Cardiopulmonary exercise testing (CPET) has many important clinical and research applications (1,2). Defining repeatability of CPET measurements is important when determining a response to a therapy or training program, or monitoring disease progression. Change in a CPET parameter that exceeds the normal biological and instrument variability suggests an interval change in the subject. Previous studies assessing short-term CPET variability have notable limitations including inconsistent methodology and statistical analysis, small sample sizes, dated technology, and a limited number of CPET parameters (1,3–19). For example, sample sizes have generally been less than 20 subjects for studies in various populations, and only the publication by Skinner et al. (19) in 1999 performed in healthy subjects has had a sample size larger than 20. Most of these studies report on few parameters, mostly work rate or exercise duration, peak oxygen consumption (V˙O2), peak heart rate (HR), and peak minute ventilation (V˙E). There are additional important parameters including V˙O2@lactate threshold (LT), the ventilatory equivalent for CO2@LT (V˙E/V˙CO2), peak respiratory exchange ratio (RER), and peak O2 pulse with limited or no information on repeatability (4,9–12,16,19). Variability in peak V˙O2, measured as coefficient of variation (CoV), has been reported as a low of 3% and a high of 13% (4–19). The threshold for determining a meaningful change in peak V˙O2 and V˙O2@LT, two of the most clinically important CPET parameters, has not been well described (2).
The aims of this study include the following: 1) characterize short-term repeatability for clinically important CPET parameters in healthy subjects using a modern instrument with accurate flow sensors and rapid gas analyzers; 2) assess if a “learning effect” is suggested by a significant difference between an initial and second CPET assessment; 3) identify the threshold for meaningful change in peak V˙O2 and V˙O2@LT; and 4) identify differences in variability related to sex, age, fitness level, and diurnal factors. Note that we have used the term “repeatability” to characterize changes in CPET because testing was obtained using the same exercise protocols and equipment in the same laboratory performed by one of two physicians (20). We use the term “lactate threshold” by convention in this manuscript but acknowledge the lack of consensus or standardization in terminology (21,22).
METHODS
This study population consisted of a convenience sample of 45 healthy, nonsmoking, volunteers 18–40 yr of age (24 women and 21 men) who performed aerobic exercise ≤3 times per week and were enrolled in a fitness-related clinical trial (NCT02941939). Pregnant women were excluded. Other inclusion criteria included spirometry within predicted limits using National Health and Nutrition Examination III reference values and a screening CPET (CPET-1) with peak V˙O2 between 75% and 125% predicted (23,24). The study was performed in the pulmonary laboratory at Intermountain Medical Center, Murray, UT, between September 2016 and April 2017. Intermountain Healthcare Institutional Review Board approved the study protocol, and each subject gave written consent. Subjects performed CPET as part of a screening visit (CPET-1) for the exercise-related clinical trial and then a second CPET within 30 d (CPET-2) before beginning the exercise intervention. Each test was a maximal, symptom-limited continuous ramp CPET using a cycle ergometer. Before each test, the format was explained to the subject and there was no familiarization protocol for cycling while wearing the equipment. A Hans Rudolph 7450 Series Silicone V2™ Oro-Nasal Mask was worn during testing. Each test was reviewed for evidence of air leak or other technical irregularities.
Testing was performed and supervised by a pulmonary physician. The CPET procedure was identical for each participant in both tests: specifically, a continuous ramp protocol with an increase of 20, 25, or 30 W·min−1, estimated to result in approximately 10 min of exercise on the basis of the predicted peak work rate (23). The protocol consisted of 2 min of resting data collection, then 2 min of unloaded cycling followed by the continuous ramp protocol and 2–3 min of recovery. Subjects were instructed to pedal between 55 and 65 rpm and exercise until they could “go no longer.” Subjects were not specifically coached or encouraged, and the test was terminated when they could no longer keep the ergometer >50 rpm or they stopped because of exhaustion.
