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Constant Work-Rate Test to Assess the Effects of Intradialytic Aerobic Training in Mildly Impaired Patients With End-Stage Renal Disease: A Randomized Controlled Trial
Núcleo Interdisciplinar de Estudos e Pesquisas em Nefrologia, Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, BrazilFederal Institute of Education, Science and Technology of Southeast of Minas Gerais, São João del Rei, Minas Gerais, Brazil
Reboredo MM, Neder JA, Pinheiro BV, Henrique DM, Faria RS, Paula RB. Constant work-rate test to assess the effects of intradialytic aerobic training in mildly impaired patients with end-stage renal disease: a randomized controlled trial.
Objective
To investigate if high-intensity constant work rate (CWR) would constitute a more appropriate testing strategy compared with incremental work rate (IWR) to assess the effectiveness of intradialytic aerobic training in patients with end-stage renal disease (ESRD).
Design
Randomized controlled trial.
Setting
Nephrology unit at the university hospital.
Participants
Patients (N=28; 47.0±11.9y) under hemodialysis (4.4±4.3y) were randomly assigned to exercise and control groups.
Intervention
Patients included in the exercise group underwent a moderate-intensity intradialytic aerobic training program 3 times per week for 12 weeks.
Main Outcome Measures
Cardiopulmonary and perceptual responses were obtained during an IWR and a high-intensity CWR test to the limit of tolerance on a cycle ergometer.
Results
Training-induced increases in peak oxygen uptake (Vo2peak) and time to exercise intolerance (Tlim). Mean improvement in Tlim (97.4%±75.6%) was significantly higher than increases in Vo2peak (12%±11.3%) (P<.01); in fact, while Tlim improved 50% to 200% in 9 of 12 patients, Vo2peak increases were typically in the 15% to 20% range. CWR test revealed lower metabolic, ventilatory, cardiovascular, and subjective stresses at isotime; in contrast, submaximal responses during the incremental work rate (at the gas exchange threshold) remained unaltered after training.
Conclusions
A laboratory-based measure of endurance exercise capacity (high-intensity CWR test to Tlim) was substantially more sensitive than oxygen uptake at the peak IWR test to unravel the physiologic benefits of an intradialytic aerobic training program in mildly impaired patients with ESRD.
PATIENTS WITH end-stage renal disease (ESRD), especially those undergoing hemodialysis (HD), have decreased exercise tolerance because of renal failure by itself (uremic neuro- and myopathy, anemia, cardiovascular abnormalities), comorbidities (diabetes, hypertension, osteoporosis, depression), and HD-related factors (immobility and postdialysis fatigue).
Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.
The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counseling for sedentary haemodialysis patients in the Netherlands: results of a randomized clinical trial.
A matter of considerable debate remains, however, about a specific testing strategy that should be used to assess the potential beneficial effects of intradialytic training in patients with ESRD.
In fact, most of the available literature relies on the changes in oxygen uptake (Vo2) at peak incremental work rate (IWR) exercise testing as the main laboratory-based criterion to judge the effectiveness of intradialytic training in these patients.
Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.
The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counseling for sedentary haemodialysis patients in the Netherlands: results of a randomized clinical trial.
However, training may improve several submaximal responses (eg, work and ventilatory efficiencies, cardiovascular stress) which are not necessarily translated into higher maximal aerobic capacity.
Moreover, the incremental nature of the IWR test barely resembles the physical challenges that patients face on daily life, and improvement in peak oxygen uptake (Vo2peak) after training might not be accompanied by similar changes in physical functioning.
Also important, the reported increase in Vo2peak may fall within test variability, especially in mildly-to-moderately impaired patients in whom training-induced changes in Vo2peak are relatively modest.
These limitations might be severe enough not only to raise concerns on the current approaches to objectively evaluate the effects of training in ESRD patients but also question the actual effectiveness of intradialytic training, a procedure that certainly increases the complexity (and costs) of the dialytic treatment.
