Over the last two decades, the cardiopulmonary exercise test (CPX) has been widely used to help establish the severity of disease and to estimate prognosis in patients with chronic heart failure (CHF). The most commonly applied CPX response has been V˙O2 peak; specific V˙O2 peak values achieved have been used to stratify the degree of risk and have thus been recommended in consensus reports and guidelines on heart failure management (11,30,39). However, limitations to the use of V˙O2 peak for predicting prognosis have been widely described; these include an inability to determine "maximal" effort in some patients, its dependence on motivation, its questionable prognostic utility among patients who fall into an intermediate range (10-18 mL·kg−1·min−1) (7,9,23,25), and a discordance between V˙O2 peak, ventricular performance, and disease severity (24,36-38).
More recently, CPX responses reflecting ventilatory inefficiency during exercise have generated a great deal of interest. These indices include the ventilation to carbon dioxide production (V˙ E/V˙CO2) slope, V˙O2 kinetics at exercise onset or in recovery, the oxygen uptake efficiency slope (OUES), an oscillatory breathing pattern, and a reduced end-tidal CO2 pressure (PetCO2) (1,3,13,20). Although the mechanisms underlying abnormal V˙ E/V˙CO2 slope and OUES responses to exercise and their prognostic value have been extensively studied (1,3,13,20), little is known regarding clinical applications of PetCO2. Based on studies performed in the intensive care unit (ICU) setting in a variety of disease states at rest, reduced PetCO2 has been related to impaired cardiac output (5,12,14,27,31). Because an impaired cardiac output response to exercise underlies ventilation/perfusion mismatching leading to ventilatory inefficiency, there has been interest in PetCO2 as a prognostic marker. Indeed, both resting and exercise PetCO2 have recently been demonstrated to be strong predictors of risk for adverse events in CHF (2,5); it has been reported that reduced PetCO2 is an even more powerful predictor of risk than V˙O2 peak (5).
Studies describing the association between PetCO2 and cardiac performance have largely done so using only cardiac performance measures at rest. Given the strong association between PetCO2 and outcomes in patients with CHF, it would be useful to further explore the mechanisms underlying abnormalities in PetCO2 at rest and during exercise. Historically, accurately acquiring cardiac output during exercise was a cumbersome process requiring right heart catheterization, which is costly and carries an inherent risk. The development of new technologies using transthoracic electrical properties offers the possibility of reasonably accurate, easy to perform, noninvasive measurements of cardiac output during exercise (17). One such approach is based on analysis of blood-flow-dependent changes in the phase shift of electrical currents applied across the chest. In contrast to the bioimpedance approach, which relies on detection of flow-dependent changes in electrical signal amplitude, phase shifts are inherently more accurately detectable and less subject to noise. Accordingly, this approach (termed bioreactance) has an improved signal-to-noise ratio and is less susceptible to physical factors such as body habitus, body motion, and ambient conditions. This approach has recently been reported to have acceptable precision and responsiveness for monitoring cardiac output in the catheterization laboratory and in the ICU among patients with a wide range of circulatory dysfunction (15,26) and during exercise among patients with CHF (22).
In light of recent studies demonstrating PetCO2 to be a strong prognostic marker and the ability to measure cardiac performance noninvasively, we performed the current study. Our objectives were 1) to evaluate the association between PetCO2 at rest and during exercise, other CPX responses, and the severity of CHF; and 2) to determine the ability of PetCO2 to identify CHF patients with impaired cardiac output responses to exercise.
This was a retrospective analysis of clinical data obtained from 61 consecutive subjects referred to two private cardiology clinics for CPX testing for evaluation of dyspnea. All subjects provided written consent for the use of their data in the analysis; Investigational Review Board approval for the study was obtained from each institution. Forty-eight of the subjects had HF (31 with low ejection fraction [EF], 17 with normal EF) and 13 were ultimately diagnosed as normal (normal EF and V˙O2 peak, dyspnea based on noncardiac factors). Demographic and clinical characteristics of the subjects are summarized in Table 1. In the overall population, there was a broad range of EF, V˙O2 peak, and peak cardiac output values. All subjects were limited during exercise by fatigue or dyspnea, and none had clinical evidence of pulmonary disease or ischemic changes on the ECG.