CPET was performed using a computer-controlled cycle ergometer with a CareFusion Vmax System (CareFusion, Yorba Linda, CA). The mass flow sensor and gas analyzers were calibrated before each test and met current standards for accuracy, reproducibility, and response time (1,21). Equipment quality control was also monitored throughout the study duration with biweekly biological control testing as previously suggested (1). The data were measured breath-by-breath and averaged during 20-s intervals. The peak V˙O2 was the highest V˙O2 during a 20-s interval obtained at the end of exercise. The LT was determined using a 10-s interval, and both the V-slope and the ventilatory equivalent for O2 (V˙E/V˙O2) graphs were used to identify LT (22). The LT was agreed on by consensus between the two pulmonologists supervising all tests.
Clinically important CPET parameters were measured at peak exercise and/or LT as appropriate and included the following: time to exhaustion, work rate, V˙O2, HR, RER, O2 pulse, V˙E, V˙E/V˙CO2, V˙E/V˙O2, and end-expiratory pressure of CO2 (PETCO2). Other CPET variables collected at peak exercise included the following: systolic and diastolic blood pressure, Borg dyspnea scale (1–10), rate of perceived exertion scale (6–20), and reason for test termination. Automated blood pressures (Suntech Tango M2) were measured at rest, during the warm-up, at 2-min intervals throughout exercise, and during the third minute of recovery. The Borg dyspnea scale and rate of perceived exertion were recorded at baseline and peak exercise for this study as have been previously described (25–27).
Statistical analysis
Patient-level CoV was calculated for each parameter using the mean ± SD of the paired tests; the average CoV is reported for each parameter. Differences between CPET-1 and CPET-2 parameters were assessed using a paired t-test, controlling for multiple comparisons using the false discovery rate described by Benjamini and Yekutieli (28). Bland–Altman plots were also created to assess repeatability (29).
Wilcoxon rank sum tests were used to assess whether variability (estimated by CoV) was significantly different by sex or tests performed at different times of the day (time of tests, greater than 4-h difference) among the following parameters: peak V˙O2, V˙O2@LT, V˙E/V˙O2@LT, and V˙E/V˙CO2@LT. We also compared the peak RER, RER@LT, and peak V˙E for tests performed more than 4 h apart. Spearman correlation coefficients were used to compare age and fitness level (estimated by the averaged % predicted peak V˙O2) with the CoV of the parameters selected above.
Finally, to determine a threshold for meaningful change, we calculated the 95% coefficient of repeatability (defined as 2 SD of the differences), with the repeatability interval defined as the mean of the differences ± coefficient of repeatability (20). A change outside the bounds of this interval in an individual subject can be concluded with 95% confidence to be a change not due to natural variation. We report the threshold for meaningful change for peak V˙O2 and V˙O2@LT, both as a raw change (L·min−1), indexed for body weight (mL·kg−1·min−1), and as a percent change for both.
RESULTS
A total of 49 subjects had two tests performed within 30 d. Four subjects were excluded because of technical factors (three with mask leaks during one test and one with a different ramp protocol). Of the 45 subjects analyzed, 24 (53%) were women and 21 (47%) were men, 44 (98%) were Caucasian, and the mean age was 31 yr. Characteristics of the study population are summarized in Table 1. The mean ± SD time between CPET-1 and CPET-2 was 10 ± 9 d (range, 1–30 d). All tests had a peak RER of >1.0 and 90% had a peak RER of >1.10, suggesting near maximal effort. The results were not different when tests with a peak RER of <1.10 were removed.
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TABLE 1: Demographic and CPET characteristics.
The mean ± SD and range for CPET-1 and CPET-2, average absolute percent difference, and CoV are reported in Table 2 for performance and physiologic variables.
TABLE 2: Repeatability of CPET parameters.
