Utility of Cardiopulmonary Exercise Testing in Chronic Obstructive Pulmonary Disease: A Review.

Chronic obstructive pulmonary disease (COPD) is a disease defined by airflow obstruction with a high morbidity and mortality and significant economic burden. Although pulmonary function testing is the cornerstone in diagnosis of COPD, it cannot fully characterize disease severity or cause of dyspnea because of disease heterogeneity and variable related and comorbid conditions affecting cardiac, vascular, and musculoskeletal systems. Cardiopulmonary exercise testing (CPET) is a valuable tool for assessing physical function in a wide range of clinical conditions, including COPD. Familiarity with measurements made during CPET and its potential to aid in clinical decision-making related to COPD can thus be useful to clinicians caring for this population. This review highlights pulmonary and extrapulmonary impairments that can contribute to exercise limitation in COPD. Key elements of CPET are identified with an emphasis on measurements most relevant to COPD. Finally, clinical applications of CPET demonstrated to be of value in the COPD setting are identified. These include quantifying functional capacity, differentiating among potential causes of symptoms and limitation, prognostication and risk assessment for operative procedures, and guiding exercise prescription.

Exercise Physiology and Cardiopulmonary Exercise Testing.

Aerobic, or endurance, exercise is an energy requiring process supported primarily by energy from oxidative adenosine triphosphate synthesis. The consumption of oxygen and production of carbon dioxide in muscle cells are dynamically linked to oxygen uptake (V̇O2) and carbon dioxide output (V̇CO2) at the lung by integrated functions of cardiovascular, pulmonary, hematologic, and neurohumoral systems. Maximum oxygen uptake (V̇O2max) is the standard expression of aerobic capacity and a predictor of outcomes in diverse populations. While commonly limited in young fit individuals by the capacity to deliver oxygen to exercising muscle, (V̇O2max) may become limited by impairment within any of the multiple systems supporting cellular or atmospheric gas exchange. In the range of available power outputs, endurance exercise can be partitioned into different intensity domains representing distinct metabolic profiles and tolerances for sustained activity. Estimates of both V̇O2max and the lactate threshold, which marks the upper limit of moderate-intensity exercise, can be determined from measures of gas exchange from respired breath during whole-body exercise. Cardiopulmonary exercise testing (CPET) includes measurement of V̇O2 and V̇CO2 along with heart rate and other variables reflecting cardiac and pulmonary responses to exercise. Clinical CPET is conducted for persons with known medical conditions to quantify impairment, contribute to prognostic assessments, and help discriminate among proximal causes of symptoms or limitations for an individual. CPET is also conducted in persons without known disease as part of the diagnostic evaluation of unexplained symptoms. Although CPET quantifies a limited sample of the complex functions and interactions underlying exercise performance, both its specific and global findings are uniquely valuable. Some specific findings can aid in individualized diagnosis and treatment decisions. At the same time, CPET provides a holistic summary of an individual's exercise function, including effects not only of the primary diagnosis, but also of secondary and coexisting conditions.

Ventilatory regulation of arterial H(+) (pH) during exercise.

We hypothesized that exercise ventilation and arterial H(+) ([H(+)]a) are mutually interactive, [H(+)]a stimulating V(E) and V(E) regulating [H(+)]a increase. Fifty-five patients were studied, 10 normal and 45 with cardio-respiratory disorders. Each patient underwent cardiopulmonary exercise testing with simultaneous serial arterial blood gas and pH measurements. Subsequently, they were classified into one of 7 clinical groups: (1) normal, (2) exercise-induced hypoxemia (PaO2<50mmHg), (3) exercise-induced myocardial ischemia, (4) heart failure, (5) COPD, (6) interstitial lung disease, and (7) pulmonary vasculopathy. The average resting pHa was 7.42 or 7.43 for each group. At anaerobic (lactic acidosis) threshold (AT), [H(+)]a increased due to PaCO2 increase (+2mmHg), primarily. At peak exercise, [H(+)]a increased further due to arterial HCO3(-) decrease. In summary, [H(+)]a appears to be closely regulated at rest to AT and further to peak exercise by CO2 elimination from the venous return. No evidence was observed for over-ventilation of CO2, causing the arterial blood to become more alkaline during exercise in the patient groups studied.

Effects of pulmonary vasodilator therapy on ventilatory efficiency during exercise in adults with Eisenmenger syndrome.