In this context, time to exercise intolerance (Tlim) in response to high-intensity (ie, 70%–80% Vo2peak, usually above the gas exchange threshold [GET]) constant work rate (CWR) test has been increasingly used to assess exercise tolerance before and after therapeutic intervention in other disease populations.
The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease A comparison of three different exercise tests.
In addition to relative changes in Tlim (%Δ), comparisons of symptom intensity and physiologic variables of interest at a standardized time (isotime) have proved very useful in unraveling the effectiveness of exercise training.
It remains unclear, however, whether the CWR test would actually be superior to the traditional IWR test in evaluating the effects of aerobic training in ESRD patients.
The objective of the present study, therefore, was to investigate if a high-intensity CWR would constitute a more appropriate testing strategy compared with IWR to assess the effectiveness of intradialytic training in patients with ESRD. We hypothesized that relatively small training-induced %Δ changes in Vo2peak would be accompanied by larger variations in Tlim, which in association with lower metabolic, cardiovascular, and ventilatory stresses at isotime during the CWR, would better reflect the benefits of intradialytic training in this patient population.
Methods
Participants
The sample included ESRD patients undergoing HD, 3 times per week totaling 12 hours weekly, for at least 6 months (values ranging from 6–162mo) in the Nephrology Unit at the University Hospital of the Federal University of Juiz de Fora, State of Minas Gerais, Brazil.
No patient had been involved in any kind of exercise training in the preceding 6 months. Exclusion criteria were: uncontrolled arrhythmia, hypertension and diabetes mellitus, unstable angina, severe respiratory diseases, acute infection, severe renal osteodystrophy, and neurologic or musculoskeletal disturbances. The study protocol was approved by the Research Ethics Committee of the Federal University of Juiz de Fora, and all patients signed an informed consent form.
Patients meeting the inclusion criteria were randomly assigned to either the exercise or the control group.
Study Design
Patients included in the exercise group were submitted to intradialytic training, 3 times per week for 12 weeks, and patients allocated to the control group remained in regular dialysis treatment during the same timeframe. Before and after the intervention or control periods, the participants were submitted to an IWR test and, after 2 days, to a CWR test to Tlim.
Intervention
Aerobic exercise training
Supervised aerobic training on a horizontal electromagnetically braked cycle ergometera was performed during the first 2 hours of HD. Initially, patients warmed-up for 10 minutes by performing lower-limb stretching exercises and low work rate (WR) (4.9Nm) and cadence (up to 35 revolutions per minute [rpm]) cycling for 5 minutes. The conditioning phase included 35 minutes of aerobic exercise in which WR and cadence were set to the tolerance of each patient as established by his/her inability to maintain Borg scale ratings for dyspnea and leg effort scores between 4 and 6. During the cool-down phase, patients cycled for 3 minutes at the same WR and cadence of the warm-up. Arterial blood pressure was monitored at rest, every 5 minutes during training, and after cool-down. Heart rate (beats per minute) was monitored continuously by a heart rate monitorb. The criteria for interruption of training included intense physical exhaustion, chest pain, dizziness, presyncope, taquichardia, and hypotension.
Measurements and Outcomes
IWR cardiopulmonary exercise testing
In order to assess maximal exercise tolerance and to ascertain the safety of exercise training, each patient completed a symptom-limited IWR exercise test on a nondialysis day. The test was carried out on an electromagnetically braked cycle ergometer.c The incremental phase was preceded by 3 minutes of warm-up without resistance at 60rpm followed by a progressive (ramp) increase in WR (5–20W each minute for an 8–10min test) to the limit of tolerance. The indications for terminating exercise testing include: angina, ataxia, dizziness, presyncope, cyanosis, pallor, fatigue, shortness of breath, leg cramps, and chest pain. Carbon dioxide output (Vco2) (mL.min−1), Vo2 (mL.min−1), and minute ventilation (V̇e) (L.min−1) were measured breath by breath using a computer-based systemd which was calibrated before each test. Heart rate and rhythm were monitored continuously using a 3-lead electrocardiogram.e Blood pressure, intensity of dyspnea (breathing discomfort), and leg discomfort were assessed every 2 minutes by a 10-point category-ratio Borg scale. The highest Vo2 attained during the exercise test was defined as the Vo2peak. The GET was estimated by a V-slope method and confirmed by the ventilatory equivalents procedure.
