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Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo-controlled trial

We assessed the eﬀ ectiveness of neuromuscular electrical stimulation (NMES) as a home-based exercise therapy.


Introduction
Chronic obstructive pulmonary disease (COPD) is a major contributor to global morbidity and mortality; it aff ects an estimated 210 million people worldwide, 1 places fi nancial burden on health-care systems, 2 and is projected to be the third most frequent cause of death by 2020. 3 COPD has systemic impact and skeletal muscle dysfunction is a well recognised extrapulmonary manifestation, with preferential weakness and atrophy noted in the lower limbs-mainly as a consequence of physical inactivity. 4 Quadriceps dysfunction and the subsequent exercise intolerance are associated with increased service use and poor prognosis, independent of lung function. [5][6][7] These and other COPD-related symptoms, such as breathlessness, can be eff ectively managed with exercise training as part of pulmonary rehabilitation, 8 which is internationally accepted as a fi rst-line disease management strategy. 9 Nonetheless, issues with service provision, uptake, and adherence-eg, lack of transport, restricting symptoms, or social isolation-restrict its reach for patient benefi t, particularly for those most impaired by their disease. 10,11 A proposed alternative treatment is neuromuscular electrical stimulation (NMES). This uses a portable stimulator and skin electrodes to produce a controlled contraction of the muscle. 12 NMES can be selfadministered at home, unsupervised, and carries a low metabolic load, providing an acceptable therapy for patients living with a high-symptom burden who fi nd travel to clinics and classes diffi cult. 13 The strengthening eff ect of NMES is well established among patients with severe disease compared with no exercise 12 and with lower limb resistance training. 14 The eff ect of NMES on functional exercise performance is not yet clear but is important to understand because this is a key determinant of health status, and relates to overall survival in this group. 6,12 Moreover, data to help to embed NMES within routine clinical practice are lacking-for example, it is unclear if training eff ects can be maintained and how they translate into everyday benefi t to patients. Therefore, this trial aimed to determine the eff ectiveness of NMES on functional exercise capacity in breathless patients with severe COPD. Our null hypothesis was that patients receiving NMES to both quadriceps over 6 weeks would have no diff erence in change in exercise performance, compared with patients receiving a placebo intervention.

Study design and participants
In this parallel, two-group, double-blind, placebocontrolled trial with nested qualitative interviews, which was conducted and reported according to CONSORT guidelines, recruitment took place across three National Health Service trusts in London, UK. Patients were screened at multidisciplinary respiratory and palliative care meetings and across pulmonary rehabilitation services. Patients were eligible if they were aged 18 years or older, with a spirometrically defi ned diagnosis of COPD consistent with GOLD criteria (forced expiratory volume in 1 s:forced vital capacity [FEV 1 :FVC] <70%), severe respiratory impairment (FEV 1 % predicted ≤50), and incapacitating breathlessness (Medical Research Council dyspnoea scale 4 or 5). 15 Patients were excluded if they had an implanted cardiac pacemaker, a coexisting neurological condition, had changed their medication, or had experienced an acute exacerbation requiring a hospital admission or systemic corticosteroids in the preceding 4 weeks. This time period was chosen to allow patients to regain a degree of function that would allow engagement with the treatment programme, and so not to impede eff orts to implement policy for patients to commence pulmonary rehabilitation within 4 weeks of hospital discharge. 9 We also excluded current regular exercisers, defi ned as those enrolled in pulmonary rehabilitation or undertaking structured exercise training (≥3 times per week) within the past month. All participants gave written informed consent before trial entry in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Randomisation and masking
After baseline assessment, participants were randomly assigned (1:1) at the individual level, using an independent web-based randomisation system within the independent UK Clinical Research Collaboration-registered King's Clinical Trials Unit (London, UK). Using a hybrid minimisation method, 20% of participants were entered using simple randomisation and 80% entered using computer-generated probabilistic minimisation to balance three potential confounders; age (<65 years or ≥65 years), GOLD stage (III or IV), and quadriceps strength (<20 kg