Symptom-limited maximal exercise tests were performed on a treadmill using a ramp protocol (21). All subjects were requested to abstain from eating or smoking at least 3 h before the test. Ventilatory oxygen uptake was measured using a CPX-D (Medical Graphics Corporation, St. Paul, MN). Gas exchange data were acquired breath by breath and expressed in 10-s intervals of rolling 30-s averages. Oxygen uptake, carbon dioxide production, minute ventilation, and respiratory exchange ratio were calculated online. The percentage of age-predicted normal V˙O2 peak was determined for each subject using the equation of Wasserman et al. (33). A 12-lead electrocardiogram was monitored continuously and recorded every minute. Blood pressure was recorded manually every 2 min throughout the test. All subjects were encouraged to provide a maximal effort; among patients with CHF, the Borg 0 to 10 perceived exertion scale was used to quantify effort.
The ventilatory threshold was determined by two experienced, independent reviewers using the V-slope method (33) and was confirmed by ventilatory criteria. PetCO2 represents the partial pressure of CO2 at the end of an exhalation; the value was taken at the point of the ventilatory threshold (2), which typically represents the highest value of PetCO2, after which it declines toward peak exercise (16,29) (termed PetCO2@VT). A value of ≤36 mm Hg was used to define an abnormal response based on our previous observation that this represented an optimal cutpoint to define high-risk patient (2). In addition, a resting PetCO2 value of ≤33 mm Hg was used to define abnormal based on previous findings that this value represents an optimal high-risk cutpoint (5). V˙E and V˙CO2 responses, acquired from the initiation of exercise to peak, were used to calculate the V˙E/V˙CO2 slope via least squares linear regression (y = mx + b, where m = slope) (1). The oxygen uptake efficiency slope (OUES) was derived by the slope of a semilog plot of minute ventilation versus V˙O2. As such, the OUES is an estimation of the efficiency of ventilation with respect to V˙O2, with greater slopes indicating greater ventilatory efficiency (1,3).
The NICOM bioreactance-based system (Cheetah Medical, Wilmington, DE) is based on an analysis of relative phase shifts of an oscillating current that occur when traversing the thoracic cavity. This contrasts with the traditional bioimpedance-based systems that rely only on measured changes in signal amplitude. The NICOM system is comprised of a radiofrequency generator for creating a high-frequency current that is injected across the thorax, four dual surface electrodes that are used to establish electrical contact with the body, a receiving amplifier for recording the transthoracic voltage in response to the injected current, and circuitry for determining the relative phase shift between the injected current and the recorded voltage. Within each of the dual electrodes, one electrode is used by the high-frequency current generator whereas the other is used by the input voltage amplifier. Signals are applied to and recorded from the left and the right sides of the thorax; these signals are processed separately and averaged after digital processing. During exercise testing, the electrodes can be placed on the subject's back so that the cables do not interfere with upper body motion.
The signal processing unit of the system determines the relative phase shift (ΔΦ˙˙) between the input signal relative to the output signal. ΔΦ in turn is due to changes in blood flow in the aorta. It has been shown that stroke volume (SV) is estimated by
where C is a constant of proportionality and VET is the ventricular ejection time that is determined from the NICOM and the ECG signal. The value of C has been optimized in prior studies and accounts for patient age, gender, and body size (28). Cardiac output (CO) is then calculated using the relation
where HR is the heart rate.
The NICOM system has conformité europeené (CE) mark in Europe and 510(k) clearance from the US Food and Drug Administration and is available for clinical use in both Europe and United States.
Differences in demographic and clinical characteristics between normal subjects and patients with CHF were assessed using unpaired t-tests for continuous data and chi-square tests for categorical data. Differences in CPX responses and indices of cardiac performance were compared between normal subjects and CHF patients achieving a PetCO2@VT <36 and ≥36 mm Hg; these comparisons were performed using one-way ANOVA. Post hoc testing was performed using the Bonferroni method. The associations between noninvasive cardiac performance indices, clinical variables, and other exercise test responses were assessed using linear regression.
Among patients with CHF, 28 had a normal PetCO2@VT response and 20 had an abnormal response. Table 2 presents exercise test responses between normal subjects and CHF patients with normal and abnormal PetCO2 responses. Normal subjects were younger (51 ± 11 yr), but the two groups of CHF patients did not differ (61 ± 12 and 66 ± 12 yr, respectively). For the overall group, the mean maximal perceived exertion was 7.8 ± 1.7 (range = 5-10), and the mean peak respiratory exchange ratio was 1.12 ± 0.09 (range = 0.87-1.28), suggesting that maximal effort was achieved by most patients. Normal subjects generally achieved higher exercise test responses than both groups of patients with CHF, and patients with an abnormal PetCO2 response achieved lower values compared to patients with a normal response. Mean maximal oxygen uptake values for normal subjects and patients with a normal and an abnormal PetCO2 response were 24.8 ± 6, 18.4 ± 6, and 13.0 ± 4 mL·kg−1·min−1, respectively (P < 0.001). Similarly, oxygen uptake at the ventilatory threshold and other CPX responses were highest among normal subjects and lowest among CHF patients with an abnormal PetCO2 response to exercise. CHF patients with an abnormal PetCO2@VT also had a higher V˙E/V˙CO2 slope and a lower OUES versus patients with a normal PetCO2 response.
