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Background
Cardiopulmonary exercise testing (CPET), also known as cardiopulmonary exercise stress testing, is a non-invasive tool that provides a comprehensive evaluation of exercise responses involving the cardiovascular, pulmonary, hematopoietic, neuropsychological, and musculoskeletal systems. Cardiopulmonary exercise testing entails measurements of oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead electrocardiography (ECG), blood pressure (BP) monitoring and pulse oximetry. These data are gathered during a maximal symptom-limited incremental exercise test. In certain circumstances, an additional measurement of arterial blood gases may be used to assess pulmonary gas exchange. Measurement of expiratory gases during exercise allows estimation of functional capacity, grades the severity of the impairment, evaluates the response to interventions, tracks disease progression, and assists in differentiating cardiac from pulmonary limitations in exercise tolerance. Cardiopulmonary exercise testing may be carried out on a treadmill or bicycle ergometer. Resting measurements are made for 3 to 5 minutes; followed by 3 minutes of unloaded cycling as a warm-up period. The workload is then increased at a rate designed to allow reaching maximum work capacity in 8 to 12 minutes. The test continues to symptom limitation (e.g., faintness, pallor, chest pain, severe dyspnea, and inability to continue pedaling or walking) or discontinuation by medical staff as a consequence of significant ECG abnormalities, drop in diastolic or systolic BP greater than 20 mm Hg below the resting value, rise in diastolic BP to greater than 120 mm Hg, rise in systolic BP to greater than 250 mm Hg, severe oxygen desaturation (less than 80 %), or achievement of maximum predicted heart rate (McCarthy and Dweik, 2006). Cardiopulmonary exercise testing is not appropriate for use as a screening test or first line test. Guidelines from the American Thoracic Society state that “In practice, CPET is considered when specific questions persist after consideration of basic clinical data, including history, physical examination, chest X-ray, pulmonary function tests (PFTs), and resting electrocardiogram (ECG).“
Cardiopulmonary exercise testing is performed in candidates for heart transplantation or other advanced therapies. In a prospective study, Myers et al (1998) examined clinical, hemodynamic, and CPET determinants of survival in patients with CHF. A total of 644 patients were included in this study. Age, cause of heart failure, body surface area, cardiac index, ejection fraction, pulmonary capillary wedge pressure, left ventricular dimensions, watts achieved during exercise, heart rate (HR), maximum systolic BP, and VO2 at the ventilatory threshold and at peak exercise were measured at baseline. Uni-variate and multi-variate analyses were carried out for clinical, hemodynamic, and exercise test predictors of death. A Cox hazards model was developed for time of death. During a mean follow-up period of 4 years, 187 patients (29 %) died and 101 underwent transplantation. Actuarial 1-year and 5-year survival rates were 90.5 % and 73.4 %, respectively. Resting systolic BP, watts achieved, peak VO2, VO2 at the ventilatory threshold, and peak HR were greater among survivors than among non-survivors. Cause of heart failure (coronary artery disease or cardiomyopathy) was a strong determinant of death (relative risk for coronary artery disease, 1.73; p < 0.01). By multi-variate analysis, only peak VO2 was a significant predictor of death. Stratification of peak VO2 above and below 12, 14, and 16 ml/kg per minute demonstrated significant differences in risk for death, but each cut-point predicted risk to a similar degree. The authors concluded that peak VO2 outperforms clinical variables, right-heart catheterization data, exercise time, and other exercise test variables in predicting outcome in severe CHF. Direct measurement of VO2 should be included when clinical or surgical decisions are being made in patients referred for evaluation of CHF or those considered for heart transplantation. Oikawa and colleagues (2003) noted that patients with CHF frequently complain of fatigue and/or dyspnea during daily life. These exertional symptoms can be evaluated by the CPET. Peak VO2, anaerobic threshold, the ratio of the increase in VE to the increase in VCO2, the slope of the increase in VO2 relative to the increase in work rate, and the time constant of VO2 are reported to be useful in evaluating the severity and prognosis of patients with CHF. The information obtained from CPET can be used to select therapeutic option to improve both functional capacity and prognosis, as well as to identify patients with the greatest need for heart transplantation.
