary reason they had to stop exercising (eg, shortness of breath, leg discomfort). Flow-volume loops may be performed during and after the test, which may be informative in patients where airflow obstruction is suspected of limiting exercise ability.
Arterial blood gases are typically obtained at rest and peak exercise to assess the effect pf exercise on the alveolar-arterial oxygen difference (A-a O2 difference) and document the development of metabolic acidosis after reaching the anaerobic threshold. In some laboratories, periodic arterial blood gases are obtained at short intervals of one to two minutes via an indwelling arterial line, although resting and peak values obtained by individual arterial sticks are typically sufficient.
Monitoring of all variables is typically continued one to five minutes into the recovery period, depending on local practice.
The data collected during the test are typically available to the interpreting physician or physiologist in tables that display the data over time of the test (eg, every 30 seconds) and also graphical displays that highlight cardiovascular and respiratory response patterns. A 9-panel plot is commonly used in final CPET reports (figure 1) [9].
The technique for continuous laryngoscopy during exercise for the evaluation of exercise-induced laryngeal obstruction is described separately. (See "Exercise-induced laryngeal obstruction", section on 'Continuous laryngoscopy during exercise'.)
OVERVIEW OF CARDIOPULMONARY EXERCISE TESTING (CPET) — CPET is a comprehensive exercise test that is designed to allow assessment of the physiological factors that limit maximal exercise capacity (table 2) [4,5,10-17]. These factors may be related to the cardiovascular system, ventilatory and gas exchange response, or metabolic issues. The ability to exercise and reach a normal maximal exercise capacity is related to the normal functioning of each of these systems as an integrated whole. A full description of normal exercise physiology is provided separately. (See "Exercise physiology".)
CPET allows the measurement and identification of the patterns of the body’s responses to exercise. Since most dyspnea is associated with exertion, CPET provides the opportunity to simulate real-world conditions to cause dyspnea on exertion under controlled and monitored circumstances. The development of dyspnea can then be related to the normal or abnormal functioning of each of the body systems that contribute to maximal exercise capacity. Other clinical uses of CPET, such as the evaluation of pulmonary disability, preoperative assessment for lung resection, and monitoring exercise capacity in heart failure, are discussed separately. (See "Evaluation of pulmonary disability" and "Preoperative physiologic pulmonary evaluation for lung resection" and "Exercise capacity and VO2 in heart failure".)
Metabolic measurements
Maximum oxygen uptake — The maximum oxygen uptake (VO2max) provides assessment of exercise capacity and differentiates normal from abnormal exercise tolerance. However, a true maximum VO2 is often not reached, so the highest peak VO2 is taken as the measure of exercise capacity, assuming a good effort on testing. VO2 is measured at the mouthpiece, using inhaled and exhaled oxygen concentrations, and reported as L/min or mL/kg/min. Normal is typically considered to be >85 percent predicted [18].
A low peak VO2 in response to exercise suggests either a problem with O2 delivery (due to cardiovascular, pulmonary, or circulatory etiologies) or a problem with peripheral utilization, which may be muscular in origin. A low-peak VO2 may also reflect poor effort. Of note, it is not uncommon for there to be a discrepancy between the percent predicted peak VO2 and the percent predicted peak work achieved. It seems reasonable to consider that the maximal metabolic capacity during exercise is assessed by the peak VO2, whereas the maximal functional capacity during exercise is assessed by the peak work [19].
Respiratory exchange ratio — Overall metabolism can be assessed by the ratio of carbon dioxide output/oxygen uptake (VCO2/VO2), known as the respiratory exchange ratio (RER). This is the noninvasive measure of the respiratory quotient (RQ) that is occurring at the cellular level. Baseline RER is approximately 0.8, reaches 1.0 at the anaerobic threshold (AT), and exceeds 1.2 during the recovery phase of exercise. A sign of good effort on CPET is an RER >1.16, unless the patient is hyperventilating, which can also increase the RER [18].
Anaerobic threshold — The AT, also known as the lactate threshold or the ventilatory threshold, represents the shift to anaerobic metabolism during exercise. The gold standard for determining AT is measurement of lactic acid or trending of serum bicarbonate during exercise. AT normally occurs at >40 percent of maximal predicted VO2 [18,20].