Research in context
Evidence before this study Pulmonary rehabilitation has known eff ectiveness on physical function and health status in chronic obstructive pulmonary disease (COPD), but uptake and adherence are restricted when patients have more severe disease. As a result, alternative, more accessible exercise therapies are sought. Home-based neuromuscular electrical stimulation (NMES) is one such approach, which is gaining interest. We extended our previous Cochrane systematic review by searching MEDLINE, Embase, and CINAHL databases with the terms "exp Electric Stimulation Therapy", "muscle* or muscular or neuromuscular or neuromuscular and electric* and stimulant*" and "NMES", without language restrictions for randomised trials published up to Nov 1, 2015. We identifi ed 15 trials across patients with COPD, chronic heart failure, and cancer, randomising a total of 445 patients to NMES off ered alone or as an adjunct to another exercise programme. Common weaknesses with the methods included limited placebo models and no outcome assessor masking. A pooled estimate of eff ect indicated that NMES improved quadriceps strength by a standardised mean diff erence of 0·9 (95% CI 0·33-1·46). There was inconclusive evidence regarding an eff ect on functional exercise capacity, and no data for the duration of any eff ect following withdrawal of NMES, which is important to understand before uptake into clinical practice.

Added value of this study
This trial provides high-quality evidence supporting the use of NMES to manage exercise intolerance among patients with severe COPD experiencing disability due to breathlessness. To our knowledge, our study is the fi rst powered with exercise capacity as a primary endpoint, and to include follow-up data. NMES led to a clinically meaningful improvement in 6-min walk test distance at 6 weeks in this patient group compared with the placebo group. During interviews, participants also reported greater ease in undertaking activities of daily living following NMES. However, the eff ect waned after withdrawal of NMES (a further 6 weeks). This short duration of eff ect underscores the need to carefully time use within clinical practice, and to explore longer programmes, which are supported by the low risk profi le observed here.

Implications of all the available evidence
Current evidence supports the use of NMES in the management of patients who are unable to engage with pulmonary rehabilitation programmes. Staff within these services could off er NMES as an extension of their current scope of practice. Future research should consider trialling longer or more comprehensive NMES based programmes, which include education and behaviour change components. or ≥20 kg). Following randomisation to active or placebo NMES, the Clinical Trials Unit informed trial staff via secure email. The trial coordinator, who arranged subsequent masked assessment visits, was informed of trial entry but not group allocation. Participants were not informed of group allocation. Trial physiotherapists and nurses were informed of group allocation and selected an active or placebo NMES device accordingly. Two linked Good Clinical Practice compliant online data entry systems (InferMed, London, UK; MACRO version 4) were created to maintain blinding; the fi rst was used by physiotherapists and nurses for data regarding compliance and safety, and the second was used by trial assessors for outcome data. The statistician undertaking the primary analysis (WG) was masked to group allocation.

Procedures
Treating clinicians identifi ed potentially eligible patients and off ered them a written information sheet. Interested patients attended a face-to-face appointment to confi rm their eligibility, provide consent, and complete baseline assessments.
The therapy was a self-administered, 6-week programme consisting of 30 min of daily bilateral NMES to the quadriceps. NMES uses a battery powered unit to produce a controlled muscular contraction, via self-adhesive electrodes, equivalent to 15-25% of a maximum voluntary contraction (MVC). NMES was delivered with a twochannel MicroStim Exercise Stimulator MS2v2 (Odstock Medical Ltd, Wiltshire, UK) and self-adhesive PALS platinum electrodes (10 cm × 13 cm) placed over the distal and proximal body of each quadriceps. Devices delivered current fi xed at 50 Hz frequency in 350 μs pulses over an on:off duty cycle, which increased on a weekly basis from 2:15 s to 5:20 s to 10:15 s, remaining constant thereafter. These parameters were selected to minimise skin irritation and muscular fatigue.
Active devices had an amplitude range of 0−120 mA, whereas placebo devices had a range of 0−20 mA (both over 1 KΩ). The placebo amplitude range was selected following piloting of four diff erent maximum outputs (12-30 mA) to provide a sensory stimulus that was detectable by the participant, but insuffi cient to elicit a tetanic muscular contraction. Devices were outwardly identical apart from a concealed "A" or "B" label, and were controlled by a physiotherapist or nurse who was aware of the participant's group allocation. The same physiotherapist or nurse instructed every participant on how to use the device during a standardised 30 min face-to-face training protocol, which included supervising the fi rst self-administered set-up in hospital or home depending on participant preference. Participants were asked to increase the amplitude until the stimulation intensity was comfortable and not painful. To maximise compliance to the intervention, training was supplemented by standardised written instructions and a self-report diary, weekly telephone calls to troubleshoot any practical problems and to prompt participants to increase the stimulation amplitude as tolerated, and home visits to reinstruct patients as required. All were completed by the physiotherapist or nurse, and communication was standardised to maintain participant masking. Both active and control groups used their devices for 6 weeks, after which they were collected by the physiotherapist or nurse.
Follow-up assessments were completed 6 weeks and 12 weeks after randomisation by face-to-face visits. The trial coordinator (masked to group allocation) undertook physical assessments; questionnaires were self-completed independently by participants. Treatment compliance was assessed with a concealed in-built logger, which recorded the number of times the NMES device had been switched on and total duration of use. All other indicated rehabilitation treatments were permitted during the trial.