On a nondialysis day, the patients underwent a symptom-limited CWR on the same electromagnetically braked cycle ergometer that was used in the IWR test. The test was preceded by 3 minutes of warm-up without resistance at 60rpm, followed by a stepwise increase in WR to 60% of the GET-peak WR difference measured at baseline. This intensity has been found to provide CWR tests whose duration usually lies within 3 to 10 minutes, that is, they are more likely to be interrupted because of true physiologic limitation instead of motivational factors.
Tlim was defined as the time point in which the patients signaled to stop exercising or could not maintain the required pedaling rate for 10 seconds despite being encouraged by the investigators. Isotime corresponded to the shortest Tlim comparing initial and final evaluations for a given patient.
Statistical Analysis
Statistical analyses were performed using SPSS version 13.0.f Data were expressed as mean ± SD or median (interquartile range) for symmetrically and asymmetrically distributed data, respectively. Differences between the 2 groups (demographic and clinical characteristics) were assessed by the unpaired t test and the Fisher exact test, as appropriate. The effects of time, group, and the interaction of time and group were evaluated by 2-way analysis of variance for repeated measures (for asymmetrically distributed data, log transforming was done). The comparisons of percent changes between groups were performed by unpaired t or Mann-Whitney U tests, as appropriate. Spearman rank correlation coefficient (ρ) was used to test associations between changes in Tlim and Vo2peak after training or control periods. A P value of less than .05 was considered statistically significant.
Results
Participants' Characteristics
Eighty-one chronic HD patients were initially considered for study inclusion. From these patients, 40 (49.4%) out of 81 met the inclusion criteria and 28 (70%) of 40 agreed to participate. A total of 24 (85.7%) out of the 28 patients completed the study (12 patients in each group) (fig 1). There were no significant differences in baseline demographic and clinical characteristics between exercise and control groups (table 1).
Average daily adherence to aerobic training was 76.8%±15.3% of the sessions. The most frequent causes of noncompliance were predialysis hypotension and reported pain in the lower limbs. No severe complications were found during intradialytic training. At the end of 12 weeks, the mean time of aerobic exercise (conditioning phase) increased from 26±9 to 33±4 minutes (P<.05). On average, patients trained at a heart rate corresponding to 72.7%±9.5% of peak heart rate attained during the IWR test at baseline.
Physiologic Responses in Exercise and Control Groups
There were no significant between-group differences at baseline for any of the variables measured during the IWR test at peak and at the GET (P>.05) (table 2). At the final evaluation, only the exercise group showed increases in maximal WR, Vo2peak, and V̇e peak (significant interaction of time and group, P<.05). At the GET, however, no significant differences for any of the physiologic and perceptual responses were found (see table 2).
Table 2Physiologic and Perceptual Responses to the IWR Cardiopulmonary Exercise Testing at Baseline and After 12 Weeks in Exercise and Control Groups
significant interaction of time and group (P<.05).
55.9±21.7
64.5±19.5
64.1±26.5
58.0±26.7
Heart rate (bpm)
142±10
141±14
139±24
135±24
Dyspnea (Borg)
5.5 (2)
6 (2.5)
5 (2.5)
5 (2.8)
Leg effort (Borg)
8.5 (3)
7.5 (2)
7 (4.8)
7 (2.8)
At the GET
WR (W)
40 (17.5)
47.5 (17.5)
50 (18.8)
42.5 (41.3)
Vo2 (mL·kg·min−1)
15.2±2.6
15.9±4.1
17.2±2.4
16.1±3.3
V̇e (L.min−1)
24.6±6.1
26.8±9.8
26.7±7.9
24.6±6.8
Heart rate (bpm)
110±14
111±11
113±24
111±20
Dyspnea (Borg)
4 (1)
3.5 (1.8)
4 (1)
3.5 (1.8)
Leg effort (Borg)
3 (1)
3 (1.8)
4 (1)
3 (1)
NOTE. Data are mean ± SD or median (interquartile range) for symmetrically and asymmetrically distributed data, respectively. Analysis of variance 2-way
Abbreviation: bpm, beats per minute.
significant interaction of time and group (P<.05).