The most common noninvasive methods for determining the AT are by determining the VO2 where the VCO2 versus VO2 slope increases (V-slope method), assessing the VO2 at the nadir of the minute ventilation (VE)/VO2 versus VO2 relationship, or evaluating where the plot of end-tidal oxygen tension (PETO2) begins to rise (figure 2) [21]. The accuracy of less invasive approaches is somewhat controversial and can be prone to error that may vary by disease state. There is no one preferred method for determining AT, and we recommend using at least two if not all three methods to determine whether the AT appears to be consistently estimated between methods.
Respiratory measurements — In normal individuals, exercise is not limited by respiratory factors, such that the maximum ventilation at peak exercise (VEmax) is normally 60 to 70 percent of maximum voluntary ventilation (MVV), leaving 30 to 40 percent of breathing reserve. The breathing reserve can be described as the difference between the MVV and the VEmax, expressed as a percentage ((MVV-VEmax)/MVV x 100), such that a normal breathing reserve is 30 to 40 percent. Values that are less than this range indicate decreased breathing reserve and are a key feature used to diagnose ventilatory limitation to exercise. A reduced or absent breathing reserve (VEmax/MVV approaching 100 percent) suggests that the limitation to exercise is due to respiratory disease. (See "Exercise physiology", section on 'Breathing reserve index'.)
In performance athletes, there may be a reduced or absent breathing reserve after the maximum VO2 has been exceeded, signifying a test that has met both the limits of cardiovascular and pulmonary physiologic responses. The patterns of such test results differ in that the maximum VO2 in performance athletes typically exceeds 100 percent predicted whereas it is reduced in the case of ventilatory limitation to exercise.
Assessment of breathing pattern entails assessment of both the tidal volume (VT) and the respiratory frequency (f). Under normal conditions, the VE increases early on primarily due to increases in VT, which should at least double over baseline, and reach a peak of approximately 50 to 60 percent of forced vital capacity (FVC) or 70 percent of inspiratory capacity (IC) [18]. The respiratory frequency rises throughout exercise but accelerates at the approach of or just beyond the AT.
In patients with interstitial lung disease (ILD), the breathing pattern is typically characterized by rapid, shallower breaths, and this corresponds with disease severity. A similar pattern can be seen in chronic obstructive pulmonary disease (COPD), although patients with COPD are typically breathing at a higher functional residual capacity (FRC) (figure 3). Psychogenic dyspnea can also be characterized by hyperventilation.
Flow-volume loops can be measured during exercise and provide insight into ventilatory function during exercise [22]. First, a maximal flow-volume loop is measured, and then the tidal breathing loop is positioned within the maximal flow-volume loop based on the end-expiratory lung volume (EELV) aligning with a volume equal to the IC below total lung capacity (TLC). As exercise proceeds, the breathing loops are recorded in real time and periodically repositioned within the maximal flow-volume loop by recording intermittent ICs during exercise. Normally, the maximal exercise flow-volume loop remains within the confines of the maximal flow-volume envelope (figure 4). Flow limitation is considered to become significant if the volume over which the exercise expiratory loop overlaps the maximal expiratory loop is greater than approximately 20 percent of the volume of the exercise tidal loop [23]. Dynamic hyperinflation results in the EELV rising toward TLC rather than falling normally toward residual volume (RV).
The ratio of physiologic dead space (VD) to VT provides an estimate of ventilation-perfusion inhomogeneity of the lung. An increased VD/VT reflects inefficiency of ventilation. Under normal conditions, VD/VT is approximately 0.3 to 0.4 at rest and decreases with exercise to approximately 0.2 at near maximal or maximal exercise.
●Patients with respiratory disease may have high normal values VD/VT at rest that increase or fail to decrease with exercise.
●Patients with cardiovascular disease typically have a normal resting VD/VT that decreases appropriately with exercise. Heart failure is an exception in which VD/VT may increase or not decrease normally because of pulmonary congestion (interstitial edema).