OBJECTIVE: Eisenmenger syndrome, characterized by systemic-level pulmonary arterial resistance with resultant right-to-left shunt, is associated with low exercise capacity and hyperpnea at rest and exercise. Because ventilatory requirements are augmented by right-to-left shunting, we hypothesized that if pulmonary vasodilator treatment improved pulmonary perfusion in this condition, this would also improve ventilatory efficiency during exercise. DESIGN: To investigate this, data from incremental cardiopulmonary exercise tests performed by Eisenmenger patients before and after beginning therapy with pulmonary hypertension medications were retrospectively analyzed. Setting. Ahmanson/University of California, Los Angeles Adult Congenital Heart Disease Center. PATIENTS: Ten adults with Eisenmenger syndrome treated with either bosentan or sildenafil. OUTCOME MEASURES: The primary analysis was comparison, before and after treatment, of the efficiency of exercise ventilation as reflected in the ratio of ventilation (.V(E)) to carbon dioxide output (.VCO2) measured at the anaerobic threshold (AT), the slope of .V(E)/.VCO2 during incremental exercise, and end tidal partial pressure of CO2 (PETCO2) at the AT. Secondary measures included peak oxygen uptake (.VO2) and AT. RESULTS: Following treatment there were significant reductions in the slope .V(E)/.VCO2 (59.5 ± 12.9 vs. 50.0 ± 7.2, P= .003), and significant decrease in .V(E)/.VCO2 ratio (56.9 ± 6.2 vs. 50.2 ± 5.9, P= .00004) and increase in PETCO2 (21.12 ± 2.43 vs. 23.9 ± 2.62 torr, P= .0092) measured at the AT. Increases in peak .VO2 (0.73 ± 0.25 vs. 0.78 ± 0.32 L/min, P= .333) and AT (0.61 ± 0.20 vs. 0.68 ± 0.25 L/min, P= .154) were not significant. CONCLUSIONS: These findings are consistent with reduction in right-to-left shunt due to improved pulmonary blood flow, though attenuation of ventilatory drive is not excluded. Treatment of adult Eisenmenger patients with pulmonary the pulmonary vasodilators bosentan or sildenafil leads to improvement in parameters of ventilatory efficiency during exercise.

Considerations in the development of drugs to treat sarcopenia.

Sarcopenia describes reduced skeletal muscle mass and impaired muscle function associated with aging and with a variety of chronic diseases prevalent in the aging population. With increasing understanding of the molecular pathways participating in the structural and functional changes affecting skeletal muscle in these conditions, a number of potential targets for pharmacological interventions to reverse sarcopenia have been identified. The clinical evaluation of therapeutic candidates directed at these targets will require that the efficacy and safety of the drug candidates be adequately evaluated to meet the regulatory standards of the Food and Drug Administration (FDA). Concerns unique to drug development may require different approaches to clinical study design than have been used in the epidemiological research that identified the clinical need for these programs and the intervention trials conducted to date. In addition to being responsive to clinical need as perceived by patients and physicians, clinical trial data must demonstrate to the FDA that the drug provides an objective and clinically meaningful advantage, and must demonstrate to all involved in healthcare decision-making that its benefits justify the associated costs and risks. Potential primary efficacy endpoints for trials of a drug for treatment of sarcopenia include physical performance, falls, fractures, and patient-reported outcomes assessing function and quality of life. Each potential endpoint has advantages and disadvantages from scientific, clinical, and regulatory perspectives that must be carefully considered in the design of trials for sarcopenia treatments.

Potential biomarkers of muscle injury after eccentric exercise.

Proteomics was utilized to identify novel potential plasma biomarkers of exercise-induced muscle injury. Muscle injury was induced in nine human volunteers by eccentric upper extremity exercise. Liquid chromatography-mass spectrometry identified 30 peptides derived from nine proteins which showed significant change in abundance post-exercise. Four of these proteins, haemoglobin alpha chain, haemoglobin beta chain, alpha1-antichymotrypsin (ACT) and plasma C-1 protease inhibitor (C1 Inh), met the criterion for inclusion based on changes in at least two distinct peptides. ACT and C1 Inh peptides peaked earlier post-exercise than creatine kinase, and thus appear to provide new information on muscle response to injury.

Clinical cardiopulmonary exercise testing: patient and referral characteristics.

PURPOSE: Cardiopulmonary exercise testing (CPET) is a well-established procedure for which applications have evolved in several different medical specialties. There are limited data describing how CPET is actually used in clinical practice. Such information would be useful for understanding the clinical conditions and questions likely to be encountered by a referral laboratory, and for informing future research related to the use of CPET. METHODS: We retrospectively reviewed 677 consecutive tests performed in a single exercise laboratory to identify characteristics of patients, and the sources and purposes of referral for testing. RESULTS: Patients ranged in age from 21 to 90 years and averaged more than 2 preexisting medical diagnoses that could affect exercise function. Most patients were referred by subspecialists, with 33% coming from cardiologists, 32% from pulmonologists, 10% from generalists, and 23% from a variety of other medical and nonmedical professionals. Sixty-one percent of tests were requested for diagnostic purposes. Most of these were for evaluating unexplained symptoms, most commonly dyspnea. The other 39% of tests were requested to quantify exercise function in individuals whose medical condition was known. These had diverse indications including preoperative risk assessment, tracking responses to medical treatments, and characterizing abnormal metabolic responses to exercise. CONCLUSIONS: The experience of this laboratory mirrored the range of indications for CPET found in published literature. The spectrum of indications and referral sources underscore both the many causes and implications of exercise intolerance relevant to clinical practice, and the challenges to laboratory personnel for appropriate testing and reporting of data.

