One participant required a test termination per safety criteria because of high systolic blood pressure of more than 210 mmHG during the baseline assessments, which was considered an adverse event. The participant's results were considered valid because both exercise tests were terminated at very high exercise intensity. The responsible ward physician/surgeon admitted the participant to the intervention phase after careful medical evaluation. The high systolic blood pressure response in this participant was not observed during any of the training sessions, or during the postintervention assessment.
With respect to the 3 criteria for maximal aerobic capacity, 2 participants (14%) showed a plateau in VO2, 1 participant (7%) achieved an RERpeak value 1.15 or more, and 4 participants (29%) reached HRpeak within 10 beats per minute of the age-predicted heart rate maximum; 2 of these had an adjusted heart rate because of β-blocker medication. None of the participants reached more than 1 criterion for maximal aerobic capacity. No significant differences were found across cardiopulmonary performance parameters at baseline, except for ΔVO2/ΔP (P = 0.017).
Peak cardiopulmonary performance showed no significant group-time interactions, but within-group analyses revealed that both groups improved over time (VO2peak absolute, P = 0.02, effect size (ES) 0.38; VO2peak relative, P = 0.01, ES = 0.58; VEpeak, P = 0.001, ES = 0.49; RERpeak, P = 0.001, ES = 0.82; O2pulse, P = 0.02, ES = 0.29) (Table 2). No other significant differences in cardiovascular performance parameters were found. Overall, absolute VO2peak increased from 1236 to 1477 mL · min−1 (48.2%-57.6% of predicted absolute VO2max56), relative VO2peak from 14.6 to 17.7 mL · kg−1 · min−1 (45.8%-55.7% of predicted relative VO2max56), and HRpeak from 122 to 128 beats/min (80.7%-84.7% of predicted maximal heart rate52).
Training intensity over the 4-week intervention period (12 sessions) was significantly different between the groups (heart rate, P = 0.002; heart rate reserve, P = 0.001). For the experimental group, heart rate was (mean ± standard deviation) 110 ± 8 beats/min (95% CI, 103-116) and heart rate reserve was 40% ± 3% (95% CI, 37-42). For the control group, heart rate was 83 ± 13 beats/min (95% CI, 73-92) and heart rate reserve was 14% ± 2% (95% CI, 12-16). The course of training intensity for both groups is shown in Figure 3.
The compliance to the intervention protocol was 100%. All participants who completed the baseline assessment were able to complete the training protocol. However, several controllable and uncontrollable events led to an attrition rate of 30% during familiarization and baseline assessment. Of the 6 participants who dropped out, only 2 gave reasons on the basis of uncontrollable factors such as suspected cerebrospinal fluid leak and acute respiratory infection. The other 4 dropouts were caused by controllable factors. The gait pattern of 1 participant was disturbed by severe spasticity, which prevented a physiological gait pattern. One participant had a tibial skin lesion and another developed severe groin pain because of inappropriate padding. Furthermore, 1 participant was able to, but not motivated to, follow the target work rate, as described previously. Although 2 cardiopulmonary exercise tests in 1 participant were considered as adverse events, no serious adverse events occurred during the study protocol (100% clinical safety), and all data could be recorded continuously (100% successful data acquisition).
This study aimed to carry out a preliminary investigation on efficacy and feasibility of FC-RATE for improving cardiovascular fitness in persons with severe motor impairments early after stroke. We hypothesized that FC-RATE would reach a substantially higher cardiovascular training intensity compared with conventional RATE in a clinical setting, thus resulting in significantly increased cardiovascular fitness after a 4-week FC-RATE intervention. In addition, we expected to affirm feasibility by achieving predefined criteria.
The results demonstrated substantial and significant overall increases in cardiovascular fitness, but no significant between-group differences when comparing FC-RATE with conventional RATE in a 4-week cardiovascular exercise intervention early after stroke. Although the FC-RATE concept achieved a significantly higher training intensity compared with conventional RATE, the difference between the 2 approaches was considered not to be clinically relevant. In detail, the experimental group did not consistently achieve the target range of 40% to 70% heart rate reserve.37 Subanalyses revealed that only 3 of the 7 participants in the experimental group (42%) achieved at least 40% heart rate reserve during the intervention phase (44%, 47%, 66% vs 28%, 28%, 29%, 35% heart rate reserve). Thus, FC-RATE did not consistently achieve recommended intensity levels for cardiovascular training,37 which highlights the need to further develop and optimize the effectiveness of this modality for training.