Outcomes
The primary outcome was change in distance covered in the 6-min walk test (6MWT) from baseline to 6 weeks. The 6MWT is a self-paced test of functional exercise capacity in which patients are asked to walk as far as possible in 6 min along a fl at corridor. 16 Tests were conducted according to European Respiratory Society/ American Thoracic Society Technical Standard. 17 Secondary outcomes related to skeletal muscle were quadriceps twitch tension (TwQ) elicited in an unpotentiated state by supramaximal femoral nerve stimulation, 18 isometric quadriceps maximum voluntary contraction (QMVC) assessed using a chair-mounted strain gauge, 19 with percent predicted QMVC calculated using a disease-specifi c and sex-specifi c regression equation, 20 rectus femoris cross-sectional area (RF CSA ) assessed by ultrasonography, 21 and whole-body fat-free mass assessed by bioelectrical impedance analysis and disease-specifi c regression equations. 22 Physical activity level was assessed as mean daily step count, time spent upright, and number of sit-to-stand transitions using a multiaxial accelerometer (activPAL; PAL Technologies, Glasgow, UK) worn for 21 h or more per day over 6 days. 23 We assessed health-related quality of life using the EuroQol 5-dimension (EQ-5D; visual analogue scale 0-100; lower score indicates poorer quality of life), 24 (20) Spirometry Mean daily physical activity Step count 2057 (1591) 1900 (1564) Up-down transitions 40 (16) 33 (20) Time  indicates better health status), 25 and Chronic Respiratory Questionnaire (CRQ; total scale 0-28; higher score indicates better health status). Formal and informal care was assessed with the Client Service Receipt Inventory, in which participants reported health, voluntary, and social care services and carer support received over the 12-week trial period. 26 Participants allocated to receive active NMES were, following the 6-week assessment, routinely invited to complete semistructured interviews to explore their experiences and views about the intervention, and any perceived eff ect on their daily lives. Questions were open-ended and covered the areas of concern without being leading. Interviews were tape-recorded and transcribed verbatim.
Trial nurses and physiotherapists recorded adverse events during assessment visits and weekly telephone calls. These were classifi ed without unmasking of group allocation by the trial lead (MM) as related, unrelated, or possibly related to treatment, using as much information as available to help to determine the potential attribution of the event.