The ventilation-perfusion abnormalities that result from cardiovascular and pulmonary vascular disease may also be manifested in elevation of the nadir of the VE/VCO2 versus VO2 relationship (>32 to 34), or an elevation of VE versus VCO2 slope (>30 to 32) (figure 5) [18].
Cardiovascular measurements — The slope of the heart rate (HR) to VO2 relationship is linear with a progressive increase in HR to near maximal predicted values in the normal response to exercise.
●Heart rate reserve – The heart rate reserve (HRR) is the difference between the age predicted HR response (approximately 220 beats/min – age) and the measured HR at peak exercise, and there is little or no HRR at the end of exercise under normal conditions.
●Blood pressure – Blood pressure (BP) is measured intermittently during exercise protocols and the normal response is an increase in both systolic and diastolic BP with exercise, but the diastolic BP should not rise more than 20 mmHg above baseline. A decrease in systolic BP below the resting pressure is a sign of left ventricular dysfunction and an indication to stop the test.
●Oxygen pulse – The O2 pulse (VO2/HR) reflects the delivery of O2 per heartbeat (figure 6). The value of the VO2 divided by heart rate is equal to the stroke volume multiplied by the arterial-mixed venous O2 difference ([a-v]O2). Assuming the (a-v)O2 remains relatively constant, the O2 pulse pattern reflects the pattern in change of the stroke volume during exercise. A peak value of less than 80 percent predicted is generally considered abnormal. The appearance of a plateau in the slope of the VO2/HR versus time below 80 percent predicted, particularly in comparison with the slope of the HR versus time, suggests a cardiovascular etiology of abnormal exercise response.
Conditions that are associated with reduction in stroke volume are associated with reduction in O2 pulse, including reduction in left ventricular function and pulmonary vascular disease. Anemia, metabolic deconditioning, and deconditioning can also contribute to a low O2 pulse.
USING CPET TO DETERMINE THE CAUSE OF DYSPNEA
Approach — Each CPET yields a large amount of data, both individual numerical results and graphic displays. By examining CPET results sequentially, the CPET can lead to the appropriate category of differential diagnosis for further evaluation (table 2).
The first step is to assess whether a normal peak oxygen uptake (VO2; >85 percent predicted) or peak work load (>80 percent predicted) was achieved. In addition, an assessment is made about whether the test reflects a maximal volitional effort, as indicated by a respiratory exchange ratio (RER; carbon dioxide output [VCO2]/VO2) >1.16, or heart rate (HR) >90 percent of predicted [18].
If the maximal work or VO2 is less than 80 percent predicted, the next step is to assess the ventilatory response (ie, respiratory rate, tidal volume [VT], breathing reserve, and dead space [VD]/VT). A low breathing reserve ([maximum voluntary ventilation (MVV) – maximum ventilation at peak exercise (VEmax)]/MVV) <30 to 40 percent suggests a respiratory limitation. A ventilatory limitation is also suggested when VD/VT is higher than the normal 0.3 to 0.4 at rest and/or fails to decrease with exercise to approximately 0.2. (See 'Ventilatory causes of dyspnea' below.)
If the ventilatory response is normal, the cardiovascular response is examined (heart rate, blood pressure [BP], heart rate reserve, electrocardiogram [ECG], and anaerobic threshold [AT]) for evidence of ischemia on the ECG, a drop in systolic BP during exertion, a rise in diastolic BP >20 mmHg, or AT occurring at <40 percent of maximal predicted VO2. (See 'Cardiac causes of dyspnea' below.)
If no cardiovascular limitation is noted, gas exchange parameters are examined (eg, pulse oxygen [SpO2], alveolar-arterial oxygen difference [A-a O2 difference], VD/VT, and AT).
Most metabolic carts generate a 9-panel display (figure 1). While all of the responses are interrelated, the top row (panels 1 to 3) relates to metabolic and cardiovascular responses, the middle row (panels 4 to 6) to ventilatory and gas exchange responses, and the bottom row (panels 7 to 9) to mechanical responses.
Ventilatory causes of dyspnea — Certain patterns of CPET results are associated with the major categories of lung disease (table 2).
