INTRODUCTION
Evidence suggests that individuals with stroke benefit from cardiovascular exercise interventions. Several prospective trials and meta-analyses investigating cardiovascular fitness interventions using leg cycle ergometry, treadmill training , and combined upper- and lower-limb ergometry demonstrated beneficial effects on cardiovascular fitness in subacute1–12 13–17 18 19 20 , 21 22 , 23 24 , 25
A promising approach to overcome motor limitations while facilitating task-specific activity and cardiovascular stress is body weight-supported treadmill training . Research has shown that gait symmetry improves with increasing body weight support.26 treadmill training compared with conventional treadmill exercise.27 , 28
Studies on motor recovery after stroke have shown that RATE seems to facilitate similar outcomes compared with body weight-supported treadmill training .29–31 32 treadmill training in persons with incomplete spinal cord injury.33 34–36 34
Optimal exercise intensity is a crucial factor for improving cardiovascular fitness. Recent guidelines for individuals with stroke recommend regular cardiovascular exercise at an intensity level of 40% to 70% heart rate reserve (55%-80% of heart rate maximum; rate of perceived exertion 11-14 [scale of 6-20]).37 38 35 , 36 39 40 , 41 42
The aim of this study was to carry out a preliminary investigation of 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.
METHODS
Design
This was a single-center, single-blind, randomized controlled pilot trial. The study protocol was published previously.43
Participants
Twenty participants with first-ever stroke were recruited by research staff at a neurological rehabilitation clinic in Switzerland between October 2012 and March 2014. Participants were presented to the responsible ward physician and a cardiologist to confirm eligibility. Inclusion criteria were (1) clinical diagnosis of a first-ever stroke, (2) less than 20 weeks poststroke, (3) older than 18 years, (4) Functional Ambulation Classification less than 3, and (5) ability to understand the procedures and provide informed consent. Exclusion criteria were (1) contraindications for cardiopulmonary exercise testing as outlined by the American College of Sports Medicine,44
Randomization was performed using a computer-generated permuted 4-block allocation scheme. A researcher not otherwise associated with the study generated the list and sent it to the clinic pharmacy for safekeeping. The lead trial therapist contacted the pharmacy for assignment. A blinded examiner conducted all assessments and the randomization was concealed until the last postintervention assessment was performed and the data processing and acquisition was terminated.
Outcomes
The primary outcome of this study was efficacy, which was evaluated by cardiovascular fitness and training intensity. Peak cardiopulmonary performance was assessed by peak oxygen uptake (VO2peak ), peak work rate (Ppeak ), peak ventilation rate (VEpeak ), peak respiratory rate (Rfpeak ), peak heart rate (HRpeak ), and respiratory exchange ratio (VCO2 /VO2 ) at VO2peak (RERpeak ). Additional cardiovascular parameters included the gas exchange threshold and important derivatives such as O2 cost of work (ΔVO2 /ΔP), O2 pulse at VO2peak (O2pulse ), and VE versus VCO2 slope (ΔVE /ΔVCO2 ). Continuous heart rate monitoring was used to evaluate the training intensity. The secondary outcome was feasibility, which was rated on the basis of predefined criteria.45
Instrumentation
Robotics-assisted treadmill exercise was implemented using a robotic gait orthosis (Lokomat, Hocoma AG, Volketswil, Switzerland). The powered exoskeleton provides control of both legs, synchronized with an integrated treadmill (h/p/cosmos sports & medical GmbH, Traunstein, Germany) and a motor-driven body weight support system with real-time feedback control for body weight unloading (Lokolift, Hocoma AG, Volketswil, Switzerland). The feedback-control approach for exercise testing and experimental training was based on the work rate exerted on the exoskeleton by the participant calculated from the force, moment arm, and velocity data at the 4 active joints (hip and knee). The participant was instructed to vary the forces applied on the exoskeleton by volitional muscle activity and to keep the measured and visualized active work rate as close as possible to the target (Figure 1). Detailed information on FC-RATE can be found elsewhere.40
Figure 1: Feedback-controlled robotics-assisted treadmill exercise. Hip and knee joint forces and angles are measured in real time to allow calculation of the mechanical work rate (P mech , solid line) and projection onto a screen in front of the person. Individual target work rate profiles (P *mech , dashed line) are used to guide exercise intensity during robotics-assisted walking. The passive mechanical work rate (P passive ) is evaluated before every session and subtracted from P mech . M i , moments of force; P raw , raw mechanical work rate; P total , total mechanical work rate; ωi , angular velocity.
Pulmonary gas exchange and ventilatory measurements were carried out using breath-by-breath ergospirometry (MetaMax 3B, Cortex Biophysik GmbH, Leipzig, Germany). Heart rate was recorded by a heart rate belt (T31, Polar Electro, Kempele, Finland) and a receiver board (HRMI, Sparkfun, Boulder, CO). A software module for the overall procedure was programmed in LabVIEW (Version 2009, National Instruments, Austin, TX).46
Testing Procedure
Cardiovascular fitness was assessed using FC-RATE-based cardiopulmonary exercise testing. At study entry, all participants completed a familiarization session with the FC-RATE concept, starting with a trained physical therapists adjusting the robotic orthosis to provide a physiological gait pattern and ensuring the participants could walk comfortably. An initial test of decreasing body weight support continuously by 5% per minute was implemented to define the minimal possible body weight support level. After the first adjustments, participants were asked to perform a short constant load exercise test for 5 minutes (target work rate = 20 W) to practice using the feedback-control structure. Finally, the safety procedures for potential adverse events were explained in detail.