A major issue was the severely impaired status of the participants, which restricted exercise at higher target work rate values. This is underlined by the fact that the main reason for test termination during FC-RATE-based cardiopulmonary exercise testing was the inability to reach the target work rate because of generalized and/or leg fatigue. In addition, Ppeak in the experimental group was much lower at both time points compared with the control group, although not statistically different. This finding might have led to further limitations for the experimental group to achieve higher intensity levels. Even so, the high demand of coordinated limb movement, in combination with the severe neurological impairment of the participants, is a challenge. The period of time where participants could apply mechanical forces was probably too short, despite the slow walking speed of 0.57 m/s. Individuals generally tend to exercise using the unaffected side more dominantly, which leads to deviations from the predefined physiological gait pattern and further challenges in bilateral limb coordination. A further issue might be the low cardiovascular fitness status of the participants. The fact that all participants presented with severe motor impairments, low cardiovascular fitness status and were not used to physical exercise training complicated the implementation of prolonged FC-RATE. The results clearly indicated a slow increase in mean training intensity over time for the experimental group (Figure 3).
However, it has been shown that even light to moderate exercise intensity is beneficial in deconditioned persons.57 Feedback-controlled robotics-assisted treadmill exercise in its current form could, therefore, have potential for cardiovascular training. But the approach might have only limited power to promote significant between-group differences when compared with conventional RATE that has been shown to slightly increase exercise intensity.34–36 Unfortunately, the present study protocol provided light training intensity for both groups and, thus, washed out potential between-group differences. It can be hypothesized that a longer intervention period and/or a comparison to conventional care (no RATE) would lead to significant differences in cardiovascular fitness, as FC-RATE has been shown to significantly increase exercise intensity to a moderate level.
A recent study that compared conventional RATE with standard care in a comparable sample found promising results, favoring RATE within only 2 weeks.38 Unfortunately, the authors did not report the effective training intensity (eg, % heart rate reserve), which led to difficulties for comparisons. They guided the training intensity for the RATE group by decreasing body weight support from 40% to 0% and guidance force from 100% to 10%. Although the sample in this earlier study was not able to walk with body weight support of less than 40% because of severe motor limitations, their findings might be based on the comparison with a sedentary control group (conventional care), and the fact that the sample described was admitted earlier poststroke. Previously, the interval between stroke onset and intervention start as well as exercise intensity was shown to be predictive of training-induced gains in cardiovascular fitness.58
The protocol presented here evaluated the minimal body weight support at baseline, and adjustments during the intervention were only allowed within a range of ±10% to maintain a physiological gait pattern. Although a further decrease in body weight support was not feasible because of the low motor function status of the included participants, the goal to substantially reduce body weight support remains important to optimally facilitate hemiparetic leg loading (activate relevant weight-bearing muscles).59 Advanced orthoses along with sophisticated controllers might provide solutions to enable unilateral assist-as-needed support during RATE in the future.
Although the compliance to the intervention protocol was high, there was a dropout of 6 participants (30%) during familiarization and baseline assessment. Skin lesions and severe groin pain because of inappropriate padding are readily preventable by careful familiarization and padding procedures; however, abnormal gait patterns because of spasticity and lack of motivation are more difficult to control. Extended familiarization procedures, securing a careful padding of the limbs during all times, advances in harness design, and sophisticated work rate controllers are required to decrease attrition rates and improve motivation to elicit high target work rate levels in future trials.
The study demonstrated clinical safety and successful data acquisition. No serious adverse events occurred during FC-RATE-based cardiopulmonary exercise testing or during the intervention protocol. The strict eligibility criteria, designed to prevent adverse events in this pilot approach, led to the exclusion of a variety of individuals (97% of the initially screened population). For example, 21% were excluded because of cardiac contraindications for cardiopulmonary exercise testing. This large proportion of individuals with cardiac pathologies could profit from controlled cardiovascular exercise interventions. The number of individuals who cannot receive FC-RATE is rather small (ie, only 6% had contraindications for RATE), which underlines the potential impact of the concept.