Although CPX and cardiac output responses tended to be highest among normal subjects and lowest among patients with an abnormal PetCO2 at rest, the differences were not as striking as those for PetCO2 during exercise (PetCO2@VT). The V˙E/V˙CO2 slope, however, was notably different between the three groups (0.28 ± 0.03, 0.31 ± 0.06, and 0.38 ± 0.09 for normal subjects and CHF patients with a normal and abnormal resting PetCO2, respectively, P < 0.001)
Table 3 shows resting and peak exercise cardiac output, cardiac index, index of peak aortic flow (dx/dt), and ventricular ejection time (VET) between normal subjects and CHF patients with normal and abnormal PetCO2 responses to exercise. Resting EF was lower in CHF patients with an abnormal PetCO2 response to exercise versus normal subjects. No other differences were observed in measures of cardiac performance at rest between groups. CHF patients with an abnormal PetCO2@VT had reduced cardiac output and cardiac index responses to exercise (cardiac output = 20.0 ± 10, 17.8 ± 5.9, and 13.7 ± 6.6 L·min−1 for normal subjects and CHF patients with normal and abnormal PetCO2@VT responses, respectively, P = 0.04). Similar results were observed for cardiac output responses at the VT (Fig. 1). When CHF patients were separated by high and low EF (<45% or ≥45%), no differences were observed in exercise test or cardiac performance measures between groups.
Table 4 presents correlation coefficients between CPX responses and indices of cardiac performance. Peak cardiac output was significantly correlated to the OUES (r = 0.57, P < 0.001) and inversely related to the V˙E/V˙CO2 slope (r = −0.36, P < 0.01). PetCO2@VT was significantly but weakly related to peak cardiac output (r = 0.28, P < 0.05) but strongly related to markers of ventilatory inefficiency (r = −0.78, P < 0.001, and r = 0.55, P < 0.001, for the relation between PetCO2@VT and V˙E/V˙CO2 slope and OUES, respectively; Fig. 2).
PetCO2 has been associated with cardiac output in a variety of experimental and clinical settings, including the ICU, in cardiogenic shock, and during surgery. Idris et al. (12), for example, observed that PetCO2, at a constant ventilation, paralleled cardiac output over a wide range of flow rates in an animal model. Sibutani et al. (27) reported that across a range of cardiac output responses and at a constant ventilation among subjects undergoing abdominal aortic aneurysm repair, PetCO2 correlated closely with changes in cardiac output. Using dye dilution measurements of cardiac output, Matsumoto et al. (18) reported that the sensitivity and the specificity of a low PetCO2 during exercise to predict an impaired cardiac output response to exercise were 77% and 75%, respectively, in a heterogeneous group of patients with cardiovascular disease. Over the last decade, numerous other studies have proposed the application of PetCO2 as a surrogate marker of cardiac impairment in various disease states (2,4,5,8,14,32), but few data are available during exercise. Moreover, despite recent interest in PetCO2 at rest and during exercise as a prognostic marker (2,5), little is known regarding the relationship between PetCO2 and cardiac performance during exercise in patients with CHF.
The current results
Using a PetCO2 response to exercise that has previously identified CHF patients at high risk for adverse outcomes (2), we observed that PetCO2 identified patients with a reduced exercise capacity, a ventilatory inefficiency, an earlier onset of the ventilatory threshold, and reduced cardiac performance during exercise. The mean V˙O2 peak among patients with an abnormal PetCO2 response to exercise was 13.0 mL·kg−1·min−1, a value below the cut point that has long been recognized in CHF guidelines as a marker for high risk (11,30,39). This suggests that that PetCO2, a variable that is readily available from a typical metabolic system, can be used as a rough surrogate for the degree of cardiac impairment in response to exercise. The clinical implications of these results include the fact that PetCO2 can complement other clinical and exercise test responses in the evaluation of patients with CHF. The observations that PetCO2 reflects cardiac impairment during exercise (Fig. 1), is a marker of ventilatory inefficiency (Fig. 2), and strongly predicts prognosis (2,5) suggest that PetCO2 should be routinely measured and included in the CPX test report when evaluating patients with CHF.