The American Thoracic Society (ATS)/American College of Chest Physicians (ACCP)'s statement on CPET (2003) noted that this approach has been used for over a decade as a standard assessment tool of CHF, especially to determine candidacy for heart transplantation. The ATS/ACCP (2003) also listed evaluation of undiagnosed exercise intolerance, prescription of pulmonary rehabilitation, as well as evaluation of lung, heart, and heart-lung transplantation as indications for CPET. Furthermore, Ingle (2008) stated that CPET is a well-established tool for stratifying cardiovascular risk in patients with CHF. Important prognostic variables include a reduced peak VO2, which has a central use in the selection criteria of heart transplantation, as well as the abnormal relation between VE and VCO2, often referred to as the elevated VE/VCO2 slope.
Cardiopulmonary exercise testing has also been used for pre-operative evaluation for lung cancer resection surgery or lung volume reduction surgery. Beckles et al (2003) stated that the pre-operative physiologic assessment of patients being considered for surgical resection of lung cancer must consider the immediate peri-operative risks from co-morbid cardiopulmonary disease, the long-term risks of pulmonary disability, and the threat to survival due to inadequately treated lung cancer. As with any planned major surgery, especially in a population predisposed to atherosclerotic cardiovascular disease by cigarette smoking, a cardiovascular evaluation is an important component in assessing peri-operative risks. Measurements of the forced expiratory volume in 1 second (FEV1) and the diffusing capacity of the lung for carbon monoxide (DLCO) should be viewed as complementary physiologic tests for assessing risk related to pulmonary function. If there is evidence of interstitial lung disease on radiographical studies or undue dyspnea on exertion, even though the FEV1 may be adequate, a DLCO should be obtained. In patients with abnormalities in FEV1 or DLCO identified pre-operatively, it is essential to estimate the likely post-resection pulmonary reserve. The amount of lung function lost in lung cancer resection can be estimated by using either a perfusion scan or the number of segments removed. A predicted post-operative FEV1 or DLCO less than 40 % indicates an increased risk for peri-operative complications, including death, from lung cancer resection. Exercise testing should be performed in these patients to further define the peri-operative risks prior to surgery. Formal CPET is a sophisticated tool that includes recording the exercise ECG, HR response to exercise, VE, and VO2 per minute, and allows calculation of maximal oxygen consumption (VO2max). Risk for peri-operative complications can generally be stratified by VO2max. Patients with pre-operative VO2max greater than 20 ml/kg/min are not at increased risk of complications or death; VO2max less than 15 ml/kg/min indicates an increased risk of peri-operative complications; and patients with VO2max less than 10 ml/kg/min have a very high risk for post-operative complications. Alternative types of exercise testing include stair climbing, the shuttle walk, and the 6-min walk test (6MWT). Desaturation during an exercise test has been associated with an increased risk for peri-operative complications.
Lung volume reduction surgery (LVRS) for patients with severe emphysema is a controversial procedure. Some reports document substantial improvements in lung function, exercise capability, and quality of life in highly selected patients with emphysema following LVRS. Case series of patients referred for LVRS indicate that perhaps 3 to 6 % of these patients may have co-existing lung cancer. Anecdotal experience from these case series suggested that patients with extremely poor lung function can tolerate combined LVRS and resection of the lung cancer with an acceptable mortality rate and good post-operative outcomes. Combining LVRS and lung cancer resection should probably be limited to those patients with heterogeneous emphysema, particularly emphysema limited to the lobe containing the tumor (Beckles et al, 2003). DeCamp and colleagues (2008) stated that potential candidates for LVRS should undergo extensive evaluation and preparation to minimize peri-operative risks and optimize surgical outcomes. Initial screening includes spirometry, diffusion capacity, lung volumes by body plethysmography, and high-resolution computerized tomography scanning. Patients who have been successfully screened must complete a pre-operative pulmonary rehabilitation program of 6 to 10 weeks duration. During the pulmonary rehabilitation program, medical therapy should be maximized. Post-rehabilitation studies include CPET, arterial blood gas analysis, oxygen titration, 6MWT, and cardiac testing. The evaluation process aims at defining the severity and distribution of emphysema and attempts to eliminate those who do not meet criteria outlined by the National Emphysema Treatment Trial. Optimal candidates have upper-lobe-predominant emphysema and acceptable operative risks.