We found that neither Tlim nor any the physiologic responses at isotime differed between exercise and control groups, except the intensity of dyspnea and leg effort (table 3). After intradialytic training, Tlim increased and metabolic (Vo2 and Vco2), ventilatory (V̇e), cardiovascular (heart rate), and subjective stresses (dyspnea and leg effort scores) were reduced at isotime (significant interaction of time and group, P<.05) (see table 3).
Table 3Physiologic and Perceptual Responses at Isotime
NOTE. Data are mean ± SD or median (interquartile range) for symmetricallyand asymmetrically distributed data, respectively. Analysis of variance 2-way:
Abbreviations: bpm, beats per minute; RER, respiratory exchange ratio.
Isotime mean was 311 seconds and 253 seconds at 60W and 76W in the exercise and control groups, respectively.
† Significant interaction of time and group (P<.05).
Consistent with these findings, table 4 shows that there were significant differences in percent change of Tlim and responses at peak IWR (WR, Vo2, and V̇e) and at isotime in the CWR (Vo2, Vco2, V̇e, and heart rate) between exercise and control groups.
Table 4Percent Change of Physiologic and Perceptual Responses to IWR (at peak and at the GET) and CWR (at isotime) Cardiopulmonary Exercise Tests
Changes in Tlim and Vo2peak after training or control periods were significantly related to each other (fig 2). Improvement with intradialytic training in both parameters were not related to baseline values (P>.05). Importantly, patients from the exercise group had significantly higher percent increase in Tlim than Vo2peak (P=.002); in fact, improvement in Tlim ranged from 50% to 200% for a typical 15% to 20% increase in Vo2peak (fig 3, table 4).
Fig 2Significant association between relative changes in Vo2 obtained on an IWR test and Tlim in response to a CWR test in the whole group of patients. Note, however, the differences in x- and y-axis scales.
Fig 3Relative changes in Vo2 at the end of an IWR test and Tlim in response to a CWR test in ESRD patients who were or not submitted to an intradialytic aerobic training program. P=.002 comparing ΔVo2peak with ΔTlim (paired t test).
The present study demonstrates that a laboratory-based measure of endurance exercise capacity (a high-intensity CWR test to the limit of tolerance) was appreciably more sensitive than Vo2peak to unravel the physiologic benefits of a 12-week aerobic intradialytic training program in mildly impaired patients with ESRD. The main supporting findings for this contention were: (1) Tlim increased after training at a much larger extent than Vo2peak (∼8-fold greater increases on average) and (2) metabolic, cardiovascular, ventilatory, and subjective stresses were significantly lower at a given time point (isotime) in the CWR test, while improvement in these responses at a submaximal intensity (GET) were not found during the IWR test. These data, therefore, not only provide evidence that measurements of maximal exercise performance might underestimate the benefits of intradialytic training but also lend support to the notion that indices of endurance exercise capacity (Tlim on a CWR test) should be clinically valued in this patient population.
There is an impressive body of evidence showing that either on-dialysis (intradialytic) or off-dialysis (extra-dialytic) exercise training are associated with clinically important outcomes in patients with ESRD. These benefits have been found to range from increased HD adherence and lower cardiovascular risk to improved health status and quality of life.
Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.
The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counseling for sedentary haemodialysis patients in the Netherlands: results of a randomized clinical trial.
Surprisingly, however, results derived from studies which looked at objective measurements of physical performance after training are much less impressive, especially if we consider those investigations which relied on Vo2peak after intradialytic training in patients who were not extremely detrained.