●Obstructive airways disease – Asthma and chronic obstructive pulmonary disease (COPD) are the most common pulmonary causes of dyspnea [24]. The primary physiological abnormality in both diseases is airflow limitation, but air trapping and hyperinflation are generally the consequences of airflow limitation that mediate dyspnea [25-27]. The importance of hyperinflation as a cause of dyspnea is supported by the finding that dyspnea is more strongly associated with inspiratory capacity (IC, an indirect measure of hyperinflation) than with forced expiratory volume in one second (FEV1) [28].
Among patients with obstructive airways disease, the following pattern is noted on CPET. First, VT, respiratory rate, and minute ventilation (VE) increase initially, as expected during exercise, but as the work load increases, dynamic hyperinflation limits the degree to which VT may rise (figure 7) [29]. This results in a compensatory rise in respiratory rate, resulting in a rapid, relatively shallow breathing pattern. Since shallower breathing involves a disproportionate rise in VD, the pattern is energy inefficient, and VE must increase more than expected, reflected in an elevated VE versus VCO2 slope, or nadir of the VE/VCO2 versus VCO2 curve [18], similar to the changes seen in patients with cardiovascular or pulmonary vascular disease (figure 5).
Arterial blood gas (ABG) analysis may reveal an increased partial pressure of carbon dioxide (PaCO2), reflecting a failure to clear carbon dioxide as expected at peak exercise, with the possible contribution of respiratory acidosis to the expected metabolic acidosis at maximal exercise. The increase in VE can also result in the patient approaching the limit of their ventilatory ceiling (estimated as MVV, which is approximately equal to FEV1 multiplied by 40), resulting in a decreased breathing reserve and severe dyspnea. ABG analysis may also reveal exercise desaturation with a fall in PaO2 and rise in the alveolar-arterial oxygen difference.
In addition, dynamic hyperinflation prevents VT recruitment that is normally accomplished by exhaling closer to residual volume (RV), thus preventing the expected decrease in end-expiratory lung volume (EELV) (figure 7 and figure 4) [23,29]. Instead, VT is recruited during inspiration toward total lung capacity (TLC), and as soon as an absolute threshold of inspiratory reserve volume (IRV) is reached, dyspnea becomes severe (figure 8) [25,30,31]. Finally, airflow limitation may worsen at low levels of work, further limiting expiration, worsening hyperinflation, and resulting in excessive dyspnea.
●Restrictive disease – In restrictive disease (eg, chest wall abnormalities, interstitial lung disease, neuromuscular disease, obesity, pleural disease), similar patterns are seen, but for different reasons [24,32]. In this case, the failure to augment VT is due to lung volume restriction. The result is the adoption of rapid, shallow breathing, with the consequences of inefficient ventilation described above.
If restriction is due, in part, to obesity, the exercise flow-volume loop may start off close to RV, and may quickly encroach on the maximal flow-volume envelope, resulting in airflow limitation, further contributing to dyspnea. Of course, other factors are associated with dyspnea in obesity, including increased work of breathing, concomitant deconditioning, and psychological factors (eg, perception of breathlessness, anxiety) [33].
In restrictive disease associated with pulmonary vascular disease, there may also be derangements in gas exchange, resulting in O2 desaturation and excessive ventilation due to relatively high VD/VT [32].
●Gas transfer abnormalities – Ventilatory causes of dyspnea such as emphysema and interstitial lung diseases may also lead to gas exchange abnormalities during exercise due to increasing blood flow to poorly ventilated lung (ie, worsened ventilation-perfusion matching). This can be detected based on worsening oxygenation, excessive widening of the A-a O2 difference (>35 mmHg), or a failure to decrease the dead space ratio (VD/VT) during exercise [18].
●Dysfunctional breathing – Abnormal patterns of breathing, or so-called dysfunctional breathing due to fear, anxiety, or learned behaviors, may cause dyspnea in the absence of underlying pulmonary disease [34]. The most common pattern is rapid, shallow breathing, which leads to relatively high VD/VT and the need for increased VE, thus causing ventilatory limitation. Another pattern that has been recognized is breathing at abnormally high functional residual capacity (FRC), sometimes seen in athletes. In addition, patients may simply hyperventilate during exercise, with development of a respiratory alkalosis. This may be seen in association with anxiety or fear of exertion.