After a break of at least 24 hours, participants performed consecutive cardiopulmonary exercise testing with 48 to 72 hours between the trials. All sessions were controlled for time of day. Participants were instructed not to consume food, alcohol, nicotine, or caffeine at least 3 hours before testing.
Participants were asked at the beginning of the first exercise test to increase their maximal voluntary effort during FC-RATE within 30 seconds to define the maximal work rate for the subsequent tests. The progressive ramp was defined as a continuous slope aiming to reach the predefined maximal work rate in 10 minutes. All participants performed 2 tests at baseline (on separate days) and 1 test at postintervention. The test protocol followed strict termination criteria and there was close adherence to established models for cardiopulmonary exercise testing according to international guidelines.44 , 47 41
Intervention
Both groups were balanced in terms of exposure (3/wk, 30 min/session) over a period of 4 weeks (12 sessions). All training sessions were led by 1 of 2 experienced physical therapists, who were trained in the intervention protocols. The training intensity was monitored in both groups by continuous heart rate measurement and further confirmed by rating of perceived exertion on the Borg scale of 6 to 20.48
The experimental group received progressive cardiovascular exercise using FC-RATE. The first training session was defined to start at 40% of Ppeak (determined from a previous exercise test) to approach 40% of heart rate reserve (Borg scale approximately 11-14). The intensity was then adjusted on the basis of continuous heart rate data and rating of perceived exertion indications by modulating the target work rate in 5% increments for every subsequent session to reach the target intensity. The target heart rate was set at 40% to 70% of heart rate reserve.37
All participants received individually tailored conventional care, in addition to RATE or FC-RATE, including physiotherapy (4-5 sessions/wk, 30-60 min/session), occupational therapy (2-3 sessions/wk, 30-60 min/session), and individual speech and language therapy. Because of the severely impaired status of the participants, no specific aerobic exercise training was provided during conventional care.
Data Processing
Raw breath-by-breath data were processed using a zero phase shift moving average filter over 15 breaths.49 2peak was considered for analysis. Criteria for maximal aerobic capacity were (1) plateau in oxygen uptake, (2) respiratory exchange ratio 1.15 or more, and (3) peak heart rate within 10 beats per minute of the age-predicted heart rate maximum (adjusted for participants on β-blocker medications).44 2 plateau was performed by plotting the slope and 95% confidence interval (CI) of the ΔVO2 /ΔP slope, where data points outside the extrapolated 95% CI were taken as evidence of plateauing or leveling off behavior.50 51 52 53 54
Statistical Analysis
Descriptive statistics were calculated on all outcome variables. For comparisons of baseline characteristics and training intensity between groups, a Mann-Whitney U test was applied for continuous and ordinal variables and an x2 test for nominal variables. The analyses were based on the intention-to-treat approach. The F1-LD-F1 model by Brunner and Langer was used to test the median treatment effect, time effect, and the effect of the interaction by an analysis of variance-type test statistic (F n ).55 P values (P ≤ 0.05) were considered significant and no adjustment for multiple endpoints was performed.
RESULTS
Participants
The number of individuals screened, enrolled, randomized, and completing the trial is shown in Figure 2. There were no significant differences in baseline characteristics between the 2 groups (Table 1 ). No serious adverse events occurred during FC-RATE-based cardiopulmonary exercise testing. Thirteen participants (93%) completed the tests without symptomatic responses. The overall reason for test termination was inability to reach the target work rate because of generalized and/or leg fatigue.
Figure 2: Study flowchart.
Table 1: Participant Characteristics at Baselinea
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).
Efficacy
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 VO2 max 56 2peak from 14.6 to 17.7 mL · kg−1 · min−1 (45.8%-55.7% of predicted relative VO2 max 56 peak from 122 to 128 beats/min (80.7%-84.7% of predicted maximal heart rate52
Table 2: Feedback-Controlled Robotics-Assisted Treadmill Exercise-Based Cardiopulmonary Exercise Testing Results and Group, Time, and Interaction Effects
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.
Figure 3: Training intensity given as heart rate reserve (predicted maximal heart rate − resting heart rate) during the 4-week intervention (12 sessions). Values represent mean ± 95% confidence intervals.
Feasibility
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).
DISCUSSION
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.
Efficacy
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 37
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 34–36
A recent study that compared conventional RATE with standard care in a comparable sample found promising results, favoring RATE within only 2 weeks.38 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
Both groups improved their VO2peak , the accepted criterion for cardiovascular fitness, after the 4-week intervention. The mean overall increase in relative VO2peak of 3.1 mL · kg−1 · min−1 (+17.8%, ES 0.58) is nearly clinically meaningful, considering that 3.5 mL · kg−1 · min−1 has been associated with significantly fewer coronary events such as coronary artery disease60 61 2peak of +17.8% within 4 weeks, this is a promising result related to the spontaneous recovery of VO2peak of 16.9% in a 4-times longer period (20 weeks) reported in a comparable sample.62 Epeak (+19.9%), RERpeak (+7.2%), and O2 pulse at VO2peak (+11.6%) further underlines the improvement in exercise tolerance for both groups. Finally, the findings confirm the seriously compromised exercise capacity of individuals with severe impairments early after stroke, given the relative VO2peak values at postintervention of 17.7 ± 5.8 mL · kg−1 · min−1 , which are 55.7% of predicted VO2 max .56
Feasibility
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 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
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.
Limitations
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 57 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.
CONCLUSIONS
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.
Acknowledgments
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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