Exercise capacity as a predictor of survival among ambulatory patients with end-stage renal disease.

BACKGROUND: Exercise capacity is reduced in end-stage renal disease (ESRD). Exercise requires the integrated function of multiple vital organs, and low exercise capacity is an independent predictor of mortality in a number of clinical populations. We analyzed the value of exercise capacity, characterized as peak oxygen uptake (VO2), for predicting survival in a cohort of 175 hemodialysis patients over a median follow-up of 39 months. METHODS: Survival status was determined for 175 ESRD patients who had participated in previous studies for which peak VO2 and other clinical data had been determined. Chi-square and Kaplan-Meier survival analyses were performed, and a minimal model of factors related to mortality was developed by Cox multiple regression. RESULTS: There were 23 deaths during the follow-up period. Peak VO2 (>17.5 mL/min/kg) was a powerful predictor of survival (P= 0.009 by Kaplan-Meier). Age (<65 years), dialysis vintage (<39 months), pulse pressure (<54 mm Hg), and absence of diagnoses of diabetes or heart failure were also associated with better survival on univariate analyses. On multivariate analysis peak VO2 contributed significantly to the minimal explanatory model relating clinical variables to mortality (overall chi2= 25.5, P= 0.00001). CONCLUSION: Among these ambulatory ESRD patients, peak VO2 was a stronger predictor of survival than many traditional prognostic variables, some of which are subject to ceiling effects. Exercise capacity may thus provide incremental prognostic information concerning healthier ESRD patients. Because peak VO2 may be modified by exercise training, the potential of exercise as an intervention to improve survival is suggested.

Peripheral arterial disease is not associated with an increased prevalence of intradialytic cramps in patients on maintenance hemodialysis.

BACKGROUND/AIMS: Peripheral arterial disease (PAD) has been suggested as a contributing factor to the development of intradialytic muscle cramps in patients on maintenance hemodialysis. METHODS: To test this hypothesis, 122 patients from two dialysis centers were studied. The presence of PAD was determined by measurement of the ankle-brachial index (ABI) in the lower extremities of patients pre- and postdialysis. The experience of intradialytic cramps was assessed using patient history and review of medical records. RESULTS: PAD defined as a predialysis ABI < or =0.90 had an overall prevalence of 16.4% among patients studied. The prevalence of PAD was age-dependent, reaching 37.5% in patients 80-89 years old. Intradialytic muscle cramps were common, with 52.1% of patients reporting cramps within the previous two months, but there was no relationship between cramps during dialysis and PAD (p > 0.05). CONCLUSIONS: PAD was common in hemodialysis patients, but there was no association between the presence of PAD and the prevalence of intradialytic muscle cramps.

Clinical and demographic predictors of exercise capacity in end-stage renal disease.

Patients on maintenance hemodialysis therapy for end-stage renal disease have reduced exercise tolerance. Multiple processes related to uremia and hemodialysis have been implicated in the pathophysiology of this impairment. However, limited data are available to identify the separate and combined effects of clinical factors on the degree of impairment for individuals within this population. For this purpose, data from 193 patients who had undergone exercise testing for two clinical trials were retrospectively analyzed. Univariate and multiple linear regression analyses were used to identify demographic and clinical correlates of peak exercise oxygen uptake (VO2). Peak VO2 averaged 18.5 +/- 6.4 mL/min/kg. On univariate analysis, peak VO2 correlated positively with male sex and hemoglobin, serum albumin, and serum creatinine concentrations and correlated negatively with dialytic age and diagnosis of diabetes or chronic heart failure. In a multiple linear regression model, sex, hemoglobin concentration, age, and diagnosis of diabetes each remained statistically significant. Together, factors included in the model accounted for 41% of the variability in peak VO2 (P = 0.0001). Among factors not correlating significantly with peak VO2 were resting blood pressure, serum carnitine level, and urea clearance assessed by Kt/V. Findings show the range of exercise impairment among clinically stable ambulatory hemodialysis patients, which may be sufficient to interfere with normal daily activities for many of these patients. Although this impairment may be broadly attributable to physiological consequences of uremia, the degree of impairment for individual patients is predicted by demographic factors, coexistent disease, and factors potentially modified by medical therapeutics.