●Upper airway obstruction – Other pulmonary causes of dyspnea that may be discovered during CPET include exercise-induced laryngeal obstruction (EILO; also called paradoxical vocal fold motion) [35] and tracheobronchomalacia [36], both of which may manifest as abnormalities in the exercise flow-volume loops obtained during the test [23]. However, the sensitivity of exercise flow-volume loops is not optimal and other diagnostic methods are generally needed. Descriptions of continuous laryngoscopy during exercise testing in the evaluation of EILO and the use of bronchoscopy and dynamic computed tomography to diagnose tracheomalacia are provided separately. (See "Exercise-induced laryngeal obstruction", section on 'Continuous laryngoscopy during exercise' and "Tracheomalacia and tracheobronchomalacia in adults".)
Cardiac causes of dyspnea — Cardiac limitation is the primary factor that determines maximal exercise capacity under normal circumstances. In the overall pathway for O2 delivery, the cardiovascular system offers the most resistance to the flow of O2 from air to mitochondria [37]. In clinical terms, this means that maximal exercise capacity is reached when no further cardiac output can be achieved, and this is usually signaled by reaching maximal predicted HR.
Accordingly, detecting cardiac limitation as the reason for dyspnea can be challenging, because cardiac limitation also occurs in health. The key is determining what other factors may be limiting exercise at the time that cardiac limitation occurs. If no other factors are evident, then cardiac limitation is either physiologic or pathologic, depending on the overall response to exercise.
Cardiac disease is a common cause of dyspnea, and typically relates to ischemic heart disease, cardiomyopathy, or valvular heart disease. In each case, cardiac performance is compromised, such that cardiac output becomes limited.
The CPET parameters used to characterize cardiac disease include in heart rate, oxygen pulse (VO2/HR), and appropriate changes in VE/VCO2, and ECG (table 2) [10].
HR should rise linearly with VO2, reaching a maximal value as estimated by 220 – age, or 90 percent of this value.
●O2 pulse rises with HR, but then reaches a plateau in parallel with VO2, indicating attainment of maximal stroke volume (SV) response. O2 pulse is a physiological surrogate for SV because if O2 extraction is assumed to be constant, then VO2/HR is equal to SV(CaO2-CvO2), based on Fick’s equation. When there is a problem with stroke volume, cardiac output is maintained by increasing heart rate. This yields an accelerated HR response at high workloads, and a corresponding early plateau (below 80 percent predicted) in the maximal O2 pulse.
●If dyspnea is due to ischemia, then ischemic changes, usually related to ST or T waves, may be seen on exercise ECG, although many other ECG abnormalities may be detected [38]. If due to cardiomyopathy or valvular heart disease, there will be no ischemic ECG changes associated with limited O2 pulse.
●The O2 pulse may also be limited when cardiac limitation is due to high RV afterload in the case of pulmonary hypertension.
●With decreased cardiac output, the nadir of VE/VCO2 is elevated, reflecting altered ventilation/perfusion (V/Q) matching (figure 5). Abnormal distribution of blood flow results in relatively low perfusion in areas that are well-ventilated, yielding increased VD and less efficient clearing of CO2. Similarly, there may be a decrease in the oxygen uptake efficiency slope (OUES; <1.47), indicating less efficient O2 update with any degree of ventilation (figure 9) [39-43].
●Oscillation in the VE versus time curve, known as exercise oscillatory ventilation (EOV), may be more specific for intrinsic cardiac disease and related to excessive circulation time (figure 10) [10,44]. (See "Exercise capacity and VO2 in heart failure".)
Thus, if a patient has a submaximal exercise capacity in the setting of a submaximal heart rate, then the cardiac response was likely the limiting factor, particularly if there were no ventilatory or gas exchange abnormalities. Other explanations include limitation of the heart rate response due to beta-blocker therapy and stopping the CPET early for other reasons (eg, leg pain, anxiety, suboptimal effort). If a submaximal heart rate occurs in the setting of another limiting factor, such as low breathing reserve indicating ventilatory limitation, or desaturation indicating gas exchange abnormality, then one of these other factors is suggested as the reason for exercise limitation.