Statistical analysis
Our sample size for the primary outcome, change in 6MWT distance, was based on a COPD specifi c clinically meaningful diff erence of 54 m 27 and an eff ect estimate from a pilot trial of NMES in a comparable population. 28 To detect this diff erence between groups using a two sample t test with 90% power at the 0·05 signifi cance level (twosided), assuming unequal variances, 25 participants per group were required. Allowing for a low (<5%) attrition rate based on pooled data from trials of similar duration, 12 we planned to recruit 52 participants overall.
The prespecifi ed primary analysis was by intention to treat. Missing data were explored and reported according to cause. 29 Missing data were handled by a multiple imputation approach (20 datasets), using a Monte Carlo Markov chain method and assuming a multivariate normal distribution. 30 Missing outcome imputation was based on sex, baseline MRC dyspnoea scale, and baseline QMVC as moderators of 6MWT performance. The multiple imputation was implemented with SAS Proc MI and the results of mean change comparison were combined with SAS Proc MIanalyse.
Continuous data were expressed as mean (SD or 95% CI) and compared between groups with the Student's t test. Non-normally distributed data were expressed as median (IQR). Categorical data were presented as percentages, and compared between groups with the Pearson χ² test. Outcomes were summarised as change from baseline. We used independent samples Student's t test (two-sided) to compare change in 6MWT (primary outcome) and secondary outcomes at 6 weeks and 12 weeks, by trial group. Sensitivity analyses fi rst used analysis of covariance to account for diff erences in baseline values and then considered complete-cases only-ie, with paired observations-to account for possible eff ect of data imputation. p<0·05 indicated statistical signifi cance. Graphical presentations were produced with Prism 5 (GraphPad Software, San Diego, CA, USA).
Qualitative interview data were handled with NVivo version 7 (QSR International Pty Ltd, Melbourne, Austr) and content analysis was used to explore participants' experience of the intervention and its eff ect. We identifi ed categories inductively from the interview data, with attention to terms and content, and used simple counting to discover consistency of views.  Data were exported from the independent King's Clinical Trials Unit system and analysis was completed by the trial statistician (WG) with SAS version 9.4 (SAS Institute, Cary, NC, USA).

Placebo (n=27) Treatment diff erence p value (two-sided t test)
The trial was registered as ISRCTN15985261.

Role of the funding source
The funder of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had the fi nal responsibility for the decision to submit the report for publication.

Results
Between June 29, 2012, and July 4, 2014, we screened 73 patients; 62 met eligibility criteria, of whom 52 were randomly assigned; 25 were allocated to active NMES and 27 to placebo NMES (fi gure 1  (SD 14) in the active NMES group versus 33 (18) in the placebo NMES group (p=0·84). The total duration of use was also similar (923 min [SD 546] vs 938 min [588]; p=0·93). Initial to fi nal NMES amplitudes were 49·3 mA (SD 9·8) to 72·6 mA (11·0) in the active group and 11·2 mA (SD 2·7) to 15·5 mA (2·8) in the placebo group. One participant from each group commenced pulmonary rehabilitation classes during the follow-up period, with three cumulative attendances between the 6-week and 12-week assessments in the active group and two in the placebo group.
Outcomes were obtained for 48 (92%) and 36 (69%) participants at 6 weeks and 12 weeks, respectively, with similar attrition rates across groups (fi gure 1). Missing data and dropouts were not associated with baseline FEV 1 % predicted, exacerbation frequency, exercise capacity or health status, or trial group and were considered missing at random (data not shown). Consequently, analyses involved all randomly assigned participants.
We noted a signifi cantly greater improvement in the primary endpoint, 6MWT distance, in the active NMES group compared with the placebo group (mean betweengroup diff erence 35·7 m (95% CI 10·5-60·9; eff ect size 0·41; table 2; fi gure 2). In the prespecifi ed sensitivity analyses, adjustment for baseline 6MWT changed the p value from 0·005 to 0·004, and when complete-cases only were considered the between-group diff erence for the primary outcome was increased by 1·0 m (appendix p 2). This result was accompanied by positive changes in secondary outcomes related to muscle function: QMVC and RFcsa at 6 weeks (fi gure 2). The change in TwQ favoured NMES though the eff ect was only signifi cant when adjusted for baseline (p=0·045). We observed no Functional exercise capacity (6-min walk test)