The CoV for peak V˙O2 was 4.9%. There were no statistically significant differences between any parameters from CPET-1 to CPET-2. Peak V˙O2 of CPET-2 was greater than CPET-1 in 19 (42%) subjects, including 9 subjects with an absolute increase in percent change of ≥10%. Four subjects had a decrease in peak V˙O2 from CPET-1 to CPET-2 of ≥10%. Figure 1 depicts Bland–Altman plots for nine select parameters.
FIGURE 1: Bland–Altman plots of select parameters. Pertinent CPET parameters are depicted with 95% CI lines for each. CI, confidence interval.
The CoV in peak V˙O2 was lower for women, although this did not reach significance (3.9% vs 6.1%, P = 0.14), and there were no differences in variability between men and women for V˙O2@LT (P = 0.33), V˙E/V˙O2@LT (P = 0.85), or V˙E/V˙CO2@LT (P = 0.81; see Table, Supplemental Digital Content 1, Comparing CoV (%) in men versus women for peak V˙O2, V˙O2@LT, V˙E/V˙O2@LT, and V˙E/V˙CO2@LT, https://links.lww.com/MSS/B91). RER@LT was significantly higher for tests performed >4 h apart on a given day (6.0% vs 3.3%, P = 0.02; see Table, Supplemental Digital Content 2, Comparing CoV (%) in tests performed >4 h apart for peak V˙O2, V˙O2@LT, V˙E/V˙O2@LT, V˙E/V˙CO2@LT, peak RER, RER@LT, and peak V˙E, https://links.lww.com/MSS/B92). Of the 11 subjects who performed tests >4 h apart, the RER@LT was higher in 7 (64%) subjects with CPET-2 performed in the afternoon compared with CPET-1 in the morning hours. Age (see Figure, Supplemental Digital Content 3, Comparison of CoV (%) versus age in peak V˙O2, V˙O2@LT, V˙E/V˙O2@LT, and V˙E/V˙CO2@LT, https://links.lww.com/MSS/B93) and baseline fitness level (using the average % predicted in peak V˙O2; see Figure, Supplemental Digital Content 4, Comparison of CoV (%) versus baseline fitness level in peak V˙O2, V˙O2@LT, V˙E/V˙O2@LT, and V˙E/V˙CO2@LT, https://links.lww.com/MSS/B94) did not correlate with variability in peak V˙O2 (r = −0.18, −0.16), V˙O2@LT (r = −0.05, −0.09), V˙E/V˙O2@LT (r = 0.15, −0.05), or V˙E/V˙CO2@LT (r = 0.01, −0.13), respectively.
The 95% threshold for meaningful change is 0.540 L·min−1 in peak V˙O2 and 0.520 L·min−1 in V˙O2@LT. This is reported in Table 3 in liters per minute and in Table 4 adjusted for body weight (mL·kg−1·min−1) as both raw change and percent change. The 90% threshold for meaningful change is reported in the supplemental data content (see Tables, Supplemental Digital Content 5, 90% Threshold for meaningful change in peak V˙O2 and V˙O2@LT (in liters per minute and percent change), https://links.lww.com/MSS/B95; Supplemental Digital Content 6, 90% Threshold for meaningful change in peak V˙O2 and V˙O2 at LT (weight adjusted), https://links.lww.com/MSS/B96).
TABLE 3: 95% Threshold for meaningful change in peak V˙O2 and V˙O2@LT (in L·min−1 and percent change).
TABLE 4: 95% Threshold for meaningful change in peak V˙O2 and V˙O2@LT (weight adjusted).
DISCUSSION
Using breath-by-breath data collection, and modern flow sensors and rapid gas analyzers, we provide CoV for clinically important CPET parameters in healthy subjects. As reflected in Table 5, we found lower CoV (higher repeatability) in most symptom-limited CPET parameters than in those previously reported (1,3–19,30). There were no significant differences in the measured parameters between CPET-1 and CPET-2, which indicates that there was no learning effect in these two tests. The repeatability in peak V˙O2 was not significantly higher in women and variability was otherwise not affected by age, diurnal factors, or fitness level. We have also calculated a threshold for meaningful change in peak V˙O2 and V˙O2@LT.