The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counseling for sedentary haemodialysis patients in the Netherlands: results of a randomized clinical trial.
In these studies, changes in Vo2peak were either negligible or modest. In fact, a comprehensive review showed that 1 out of 3 moderate-intensity aerobic intradialytic training programs reported improvements of 12% to 13% in Vo2peak, while the 2 other studies did not report any change in this variable.
The equivocal results of the trials, which looked to Vo2peak on isolation and the issues of complexity and costs of the IWR test, led to a greater use of self-paced tests of functional walking capacity, such as the six-minute walking test (6MWT), to assess the effects of training in ESRD patients.
Although the 6MWT is easier, cheaper, and more familiar to the patient than a laboratory-based test on a cycle ergometer, it is not free from caveats. The 6MWT requires large space to be performed, careful standardization on encouragement, and provides little physiologic information.
More important, however, there is a potential ceiling effect which means that it might not be sensitive enough to detect changes in patients who walk more at baseline.
In the specific context of intradialytic training, it could also be questioned whether the gains derived from a cycling-based program would be fully translated on a walking test. However, our patients were not submitted to a 6MWT and the sensitivity of the 6MWT remains to be compared with the CWR test in ESRD patients.
A different approach aiming to establish a compromise between costs/sophistication versus reliability/information is the goal of tests which combines physiologic measurements with indexes of endurance capacity. The high-intensity CWR test has been widely used in other disease populations such as those suffering from chronic respiratory diseases.
The effects of oxitropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease A comparison of three different exercise tests.
The rationale for these tests is based on the notion that the ability to sustain a physical effort, which promotes a sufficiently intense stress, is a finite construct as defined by the hyperbolic relationship between the imposed load and Tlim.
Consequently, it can be anticipated that any WR above a so-called critical power will be sustained for a time frame that decreases sharply as an inverse function of the critical power-peak difference.
In the specific context of ESRD, results from a single study suggest that Tlim during CWR might indeed be more sensitive than Vo2peak in these patients.
Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.
In this particular study, however, patients were required to stop the CWR test after 15 minutes (which may have reduced test responsiveness) and the authors did not look at the individual tests sensitivity. In the present study, for instance, an increase in Tlim after intradialytic training was 8-fold greater than a Vo2peak change, which highlights the large difference in the potential of individual tests in show the effects of interventions. Although the MCID remains to be established for ESRD patients, it is noteworthy that increases in Tlim typically exceeded the cutoff values suggested for pulmonary patients, that is, 100 seconds or 33%.
Factors determining constant work rate exercise tolerance in COPD and their role in dictating the minimal clinically important difference in response to interventions.
In fact, Tlim improved more than 33% from baseline in 10 of 12 patients, while increases in Vo2peak in excess of 20% were found only in 3 of 12 patients.
These data suggest that the observed changes in endurance capacity were of clinical importance, even if our patients were not particularly impaired.
The physiologic and subjective measurements at a standardized time point (isotime) during the CWR test were particularly informative to unravel the mechanisms underlying improved exercise tolerance. Therefore, it is interesting to note that not only Vco2 decreased at isotime but, albeit at a lesser extent, Vo2 (see table 3). Considering that the test was performed at a supra-GET exercise intensity domain, it is conceivable that the contribution of nonaerobic sources for adenosine triphosphate regeneration had been lessened after training, that is, decreased co2 production secondary to less H+ buffering at a given exercise intensity. The more logical explanation for a lower submaximal Vo2 despite an improvement in aerobic metabolism relies again on the metabolic consequences of performing a supra-GET exercise bout: at this exercise intensity, Vo2 fails to stabilize and there is a slow increase in Vo2 above the projected steady-state value.
Although a debatable issue, the more likely explanation for this extra Vo2 is the activation of less efficient muscle type II fibers, which are known to be less recruited after training-induced improvement in peripheral o2 delivery.