The ACCP's practice guidelines on physiologic evaluation of the patient with lung cancer being considered for resectional surgery (Colice et al, 2007) stated that CPET for measuring VO2max should be performed to further define the peri-operative risk of surgery; a VO2max of less than 15 ml/kg/min indicates an increased risk of peri-operative complications. Alternative types of exercise testing (e.g., stair climbing, the shuttle walk, and the 6MWT) should be considered if CPET is unavailable.
Cardiopulmonary exercise testing is being used increasingly in a wide spectrum of clinical applications including pectus excavatum, polycystic ovary syndrome, and sickle cell disease (Malek and Coburn, 2008, Giallauria et al, 2008, and Das et al, 2008). However, there is insufficient evidence that CPET should be used as a screening tool or as a first-line test. The ATS/ACCP statement on CPET (2003) noted that this approach is generally not considered a first-line test, and is usually used when the diagnosis is still uncertain after standard work up with resting pulmonary function tests or ECG. Furthermore, the American Heart Association (AHA) Council on Clinical Cardiology's statement on exercise testing in asymptomatic adults (Lauer et al, 2005) noted that a wealth of data indicate that exercise testing can be used to evaluate and refine prognosis, especially when emphasis is placed on non-ECG measures (e.g., exercise capacity, chronotropic response, HR recovery, and ventricular ectopy). Nevertheless, randomized trial data on the clinical value of screening exercise testing are absent. It is unclear if a strategy of routine screening exercise testing in selected subjects reduces the risk for premature mortality or major cardiac morbidity. The writing group from the AHA believed that a large-scale randomized study of such a strategy should be carried out.
Forshaw and associates (2008) stated that CPET may identify patients at high risk of post-operative cardiopulmonary morbidity and mortality. These investigators evaluated the utility of CPET before esophagectomy. A total of 78 consecutive patients (64 men) with a median age of 65 years (range of 40 to 81 years) underwent CPET before esophagectomy (50 % transhiatal; 50 % transthoracic). Measured variables included anaerobic threshold (AT) and VO2peak. Outcome measures were post-operative morbidity and mortality, length of hospital stay, and unplanned intensive therapy unit admission. Cardiopulmonary complications occurred in 33 (42 %) patients and non-cardiopulmonary complications in 19 (24 %). One in-hospital death (1.3 %) occurred, and 13 patients (17 %) required an unplanned intensive therapy unit admission. The level of VO2peak was significantly lower in patients with post-operative cardiopulmonary morbidity (p = 0.04). The area under a receiver operating characteristic curve was 0.63 (95 % confidence interval [CI], 0.50 to 0.76) for the VO2peak and 0.62 (95 % CI, 0.49 to 0.75) for AT. An AT cutoff of 11 ml/kg/min was a poor predictor of post-operative cardiopulmonary morbidity. The authors concluded that although the VO2peak was significantly lower in those patients who developed cardiopulmonary complications, CPET is of limited value in predicting post-operative cardiopulmonary morbidity in patients undergoing esophagectomy.
Brown and colleagues (2008) stated that 6MWT and CPET are used to evaluate impairment in emphysema. However, the extent of impairment in these tests as well as the correlation of these tests with each other and lung function in advanced emphysema is not well characterized. During screening for the National Emphysema Treatment Trial, maximum ergometer CPET and 6MWT were performed in 1218 individuals with severe COPD with an average FEV1 of 26.9 +/- 7.1 % predicted. Predicted values for 6MWT and CPET were calculated from reference equations. Correlation coefficients and multi-variable regression models were used to determine the association between lung function, quality of life (QOL) scores, and exercise measures. The two forms of exercise testing were correlated with each other (r = 0.57, p < 0.0001). However, the impairment of performance on CPET was greater than on the 6MWT (27.6 +/- 16.8 versus 67.9 +/- 18.9 % predicted). Both exercise tests had similar correlation with measures of QOL, but maximum exercise capacity was better correlated with lung function measures than 6-min walk distance. After adjustment, 6-min walk distance had a slightly greater association with total St George’s Respiratory Questionnaire score than maximal exercise (effect size 0.37 +/- 0.04 versus 0.25 +/- 0.03 % predicted/unit). Despite advanced emphysema, patients are able to maintain 6-min walk distance to a greater degree than maximum exercise capacity. Moreover, the 6MWT may be a better test of functional capacity given its greater association with QOL measures whereas CPET is a better test of physiologic impairment.
