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Effectiveness of neuromuscular electrical stimulation for the rehabilitation of moderate-to-severe COPD: a meta-analysis

Purpose Patients with COPD often experience skeletal muscle dysfunction. For those who are unable or unwilling to undertake physical training, neuromuscular electrical stimulation (NMES) may provide an alternative method of rehabilitation. The purpose of this meta-analysis was to investigate the controversial topic of whether this therapy is effective in patients with moderate-to-severe COPD. Patients and methods We pooled data from nine trials published between January 9, 2002 and January 4, 2016 across PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, and relevant websites for randomized controlled trials. In these trials, patients with moderate-to-severe COPD were randomly allocated to receive NMES. Primary outcomes were quadricep strength and exercise capacity. The secondary outcome was health-related quality of life. Results We extracted data from 276 patients. NMES contributed to statistically improved quadricep strength (standardized mean difference 1.12, 95% confidence interval [CI] 0.64–1.59, I2=54%; P<0.00001) and exercise capacity, including longer exercise distance (weighted mean difference 51.53, 95% CI 20.13–82.93, I2=90%; P=0.001), and longer exercise endurance (standardized mean difference 1.11, 95% CI 0.14–2.08, I2=85%; P=0.02). There was no significant difference in St George’s Respiratory Questionnaire scores (weighted mean difference −0.07, 95% CI −2.44 to 2.30, I2=56%; P=0.95). Conclusion NMES appears an effectual means of enhancing quadricep strength and exercise capacity in moderate-to-severe COPD patients. Further research is demanded to clarify its effect on other outcomes and determine the optimal parameters for an NMES program.


Introduction
COPD is a major cause of morbidity and mortality worldwide, and leads to a significant economic and social burden. It is predicted to become the third-leading cause of death in 2020. [1][2][3] It is now recognized that COPD is characteristic with inspiratory muscle fatigue and skeletal muscle deconditioning, which is associated with reduced quality of life and premature mortality. 4 It has been well established that physical and respiratory muscle training is beneficial for patient rehabilitation in COPD, and physical training especially is considered one of the best treatments available for enhancing limb-muscle function. 1,[5][6][7] A recent study showed that physical training may prevent cognitive decline and associated comorbidities in male patients with COPD. 8  patients may be too frail to tolerate physical training because of intense breathlessness at rest or on minimum exertion. 9 Neuromuscular electrical stimulation (NMES) is emerging as a new rehabilitation modality that does not evoke dyspnea to obtain a benefit in patients who are unable to participate in a traditional rehabilitation program. Also, it has been intensively applied in healthy people and athletes for curative care rehabilitation and preventing deconditioning. 10 Previous studies [11][12][13][14][15][16][17][18][19][20] have not reached consistent conclusions, and a meta-analysis 21 published in 2014 draw equivocal findings on the effects of NMES in moderate-to-severe COPD. Also, there have been several larger-scale and higher-quality trials [22][23][24][25][26][27][28] published in recent years; therefore, we performed a meta-analysis to investigate the effects of NMES in these patients.

Patients and methods search strategy
We searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Google Scholar, and relevant websites to detect randomized controlled trials (RCTs) published up to June 2016 in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. [29][30][31] Search terms were "chronic obstructive pulmonary disease", "neuromuscular electrical stimulation", and their corresponding Medical Subject Headings terms. Studies were filtered for human subjects and RCTs; only published trials written in English were included. We excluded studies of comparisons other than NMES and those with duplicated data.

study selection
The inclusive selection criteria were RCTs investigating the role of NMES in patients with moderate-to-severe COPD, predefined program of NMES applied to the lower limbs, unstimulated or other treatment (ie, sham stimulation) defined as the control group, and primary outcome quadricep strength and exercise capacity, defined as moving distance and endurance time. The secondary outcome was St George's Respiratory Questionnaire (SGRQ) score. 32 The criteria complied with PICO (patient/problem/population, intervention, comparison/ control/comparator, outcomes) principles. For articles reported in more than two publications, only the full version was used for meta-analysis. Abstracts published merely in academic conferences or website materials were excluded.

Data extraction
Two investigators (XL and LG) assessed the title or abstract for eligibility. In cases of discordance, a third investigator (BG) participated in discussion to reach a final consensus.
For studies that met the inclusion criteria, full papers were obtained for further analysis. Information related to trial design, characteristics of the patients, and relevant results were noted according to a redesigned form. We recorded first author, year, patient numbers, age, sex, body mass index, forced expiratory volume in 1 second, stage of COPD, experimental and control interventions (ie, type of intervention, pulse duration, pulse frequency, duty cycle, intensity of current used, training intensity, session time, and duration in weeks), and outcome parameters and their results. When data were insufficient or inapplicable, we attempted to contact the authors by email or used a formula [29][30][31] to convert into available data.