TABLE 5: Summary of the Reproducibilitya of CPET parameters.
Prior studies have addressed CPET repeatability in healthy subjects and patients with cardiopulmonary disease (1–14,17–19). Most studies have reported the CoV for a limited number of CPET parameters, most often work rate/exercise duration, peak V˙O2, HR, and peak V˙E. We found lower variation for most parameters than for those reported in prior studies. Whether the variability reported during a maximal symptom–limited test can be applied to performing biologic controls is unclear, but Porszasz et al. (31) suggest that the physiologic variability of maximal testing may not be reflective of that from submaximal steady-state measurements. Therefore, extrapolating these data for use in biologic controls during steady-state measurements may not be accurate.
Peak V˙O2 is one of the most important CPET parameter for determining cardiorespiratory fitness and is commonly used as a primary end point for studies using CPET to determine the effect of therapeutic interventions or training programs. Studies evaluating short-term variability for peak V˙O2 have produced varying results, with a CoV ranging from 3% to 13% (4,6). Increased variability is not unexpected in studies using less accurate instruments, inconsistent exercise protocols, and inexperienced technicians among other factors. Using highly consistent exercise testing methodology, we found a CoV for peak V˙O2 of 4.9%. The largest prior study in healthy subjects (n = 390) found a similar CoV of 5.1% for peak V˙O2 (19). Previous studies reported repeatability for peak V˙O2 in patients with chronic obstructive pulmonary disease (COPD) (5,6,17,18), cystic fibrosis (14), congestive heart failure (7,10,11,15), and pulmonary arterial hypertension (9) with varied results (Table 5). We found high repeatability for peak work rate with a CoV of 2.7% compared with a 3.6% to 13.8% in prior studies.
Accurate and repeatable measurement of V˙O2@LT is significant because this parameter is important for CPET interpretation and for determining the effects of interventions such as training programs and medical or surgical therapies (22). Repeatability in V˙O2@LT is less well described and CoV has been reported in the range of 6.5% to 19% (1,4,8–12,16); CoV for V˙O2@LT in our study was 10.4%. Higher variability in V˙O2@LT is expected given the absence of validated, standardized, objective methods for measuring it. One study found variability in determining LT of 16% when the same tests were reviewed independently by four exercise physiologists (32). In this study, we used two readers along with a combination of the ventilatory equivalents and V-slope methods to determine LT recommended by the American Thoracic Society/American College of Chest Physicians guidelines (1,33).
We found a lower than generally reported CoV for peak HR, peak V˙E, peak V˙O2, pulse, peak RER, and peak systolic and diastolic blood pressures (Table 5). We further report on the high repeatability of V˙E/V˙O2@LT, V˙E/V˙CO2@LT, and PETCO2@LT, which have not been well described. In particular, V˙E/V˙O2 and V˙E/V˙CO2@LT have a lower variability than V˙O2 and are important variables in identifying LT and the efficiency of ventilation respectively (Table 5). The lower variability of these measures compared with V˙O2@LT reiterates how tightly controlled ventilation is in relation to a given V˙CO2 and correspondingly its association with a given V˙O2.
The fact that our reported variability is lower than previous studies in healthy subjects may suggest that the combination of breath-by-breath analysis, and current accurate and precise flow sensors and modern gas analyzers has improved the repeatability of a symptom-limited CPET (1,3–19).
We found no evidence of “learning effect” because there was no significant difference between CPET-1 and CPET-2. This corroborates the recommendation by Puente-Maestu et al. (2) that there is no need to perform more than one baseline CPET in clinical trials when a standardized maximal effort test is performed.