Pulmonary arterial hypertension (PAH) is a debilitating chronic disorder of the pulmonary vasculature. It is characterized by a persistent elevation in pulmonary arterial pressure with normal left-sided pressures, differentiating it from left-sided heart disease. Symptoms progress from shortness of breath and decreasing exercise tolerance to right heart failure, with peripheral edema and marked functional limitation. Exercise-induced syncope, worsening symptoms at rest, and intractable right heart failure indicate critical disease. Pulmonary arterial hypertension may be idiopathic with no identifiable cause or associated with collagen vascular diseases, drugs, HIV, liver disease, and/or congenital heart disease. Familial or genetically mediated PAH accounts for a small percentage of cases. The 6MWT is the current standard to assess exercise capacity in patients with PAH (Traiger, 2007; Gomberg-Maitland et al, 2007).
Cardiopulmonary exercise testing has also been used in the management of patients with PAH, especially in assessing exercise tolerance. Guazzi and Opasich (2005) noted that the importance of studying the pathophysiological bases and clinical correlates of exercise limitation in patients with PAH is well-established. Two modes of exercise testing, the 6MWT and CPET, are currently proposed for diagnostic, therapeutic, as well as prognostic finalities. The 6MWT is inexpensive, feasible and is thought to better reproduce daily life activities and to reliably detect therapeutic benefits. On the other hand, CPET requires the patients' maximal effort and does not provide a reliable quality of life measure. However, it is highly reproducible and provides insights into the pathophysiological mechanisms that lead to exercise intolerance.
The ACCP's clinical practice guidelines on prognosis of PAH (McLaughlin et al, 2004) stated that in patients with idiopathic PAH, low VO2max and low peak exercise systolic BP and diastolic BP as determined by CPET may be used to predict a worse prognosis. Furthermore, the European Respiratory Society (ERS)'s Task Force (Palange et al, 2007) recommended the use of CPET for functional and prognostic evaluation of patients with primary pulmonary hypertension.
In a case report on the utility of CPET to detect and track early-stage ischemic heart disease, Chaudhry and colleagues (2010) concluded that "this study illustrates the potential value of CPET in the primary prevention setting to detect and track early-stage ischemic heart disease .... Research in this area should continue to more firmly establish the clinical role of CPET in the evaluation of ischemic heart disease (macrovascular or microvascular) for the purpose of improving preventive cardiac care and thus reducing long-term health are costs".
The American College of Cardiology (ACC)/AHA Task Force on Practice Guidelines guidelines for exercise testing (Gibbons et al, 1997) stated that ventilatory gas exchange analysis during exercise testing is a useful adjunctive tool in assessment of patients with cardiovascular and pulmonary disease. Measures of gas exchange primarily include VO2, VCO2, VE, and ventilatory/anaerobic threshold. VO2 at maximal exercise is considered the best index of aerobic capacity and cardiorespiratory function. Estimation of maximal aerobic capacity using published formulas without direct measurement is limited by physiological and methodological inaccuracies. Data derived from exercise testing with ventilatory gas analysis have proved to be reliable and important in evaluation of patients with heart failure. Such data are only partly influenced by resting left ventricular dysfunction. Maximal exercise capacity does not necessarily reflect the daily activities of patients with heart failure. Use of this technique in stratification of ambulatory heart failure patients has improved ability to identify those with the poorest prognosis, who should be considered for heart transplantation. The ACC/AHA published a partial update to these guidelines (Gibbons et al, 2002), however, there was no change in regard to CPET.