Peripheral vascular disease can also lead to exercise intolerance. Here, the patient may become dyspneic due to early onset of AT due to failure to deliver adequate O2 because of inability of the peripheral vessels to relax and dilate during exercise. The main clue to this during CPET is the excessive rise of diastolic BP (>20 mmHg above baseline) [18].
Pulmonary vascular causes of dyspnea — For patients with pulmonary vascular disease (eg, pulmonary hypertension, pulmonary veno-occlusive disease, thromboembolic disease) or other diseases causing abnormal ventilation-perfusion matching (eg, emphysema, ILD), the CPET may reveal gas exchange abnormalities, most commonly the development of hypoxemia or desaturation with exercise (table 2) [45]. Impaired gas exchange may be identified by measurement of arterial PaO2 or pulse oximetry (SpO2), an increase in A-a O2 gradient, or failure of VD/VT to decrease during exercise. (See 'Ventilatory causes of dyspnea' above.)
A further sign of disease affecting gas exchange is the increase in VE versus VCO2 slope or elevated nadir of the VE/VCO2 curve, both of which reflect inefficient CO2 clearance requiring increased V/Q or VT ventilation (figure 5) [46].
The oxygen uptake efficiency slope (OUES) has also been shown to be reduced in patients with pulmonary arterial hypertension and may predict a poor outcome (figure 9) [47].
Metabolic causes of dyspnea — If the key components supporting exercise are all functioning normally, with normal ventilatory, cardiovascular, and gas exchange function, and yet the patient can only attain a submaximal O2 consumption, then there may be a metabolic abnormality interfering with oxygen delivery or utilization. On the delivery side, the most common cause would be anemia, with reduced O2 carrying capacity. On the utilization side, the most common cause would be deconditioning, with early switch to anaerobic metabolism and the development of lactic acidosis and muscle pain (see 'Deconditioning' below). Less common causes of problems with oxygen utilization are metabolic or mitochondrial myopathies [48]. (See "Myophosphorylase deficiency (glycogen storage disease V, McArdle disease)" and "Mitochondrial myopathies: Clinical features and diagnosis".)
Signs on CPET of mitochondrial myopathy causing dyspnea include a low AT and a decrease in the OUES (decreased slope of VO2 versus logVE) (figure 9), similar to what is seen in patients with cardiac limitation (table 2). In these cases, VO2 is low with no apparent cardiovascular, ventilatory, or gas exchange cause. Molecular genetic studies or a muscle biopsy may be indicated. (See "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)
Deconditioning — Deconditioning is one of the most common causes of dyspnea on exertion [4,14,15]. Deconditioning refers to the inefficient delivery or utilization of oxygen at the tissue level, and usually is caused by lack of regular exercise. The results of CPET will reveal relatively low values for work load, peak VO2, and/or AT in the face of normal cardiovascular, ventilatory, and gas exchange responses (table 2), assuming a patient has given a good effort (typically RER >1.16).
Patients with specific underlying causes of dyspnea may also become deconditioned because of lack of exercise due to the dyspnea on exertion they experience. This is very common among patients with chronic heart or lung disease, and a mixed picture may be evident in which deconditioning is likely complicating the underlying disease.
Sometimes patients are deconditioned and then become motivated to exercise, during which they experience the normal, but uncomfortable, feeling of dyspnea associated with "being out of shape." In these cases, CPET can be reassuring because it can rule out major abnormalities and thereby give the patient and the provider some confidence in the continuing pursuit of an exercise program to overcome the deconditioned state.
Dyspnea associated with long COVID-19 — One of the most prominent and troublesome symptoms associated with long COVID-19 is dyspnea on exertion. A number of studies using CPET have now been performed trying to elucidate the mechanism involved. A recent review has summarized evidence to date supporting a role for abnormalities of autonomic function, the vascular endothelium, and muscle or mitochondrial function [49].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dyspnea" and "Society guideline links: Pulmonary function testing" and "Society guideline links: Stress testing and cardiopulmonary exercise testing".)