Outcomes
Outcomes were assigned to categories according to comparable features and representation. The preestablished primary outcome was quadricep strength and exercise capacity. Quadricep strength was measured using various methods, including isokinetic quadricep peak torque, maximum voluntary contraction, and author-defined score. Exercise capacity was primarily 6-minute walk test (6MWT), 33 shuttlewalk test (SWT), 34,35 and constant-work test (CWT), 36 and we pooled exercise distance and endurance time from these tests. The prespecified secondary outcome was health-related life quality measured with the SGRQ.

Data analysis
Meta-analyses were done with RevMan 5.3 software (Cochrane Collaboration, London, UK). Weighted mean difference (WMD) or standardized mean difference (SMD) with 95% confidence interval (CI) was considered for summary statistics and derived for the comparison of NMES with other rehabilitation methods. SMD was utilized when studies reported different units or scales for the outcome. To account for between-trial differences, we used mixed-effect modeling with random effect for parameters of interest, because of the anticipated heterogeneity in NMES methodology, including different stimulating parameters, different durations of therapy, and diverse study designs and study populations. Heterogeneity across studies was tested using the I 2 statistic: I 2 values of less than 25%, 25%-50%, or more than 50% indicated low, moderate, or high heterogeneity, respectively. 37 Potential heterogeneity sources were identified by sensitivity analyses conducted by eliding one study successively and comparing the influence of each study on the overall pooled estimate if I 2 .50%. Funnel plots were not constructed, owing to the limited number (below 10) of studies included in the analysis. For another primary outcome of exercise capacity, subgroup analyses were performed based on methods of exercise test: 6MWT, SWT, and CWT. Data are presented as means (±standard deviation), and a twotailed P-value ,0.05 was considered statistically significant. The overall treatment effect was compared with its minimum clinically important difference (MCID).

evaluation of bias and quality assessment
Freedom from bias was evaluated for each study in accordance with the basis of methodological domains: 29-31 adequacy of random-sequence generation and allocation concealment, attrition bias, reporting bias, and other biases. Two authors (BG and XL) reviewed all the studies and assigned a value of "high", "low", or "unclear".
The methodological quality of the identified trials was scored independently using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system. 38,39 The GRADE system classifies four levels -high, moderate, low, and very low -in terms of the quality of evidence. This approach for book reviews on the quality of the evidence is based on five items: study limitations, inconsistency of the results, indirectness of evidence, imprecision, and reporting bias. For purpose of assessing the reliability of the grade, the quality classification of the selected articles was independently assessed by two investigators, with divergences resolved by a third investigator (GB).

articles retrieved and characteristics of included trials
Primary literature searches included 370 articles, of which 62 remained after exclusion of duplicates. Following screening of titles and abstracts, 20 studies were removed owing to unrelated content; 17 studies were not RCTs. Of 25 full-text citations, nine studies with 276 participants fulfilled inclusive criteria to be reviewed. For papers excluded from this analysis, eight were due to study design, 10,13,15,16,[40][41][42][43] four were due to the fact that stimulation was acupuncture, 44-47 three 11,24,28 had insufficient or inapplicable data, and one 25 reported on the same group of participants as in another paper. 26 Figure 1 describes the different phase of the search process. The pooled articles were published between 2002 and 2016. By pooling data from these trials, 139 were assigned to NMES (intervention population) and 137 assigned to the control population. The characteristics of participants, interventions, and the main results extracted in corresponding studies are shown in Table 1. NMES was applied to the quadriceps and

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Chen et al also to accessory respiratory muscles. 27 Stimulation-pulse duration was 250-400 μs, and stimulation frequency ranged from 8 to 120 Hz. Intensities ranged from 10 to 100 mA, and were gradually increased throughout the entire stimulation according to the patient's individual tolerance.

risk-of-bias assessment and quality assessment
The risk-of-bias among studies is shown in Figure 2. Inadequate description of data on the randomization protocol or blinding strategy was reported in most of the RCTs, except for two, 22,26 which may have led to "unclear risk of bias". On the other hand, quality-assessment items are presented in Figures 3 and 4. Evidence based on RCTs is assumed to be high-quality evidence, unless there are some issues, which may reduce confidence in the study. These included limitations of study design, inconsistency, indirectness, imprecision, and publication bias. 48 For the pooled studies, we kept the original conclusion if the study quality was high and there was no violation of these criteria. 49

Primary outcomes
Results from nine RCTs (n=276) were obtained to assess the effects of NMES on patients with moderate-to-severe COPD. Aggregate analyses showed that the application of NMES was linked to significantly enhanced quadricep strength (SMD 1.12, 95% CI 0.64-1.59, I 2 =54%; P,0.00001) ( Figure 5). There was also a benefit of NMES in improving exercise capacity, evaluated as longer exercise distance traveled (WMD 51.53, 95% CI 20.13-82.93, I 2 overall =90%, I 2 subgroup differences =0; P=0.001) ( Figure 6) or longer exercise endurance time (SMD 1.11, 95% CI 0.14-2.08, I 2 overall =85%, I 2 subgroup differences =81.6%; P=0.02) (Figure 7). We failed to draw funnel plots to explore the potential source of heterogeneity, because the number of RCTs included was fewer than 10 (Figure 8). We did not perform sensitivity analyses to explore potential sources of heterogeneity, because only three RCTs were included.