The current findings extend previously demonstrated associations between PetCO2 and cardiac output at rest (4,5,8,12,14,27,31,32) by observing an association between PetCO2 during exercise and the severity of CHF, the degree of exercise intolerance, and the degree of ventilatory inefficiency. The associations between PetCO2@VT and indices of ventilatory inefficiency (V˙E/V˙CO2 slope and OUES, r = −0.78 and 0.55, respectively; Fig. 2) underscore the link between low PetCO2 and an impaired cardiac output response to exercise, leading to ventilation/perfusion mismatching, heightened dead space ventilation, and exercise intolerance. Our results are similar to those of Tanabe et al. (29), who reported a correlation coefficient of −0.84 between the peak exercise PetCO2 and the V˙E/V˙CO2 slope, and those of Matsumoto et al. (18), who observed a correlation of −0.78 between the V˙E/V˙CO2 slope and PetCO2 at the respiratory compensation point. Both these previous studies also observed that PetCO2 during exercise was strongly and inversely related to VD/VT during exercise. The relation we observed between exercise PetCO2 and V˙O2 peak was more modest (r = 0.53), similar to that observed by Wasserman et al. (34) (r = 0.36). Although numerous previous studies have reported that resting PetCO2 reflects cardiac output changes among hospitalized patients (e.g., ICU settings) and has been shown to be prognostic (4,5,8,12,14,18,27,31,32), resting PetCO2 in the current study was somewhat less effective in identifying patients with an impaired exercise response. This is likely because unlike hospitalized patients, our subjects were ambulatory and generally did not exhibit overtly reduced cardiac output at rest.
Mechanism for impaired PetCO2
In normal subjects, PetCO2 increases during exercise due to a higher rate of CO2 production and thus CO2 delivery to the lungs by venous return. Although PetCO2 is similar to arterial CO2 pressure (PaCO2) in normally perfused alveoli, it is generally lower than PaCO2 in patients with ventilation/perfusion (VD/VT) mismatching, such as that commonly present in patients with CHF (33,34). Thus, when the rise in cardiac output with exercise is impaired, PetCO2 is reduced due both to the reduction in delivery of CO2 to the lung and to the mismatching of ventilation and perfusion caused by impaired cardiac output. PetCO2 during exercise is reduced when the VD/VT ratio is high, as has been reported in patients with chronic obstructive pulmonary disease and pulmonary hypertension (10), and is reduced in accordance with the impairment in V˙O2 peak in patients with CHF (18,29,34).
Noninvasive estimation of cardiac output
The noninvasive estimation of cardiac output using the NICOM device provided a useful and an easily applied tool to gain insight into cardiac performance during exercise. An impaired cardiac output response to exercise is a widely recognized hallmark of CHF (3,13,22,33,34,39), and direct measurements of the cardiac output response to exercise have been demonstrated to predict outcomes in CHF (6,17,19,35). Data on the direct measurement of the impaired cardiac output response to exercise are limited, however, due to the difficulties associated with performing this procedure (including the fact that it is invasive, costly, and associated with higher risk). The ability to routinely quantify cardiac output during exercise easily and noninvasively potentially has a great deal of value, both in terms of quantifying the degree of cardiac impairment as well as for risk stratification. Although both the PetCO2 (2,15) and the cardiac output response to exercise (6,17,19,35) have been shown to be strong markers of prognosis in patients with CHF, the extent to which these two measures provide independent or additive prognostic value requires further study.
We did not have direct measurements of cardiac output with which to compare those of the noninvasive device, although the device has recently undergone validation in both experimental and clinical conditions (15,22,26,28). We did not measure direct arterial blood gases with which to quantify VD/VT; however, numerous prior studies have documented ventilation/perfusion mismatching with exercise in CHF. In addition, both PetCO2 and noninvasive estimates of cardiac performance require further study as determinants of prognosis.
Reduced PetCO2 during exercise reflects the severity of HF and the impaired cardiac output response to exercise in patients with CHF. PetCO2 is a marker of ventilatory inefficiency and cardiac performance that should be routinely reported when performing CPX to evaluate patients with CHF.
This study was supported in part by a grant from the Cheetah Medical Inc., Wilmington, DE. The results of the present study do not constitute endorsement by ACSM.
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Keywords:© 2009 American College of Sports Medicine
CARDIAC OUTPUT; OXYGEN UPTAKE; EXERCISE TESTING; VENTRICULAR FUNCTION; EXERCISE CAPACITY