Although the reliability of FC-RATE-based cardiopulmonary exercise testing has been demonstrated in a previous trial,41 the ability to evaluate true maximal exercise capacity using this novel approach needs to be tested. The fact that only 50% of the participants reached some criterion for maximal aerobic capacity suggests that the results on cardiovascular fitness presented here must be considered as submaximal overall. It could be that the guidelines postulated for healthy people and individuals with chronic stroke may not be realistic for determination of true exercise capacity in persons with severe motor limitations early after stroke. Further research in populations with severe motor impairments needs to establish valid criteria for maximal exercise capacity.
The clinical effort associated with the feedback-control approach presented in this study is comparable with conventional RATE. Additional measurements at baseline, such as the evaluation of minimal body weight support, can be easily implemented in clinical routine. As a minimum, 2 experienced therapists are needed to perform FC-RATE-based cardiopulmonary exercise testing, and 1 trained therapist can implement the training. Although previous work proposed a total-body recumbent stepper to implement cardiovascular exercise testing in persons with severe motor limitations,22,23 and FC-RATE might be considered as a very elaborate and costly endeavor, this is the first study that presents a task-specific training device for assessment of cardiovascular fitness and guidance of exercise intensity early after severe stroke.
Overall, the concept presented in this study is deemed feasible with a need for major modifications. Considering the complexity of implementing the procedure in a sample with severe motor impairments early after stroke and the lack of effective cardiovascular intervention strategies, the findings presented here are of high clinical importance. The study revealed major issues associated with the customization of RATE/FC-RATE and the consistent achievement of recommended intensity for prolonged training. Advances in body weight support systems and improved work rate controllers combined with appropriate visual and auditory feedback might provide solutions in the near future. For example, more degrees of freedom combined with individual joint control during the gait cycle would decrease body weight support to an absolute minimum, which in turn could increase exercise intensity in this population. Furthermore, the specific extensions of tasks (eg, robotics-assisted stair climbing) could further increase cardiovascular stress and, hence, facilitate task-specific training.
The major limitation of the current study is the small sample size, which may render the results underpowered. However, considering our pilot approach and the difficulty to implement an intensive cardiovascular exercise intervention in this early stage after severe stroke, the sample of 20 individuals at the outset was a realistic group size to obtain first estimates.
The results presented here could be partly explained by spontaneous recovery, in addition to the training intervention, and must therefore be interpreted with caution. Although most of the exercise tests can be considered as submaximal, the overall increase in exercise capacity could have been influenced by the improved motor status of the participants.
The present study was not able to include a control group that received usual care only because of ethical considerations (all included participants would have received RATE as usual care).
Although demonstrating early beneficial effects, despite the short training duration that has been reported in previous trials,8,38 the training volume and frequency in the current study was below recommended levels for cardiovascular exercise.57 The length of the inpatient stay restricted the training volume to a 4-week period, and the weekly course of in-house rehabilitation limited the training frequency. Optimal training volume and frequency should theoretically reach 5 sessions/wk for a minimum of 8 weeks.37
As this was a pilot trial, outcomes beyond basic cardiovascular fitness measures such as vascular risk factors, motor function, gait pattern, cognition, and well-being were not examined. Future trials need to establish deeper insight into the effects on cardiovascular health, motor recovery, cognition, and quality of life.
Substantial and significant overall increases in the main cardiopulmonary performance parameters were observed in both groups, but there were no significant between-group differences when comparing FC-RATE and conventional RATE. Feedback-controlled robotics-assisted treadmill exercise significantly increased exercise intensity in persons with severe impairments early after stroke, but the recommended intensity levels for cardiovascular training were not consistently achieved. Future research should focus on the development of appropriate algorithms within advanced robotic systems to promote optimal cardiovascular stress. This study is an important step toward the implementation of effective cardiovascular exercise along with task-specific training early after severe stroke.
The authors thank Prof. Dr T. Ettlin, Dr N. Urscheler, Dr B. Spoendlin, Dr A. Rohner, and Dr M. Kummer for clinical support and medical advice; H. Rosemeyer, N. Springinsfeld, and D. Vosseler for assistance during recruitment and exercise testing; and Dr J. Wandel and Dr D. Baettig for statistical support.
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