SUMMARY
●Indication for CPET in unexplained dyspnea – The cardiopulmonary exercise test (CPET) is a valuable tool in determining the cause of dyspnea on exertion that is not otherwise apparent from routine evaluation, including history, physical exam, basic metabolic and hematologic analysis, pulmonary function testing, electrocardiogram (ECG), and heart or lung imaging. (See 'Overview of cardiopulmonary exercise testing (CPET)' above.)
●Principles of CPET interpretation – Understanding normal physiologic responses to exercise, and thereby being able to recognize abnormal responses, helps to identify the factors limiting exercise (table 2). This information may pinpoint the cause of dyspnea, or at least weigh the relative contributions of heart, lung, and metabolism to the overall cause of dyspnea. (See 'Overview of cardiopulmonary exercise testing (CPET)' above.)
●CPET features of diseases with abnormal ventilation – CPET features of the various types of pulmonary disease include the following (see 'Ventilatory causes of dyspnea' above):
•Low peak oxygen uptake (VO2; <85 percent predicted), despite good effort
•Inability to fully recruit tidal volume (VT; less than twice the baseline)
•Rapid, shallow breathing or other abnormal breathing pattern
•Elevated minute ventilation (VE) resulting in reduced breathing reserve (<11 L)
•Elevated VE versus carbon dioxide output (VCO2) slope (>30 to 32) or nadir of VE/VCO2 curve (>32 to 34) (figure 5)
•Dynamic hyperinflation with low inspiratory capacity (figure 7)
•Abnormal flow-volume loops during exercise
•Dysfunctional breathing (isolated rapid, shallow breathing or other abnormal breathing pattern in the absence of pulmonary disease)
●CPET features of cardiac disease – Cardiac causes of dyspnea can be difficult to differentiate from the normal cardiac limitation that determines maximal exercise capacity. The key is determining what other factors may be limiting exercise at the time that cardiac limitation occurs. CPET features of cardiac limitation include (see 'Cardiac causes of dyspnea' above):
•Low peak VO2 (<85 percent predicted), despite good effort
•Accelerated heart rate at high work loads
•Low O2 pulse and early plateau (<80 percent predicted)
•ECG changes of ischemia or arrhythmia
•Excessive blood pressure (BP) response, especially diastolic BP (>20 mmHg above baseline) indicative of peripheral vascular disease
•Elevated VE versus VCO2 slope, or nadir of VE/VCO2 curve (figure 5)
•Decreased oxygen uptake efficiency slope (OUES <1.47) (figure 9)
•Exercise oscillatory ventilation (EOV) (figure 10)
●CPET features of pulmonary vascular disease – CPET features of pulmonary vascular disease (eg, pulmonary hypertension, chronic thromboembolic disease) include the following (see 'Pulmonary vascular causes of dyspnea' above):
•Low peak VO2 (<85 percent predicted), despite good effort
•Drop in arterial partial pressure of oxygen (PaO2) or pulse oxygen (SpO2) with exercise
•Widening of alveolar-arterial (A-a) difference >35
•Failure of ratio of dead space (VD) to VT to decrease
•Elevated VE versus VCO2 slope, or nadir of VE/VCO2 curve (figure 5)
•Low O2 pulse and early plateau
•Decreased OUES (figure 9)
●CPET features of metabolic disease – Metabolic abnormalities interfere with oxygen delivery or utilization (eg, reduced oxygen carrying capacity due to anemia, early switch to anaerobic metabolism due to deconditioning, myophosphorylase deficiency, and mitochondrial myopathies). CPET features of metabolic causes of dyspnea include (see 'Metabolic causes of dyspnea' above):
•Low peak VO2 (<85 percent predicted), despite good effort
•Low anaerobic threshold (AT; <40 percent predicted maximal VO2)
•Low O2 pulse
•Decreased OUES (figure 9)
•Otherwise normal cardiovascular, ventilatory, and gas exchange responses
●CPET features of deconditioning – Deconditioning refers to the inefficient delivery or utilization of oxygen at the tissue level, usually caused by lack of regular exercise. CPET features include (see 'Deconditioning' above):
•Low peak VO2, despite good effort
•Low AT (AT; <40 percent predicted maximal VO2)
•Otherwise normal cardiovascular, ventilatory and gas exchange responses