When comparing the CoV between male and female participants, the lower variability in women did not reach significance. We did find a significant difference in the RER@LT in tests performed >4 h apart on separate days, but not in any other CPET parameter. Garrard and Emmons (8) suggest that there may be diurnal variation in CPET measurements related to diet/substrate availability. Although we did not specifically track diet before tests, our results suggest that there are no significant diurnal effects for most CPET measurements. There was also no correlation between CoV and age or baseline fitness level, suggesting that these do not affect CPET variability.
An important practical implication of our findings is the determination of a 95% threshold for meaningful change in peak V˙O2 and V˙O2@LT. The threshold for meaningful change for peak V˙O2 is 0.540 L·min−1 (18.9%); the corresponding value for V˙O2@LT is 0.520 L·min−1 (36.8%). A change greater than these values suggests, with 95% confidence, a change due to a training program, medical or surgical therapy, or in the disease process. There is a paucity of information regarding what is a meaningful change in CPET measurements. McKone et al. (14) report that in patients with cystic fibrosis, a 19% change in peak V˙O2 is likely a meaningful change, whereas Hansen et al. (9) report a change of 8%–10% in peak V˙O2 is meaningful in patients with PAH. In the National Emphysema Treatment Trial, a change of 4 ± 1 W was the symptoms-anchored meaningful clinically important difference for COPD patients with severe obstruction; this corresponds to a peak V˙O2 change of 0.040 ± 0.01 L·min−1 (2,34).
Using the limits of a Bland–Altman plot is an alternative way of defining meaningful change (1.96 SD). It is also reasonable, with 90% confidence, that a change in a given parameter not due to natural variation is sufficient; these thresholds are provided in the online data supplement (see Tables S3, Supplemental Digital Content 5, 90% Threshold for meaningful change in peak V˙O2 and VO2@LT (in liters per minute and percent change), https://links.lww.com/MSS/B95; and S4, Supplemental Digital Content 6, 90% Threshold for meaningful change in peak V˙O2 and V˙O2 at LT (weight adjusted), https://links.lww.com/MSS/B96).
The limitations of our study and, therefore, the generalizability of our results may include that all tests were performed at a single center at 1400-m altitude using a single instrument. Although altitude presumably would not affect variability within a subject, it could increase the CoV for a respective parameter compared with sea level. For example, a lower mean peak V˙O2 with the same SD would result in a higher CoV (CoV = SD/mean). Whether or not there is a significant difference in V˙O2 at our altitude of 1400 m that would significantly affect these values or the values for meaningful threshold is unknown. Wasserman et al.(22) suggest allowing for a 5% decrease in peak V˙O2 at 1609 m (1 mile) of altitude, though again, to our knowledge, there have not been studies looking at differences in peak V˙O2 at this specific altitude. In addition, subjects were racially homogeneous (97% Caucasian), ≤40 yr of age, and healthy with normal cardiorespiratory fitness (median peak V˙O2 per subject averaged over the two tests performed was 111%). Extrapolation of our results to older subjects and patients with cardiopulmonary disease should be done with caution, although prior studies have reported similar CoV for peak V˙O2 in healthy subjects and patients with cardiac or pulmonary disease (1,3–6,8–19,30). Other limitations include the sample size (although ours was moderate compared with other published studies) and the fact that we used only cycle ergometry. Results may be different using a treadmill.
CONCLUSIONS
We report short-term repeatability for CPET parameters in healthy subjects using an accurate and precise instrument. Repeatability was higher for most CPET parameters than for those previously reported in the literature. We found no evidence for learning effect and no significant differences in variability related to sex, age, fitness level, and diurnal factors. Finally, we report on 95% confidence values for meaningful change in peak V˙O2 and V˙O2@LT, potentially providing useful information for identifying responses to therapies or training programs.
This work was funded by an Intermountain Medical Research Foundation Grant. All authors have no conflicts of interest to disclose. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine.
T. W. D. had full access to all of the data in the study and takes responsibility for the integrity of this work from study design to the published article. T. W. D., S. M. B., E. L. W., and M. J. H. all contributed to the study design, data analysis and interpretation, and the writing of this manuscript.
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