Discussion
This pooled analysis of data from nine RCTs indicated several meaningful findings for NMES for severe COPD.
The main findings of this meta-analysis are that NMES improved patients' quadricep strength and exercise capacity, particularly across a range of the subgroups, but no statistically significant improvement in the degree of healthrelated quality of life. To our knowledge, our meta-analysis involved the largest numbers of patients with nine RCTs so far. 12,[17][18][19][20]22,23,26,27 The strength and quality of this meta-analysis should be better than those with fewer patients and RCTs reported in the literature. Compared with the equivocal results of Pan et al's review 21 on the efficacy of NMES, our conclusion is contradictory. On the premise of including larger numbers and most high-quality trials, we performed subgroup analysis to classify the evaluation methodology on the outcomes. In addition, we use the GRADE system for the meta-analysis, which has advantages over other rating systems 48 for evaluating the methodological quality of pooled trials. As such, we consider our meta-analysis more convincing and providing evidence in favor of NMES.
Quadricep strength was enhanced significantly, as demonstrated by pooled data on isokinetic quadricep peak torque in three trials, 19,20,25,26 maximum voluntary contraction in two studies 17,22 and author-defined score of a seventh report ( Figure 5). 18 Compared with Pan et al's review, 21 we included more methods of evaluation of quadricep strength and highimpact articles 22,26 published shortly after Pan et al's paper. The baseline level of impairment of peripheral muscle function may have important impact on the outcome of NMES. As subjects with varying degrees of impairment of peripheral function were included in the study reports, we included only reports with peripheral muscle weakness. The inconsistent inclusion criteria would have contributed to high heterogeneity. The severity of COPD may also have an impact on the effects of NMES. In this meta-analysis, we focused on COPD patients with moderate-to-severe flow limitation. The study by Napolis et al 15    Abdellaoui et al. 14 Intensity might be the most important factor related to the efficacy of NMES on muscle strength. 12 Actually, stimulus intensity of the pooled studies differed greatly. However, it was defined as "maximal tolerance" in all trials. Therefore, stimulation intensity might be the most suitable and individualized dosage. We should emphasis the role of NMES itself firstly, instead of the dose-dependent response. The aggregate results suggested that regardless of the type of stimulation, significant increases in quadricep strength after NMES are easily achieved, in spite of the lack of an MCID for muscle strength in COPD patients, to assess whether these data are suggestive of clinically meaningful difference. 50,51 In summary, the overall results proved that quadricep strength was enhanced significantly after NMES. The methodology of evaluation of exercise capacity may influence the outcome of the study. In Pan et al's review, 21 only the 6MWT was included in the pooled analysis. In this meta-analysis, three kinds of exercise capacity tests -6MWT, SWT, and CWT -were included and subgroup analysis conducted. In order to minimize bias, WMD was used to pool walking distance and SMD to pool endurance time. Analogously, we excluded studies 14,15,21 to avoid variance in entry criteria. The aggregate random effect of NMES on walking distance was 51.53 m with a 95% CI of 20.13-82.93 ( Figure 6), exceeding the MCID ranging of 25-33 m for 6MWT distance. 52 However, there was little information on methodological variations in performance of SWT and the lack of an MCID for SWT distance to be compared. The overall pooled SMD data for NMES on endurance time was 1.11 with a 95% CI of 0.14-2.08 (Figure 7), indicating that NMES resulted in a beneficial effect on exercise tolerance. We also observed high heterogeneity, which may have come from different SWT methodologies. Incremental SWTs were used in two trials and endurance SWT in another. The sensitivity, responsiveness, and reproducibility of these tests were not the same. 53,54 In the majority of the cases included, the increasing 6MWT and longer endurance made us consider effect sizes favoring NMES over control in exercise capacity.

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Chen et al However, from the result of our meta-analysis, NMES was not associated with health-related quality of life measured by the SGRQ. The actual value of NMES for healthrelated life quality is thus uncertain, probably due to the fact that the SGRQ is influenced by many other factors. 55 Further research is required to clarify its place in these outcomes.
This meta-analysis has several limitations. Firstly, the subgroup analysis with small sample size led to insufficient evidence. Secondly, the diversity of measurement could have led to heterogeneity correspondingly. Thirdly, NMES with different parameter settings or programs may lead to different physiological effects and outcomes. Therefore, further research needs to be done to standardize this technique.
In conclusion, NMES appears to be effective in enhancing quadricep strength and exercise capacity in moderate-to-severe COPD patients. Further research is needed to clarify its effect on other outcomes and determine the optimal use of NMES.