The European Respiratory Society (ERS)'s Task Force (Palange et al, 2007) also provided the following recommendations (ranging from "A", the highest, to "D", the lowest) regarding the clinical use of CPET:
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Indication
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Recommendation grade
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| Detection of exercise-induced bronchoconstriction |
A
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| Detection of exercise-induced arterial oxygen desaturation |
B
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| Functional evaluation of subjects with unexplained exertional dyspnea and/or exercise intolerance and normal resting lung and heart function |
D
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| To recognize specific disease exercise response patterns that may help in the differential diagnosis of ventilatory versus circulatory causes of exercise limitation |
C
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| Functional and prognostic evaluation of patients with COPD |
B, C
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| Functional and prognostic evaluation of patients with ILD |
B, B
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| Functional and prognostic evaluation of patients with CF |
C, C
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| Functional and prognostic evaluation of patients with PPH |
B, B
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| Functional and prognostic evaluation of patients with CHF |
B, B
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| Evaluation of interventions (Maximal incremental test) |
C
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| Evaluation of interventions (High-intensity constant work-rate ‘‘endurance’’ tests) |
B
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| Prescription of exercise training |
B
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COPD: chronic obstructive pulmonary disease; ILD: interstitial lung disease; CF: cystic fibrosis; PPH: primary pulmonary hypertension; CHF: chronic heart failure.
The authors stated that with the use of this rigorous grading system, "A" is relatively rare and "B" is usually considered the best achievable. The low power recommendation grades are reflective not so much of well-powered statistical judgments as they are of weakness in the density of the relevant evidence base. Such areas should be regarded as important priorities for future investigation.
The American Heart Association (AHA)'s scientific statement on CPET in adults (Balady et al, 2010) stated that CPET has been studied and found to be useful in the following clinical applications (not an all inclusive list):
- Development of the exercise prescription in patients with cardiovascular disease or stroke
- Evaluation of disability in patients with cardiac or pulmonary disease
- Evaluation of patients with heart failure
- Evaluation of patients with mitochondrial myopathies
- Evaluation of patients with unexplained dyspnea.
The AHA's scientific statement on CPET in adults (Balady et al, 2010) also listed the following emerging and less well-studied clinical applications of CPET (not an all inclusive list):
- Evaluation of patients with congenital heart disease
- Evaluation of patients with cardiac arrhythmias and pacemakers
- Evaluation of patients with ischemic heart disease
- Evaluation of patients with pulmonary hypertension
- Pre-operative evaluation of patients undergoing pulmonary resection or bariatric surgery.
The AHA scientific statement (Balady et al, 2010) also stated that more studies are needed to rigorously evaluate if CPET provides additional discriminatory diagnostic and prognostic value over and above that provided by standard exercise tests and other clinical variables. In addition, more studies are needed to assess the increasing number of variables that can be derived from CPET, as well as their utility in many conditions that affect the cardiovascular and pulmonary systems.
Young and colleagues (2012) performed a systematic review of CPET in the pre-operative evaluation of patients with abdominal aortic aneurysm or peripheral vascular disease requiring surgery. Review methods and reporting were according to the PRISMA guidelines. Studies were eligible if they reported CPET-derived physiological parameters in patients undergoing abdominal aortic aneurysm repair or lower extremity arterial bypass. Data were extracted regarding patient populations and correlation between CPET and surgical outcomes including mortality, morbidity, critical care bed usage and length of hospital stay. These researchers identified a total of 1,301 articles. Although 53 abstracts referred to the index vascular procedures, only 7 articles met inclusion criteria. There were no data from randomized controlled trials. Data from prospective studies did not comprehensively correlate CPET and surgical outcomes in patients with abdominal aortic aneurysms. There were no studies reporting CPET in patients undergoing lower extremity arterial bypass. Major limitations included small sample sizes, lack of blinding, and an absence of reporting standards. The authors concluded that the paucity of robust data precludes routine adoption of CPET in risk-stratifying patients undergoing major vascular surgery. They stated that the use of CPET should be restricted to clinical trials and experimental registries, reporting to consensus-defined standards.