Other contributing factors may include lower ventilatory/cardiovascular work (see table 3) and improved mechanical efficiency after 12 weeks of training on the same exercise modality used for evaluation (cycle ergometry). As a corollary of these physiologic adaptations, dyspnea and leg effort were simultaneously reduced allowing the patients to tolerate the imposed WR for longer, if they were solely evaluated on a test paradigm that further increased the work load, that is, the conventional IWR test.
On a clinical point-of-view, it should be emphasized that the decision to incorporate intradialytic training on a HD setting takes into consideration the balance between potential benefits against the inherent increase in costs and logistics. Therefore, the issue of program efficacy is central to the decision-making process. By showing that the traditional approach to rely only on Vo2peak (IWR test) to assess patients' physical performance after intradialytic training underestimates its physiologic benefits, the present study points out the appropriateness to consider other alternatives. Although field exercise tests have gained popularity (see above), our data demonstrate that CWR test to Tlim is not only more sensitive to depict the benefits of training than the IWR test but also provide some important physiologic information which are relatively effort-independent, that is, submaximal responses at isotime. Collectively, therefore, these results are consistent with the notion that the CWR test has an enhanced ability to detect clinically relevant physiologic changes after intradialytic training in ESRD patients.
Study Limitations
There are some aspects that should be taken into consideration to adequately qualify our results. We evaluated a group of outpatients who albeit physically inactive showed only mild reductions in maximal aerobic capacity. Considering, therefore, that gains in Vo2peak after training might be inversely related to baseline values, it could be argued that patients had less room to further improve this parameter compared with Tlim. However, a recent review showed that improvement in Vo2peak after intradialytic training was largely independent of pretraining values (as confirmed in the present study).
In addition, our patients were submitted to moderate-intensity intradialytic training, and we are uncertain that high-intensity training would have a larger impact on Vo2peak. Of note, the aforementioned review failed to identify a single study which used high-intensity intradialytic training. Nevertheless, we recognize that our results should be confirmed in more disabled patients submitted to different training intensities. Interestingly, Vo2peak has been found to improve at a larger extent after aerobic intradialytic training with resistance training compared with aerobic intradialytic training alone, and it remains to be confirmed the superiority of the CWR test to evaluate the effects of combined training regimens.
Finally, the tests were not applied on a randomized sequence because the intensity of the CWR test was determined from the IWR test. Nevertheless, familiarization issues might have induced the patients to perform better on the second test, that is, the CWR.
Conclusions
A laboratory-based measure of endurance exercise capacity (high-intensity CWR test to Tlim) was substantially more sensitive than Vo2peak at the end of an IWR test demonstrating the benefits of a 12-week aerobic intradialytic training program in mildly impaired outpatients with ESRD. However, confirmation of these results in larger trials involving patients with different levels of aerobic capacity is needed before a widespread recommendation for the routine use of the CWR test in clinical practice.
TC-500; Funbec/Transform Tecnologia de Ponta, Rua Camacam - 141, Vila Anastácio, São Paulo – SP, 05095-000, Brazil.
f
SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL 60606.
Acknowledgements
We thank the nursing and medical staff at the Nephrology Unit of the University Hospital of the Federal University of Juiz de Fora. for their friendly support.
References
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Exercise capacity in hemodialysis, CAPD and renal transplant patients.
Endurance exercise training during haemodialysis improves strength, power, fatigability and physical performance in maintenance haemodialysis patients.
The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counseling for sedentary haemodialysis patients in the Netherlands: results of a randomized clinical trial.
Factors determining constant work rate exercise tolerance in COPD and their role in dictating the minimal clinically important difference in response to interventions.
Supported by a research grant from the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (grant no. APQ-02452-09 ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, and the IMEPEN Foundation.
No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Neder is an Investigator of the Conselho Nacional de Desenvolvimento Científico e Tecnológico. Neder is an investigator of the publicly funded in Brazil (Conselho Nacional de Desenvolvimento Científico e Tecnológico).
significant interaction of time and group (P<.05).
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