Marzolini et al (2012) noted that despite the importance of exercise training in mitigating cardiovascular risk, the development of exercise programs for people post-stroke has been limited by lack of feasibility data concerning CPET to inform the exercise prescription. These researches examined the feasibility of CPETs for developing an exercise prescription in people greater than or equal to 3 months post-stroke. Cardiopulmonary exercise testing results from 98 consecutively enrolled patients post-stroke with motor impairments and 98 age- and sex-matched patients with coronary artery disease were examined at baseline and after 6 months of exercise training. The proportion of patients with stroke and coronary artery disease attaining an intensity sufficient for prescribing exercise at baseline was 68.4 % versus 82.7 %, respectively (p = 0.02) and 84.7 % versus 83.8 % (p = 0.9) at 6 months. Women were less likely than men post-stroke to achieve a sufficient intensity at baseline (40 % versus 80.9 %, p < 0.001) but not at 6 months (78.3 % versus 87.1, p = 0.3). A clinically relevant abnormality occurred in 11.2 % of stroke and 12.2 % of patients with coronary artery disease on baseline CPETs (p = 0.8) and 10.6 % of stroke and 5.9 % of patients with coronary artery disease on the 6-month CPET (p = 0.4). No serious cardiovascular events occurred during 349 CPETs. The authors concluded that most patients after stroke achieved a level of exertion during the CPET sufficient to inform an exercise prescription. At least 1 of 10 patients post-stroke developed a clinically relevant abnormality on baseline and post-program CPETs with no serious cardiovascular events. Moreover, they state that these data supported the feasibility and safety of CPETs for prescribing exercise post-stroke; and strategies to improve use of baseline CPETs for women post-stroke require further investigation. The clinical value of CPET for prescribing exercise to people after stroke needs to be ascertained in well-designed studies.
The 3rd edition of the American College of Chest Physicians’ evidence-based clinical practice guidelines on “Physiologic evaluation of the patient with lung cancer being considered for resectional surgery” (Brunelli et al, 2013) states that “The preoperative physiologic assessment should begin with a cardiovascular evaluation and spirometry to measure the FEV1 and the diffusing capacity for carbon monoxide (DLCO). Predicted post-operative (PPO) lung functions should be calculated. If the % PPO FEV1 and % PPO DLCO values are both > 60 %, the patient is considered at low risk of anatomic lung resection, and no further tests are indicated. If either the % PPO FEV1 or % PPO DLCO are within 60 % and 30 % predicted, a low technology exercise test should be performed as a screening test. If performance on the low technology exercise test is satisfactory (stair climbing altitude > 22 m or shuttle walk distance > 400 m), patients are regarded as at low risk of anatomic resection. A cardiopulmonary exercise test is indicated when the PPO FEV1 or PPO DLCO (or both) are < 30 % or when the performance of the stair-climbing test or the shuttle walk test is not satisfactory. A peak oxygen consumption (V˙O2 peak) < 10 ml/kg/min or 35 % predicted indicates a high risk of mortality and long-term disability for major anatomic resection. Conversely, a V˙O2 peak > 20 mL/kg/min or 75 % predicted indicates a low risk”. The authors concluded that a careful pre-operative physiologic assessment is useful for identifying those patients at increased risk with standard lung cancer resection and for enabling an informed decision by the patient about the appropriate therapeutic approach to treating his or her lung cancer. This pre-operative risk assessment must be placed in the context that surgery for early-stage lung cancer is the most effective currently available treatment of this disease.
A European Respiratory Society Task Force (2007) stated that clear evidence now exists for the utility of CPET in children and adolescents with congenital heart diseases. The guidelines cite evidence that CPET may help to discriminate between pulmonary, cardiovascular and deconditioning causes of exercise limitation in congenital heart diseases. The authors state that CPET has been used to evaluate improvements in exercise tolerance after heart surgery. The guidelines note that the use of exercise testing to assess the long-term prognosis of children with CHD have not been reported.
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