Rectus femoris cross-sectional area
See Online for appendix signifi cant between group diff erences for gait speed, physical activity level, health status, or health-related quality of life outcomes at 6 weeks (table 2). Absolute changes for gait speed, step count, and time upright and EQ-5D visual analogue scale favoured active NMES. No consistent diff erences in health status by SGRQ or CRQ were noted (table 2). The treatment eff ects waned after withdrawing NMES, such that at 12 weeks, no between-group diff erences were noted (fi gure 2; appendix p 3). The between groupdiff erence in 6MWT distance was 7·3 m (95% CI -32·5 to 47·0; p=0·50).
12 participants allocated to active NMES completed qualitative interviews. Perceived benefi ts of NMES treatment were: greater ease in undertaking basic (eg, stair climbing) and extended (eg, shopping) activities of daily living, and an ability to complete physical activities for longer periods (panel). No participants reported negative experiences or views of the therapy.
The proportion of participants who had adverse events was similar between groups; 5 (20%) in the active NMES group and nine (33%) in the placebo group. 11 (21%) acute exacerbations requiring antibiotics were reported during the study period; four (16%) in the active NMES group and seven (26%) in the placebo NMES group (p=0·25). Nine (17%) of these exacerbations led to hospital admission, resulting in a short course of oral corticosteroids; three (12%) in the active NMES group and six (22%) in the placebo group (p=0·22). One participant (4%) received a diagnosis of laryngeal cancer. Two participants, one from each group, reported persistent erythema, which was considered to be possibly related to NMES and the use of adhesive electrodes.

Discussion
Our study shows that 6 weeks of NMES to the quadriceps improved functional exercise capacity in patients with severe COPD and incapacitating levels of breathlessness. The degree of change was lower than that reported in earlier unblinded studies and the level used to inform our sample size calculation, but exceeded the recent estimate for the minimally important diff erence for 6MWT distance which, based on all available evidence, lies between 25 m and 33 m. 31 This eff ect on functional exercise capacity was achieved by treating lower limb muscle dysfunction, with changes in quadriceps strength and mass evident in the active group, but not in the placebo group. NMES programmes have previously been shown to be acceptable to people with severe COPD across community, 32 inpatient rehabilitation, 14 and intensive care settings. 33 A strengthening eff ect is expected with a pooled mean diff erence in QMVC equivalent to about 2·5 kg, 12 consistent with the 3·1 kg diff erence we noted. The risk profi le for NMES is low and adverse events tend to refl ect the populations being trialled, as was the case here. Localised muscle discomfort can be reported in the initial few days of use, but other side-eff ects, including skin abrasion, bruising, or both are rare. 12 NMES is a practical home-based therapy well suited to populations who have high levels of disability or symptom burden. 12 Although supervised pulmonary rehabilitation programmes off er much to address common symptoms of COPD, they are not suitable for the most severely aff ected often house-bound patients, or at all times-eg, during an exacerbation of disease. 10 These data support a role for NMES in the management of those unable or unwilling to engage with such programmes.
We purposefully selected patients with a high level of impairment as our systematic review suggested this group might respond favourably 12 and this population can have diffi culty accessing pulmonary rehabilitation. Many participants had declined or dropped out of a pulmonary rehabilitation programme suggesting that we reached the intended population. Sillen and colleagues 14 previously compared resistance training to high (75 Hz) and low (15 Hz) frequency NMES in patients with COPD and breathlessness and lower limb weakness, as part of an 8-week inpatient rehabilitation programme. Functional exercise performance, breathlessness, mood, and overall health status improved with both stimulation Panel: Illustrative quotes from qualitative interviews about perceived eff ect of neuromuscular electrical stimulation on daily life ''I think…I tend to walk better now…you see before me legs were a bit numbish, but once you had the machine…you tend to want to walk (yes) and then your legs feel a bit stronger… My legs used to ache a lot you see but they haven't ached since I've had that on…I used to ache I mean a lot, I was always worrying about my legs...I tend to walk a bit further now than what I did. I mean I've still got the breathing problem but my legs were still going. I could walk a lot further than what I did before...'' (Man,60 years) ''…I was able to get around quicker um in a shorter time…I felt that it speeded up the process of strengthening my muscles so I can get up and walk as much as my body allows if you like…I found that I was able to, um, increase the length of time I was actually walking…I felt I could move around easier and wasn't having to work so hard to do it'' (Woman, 62 years) ''…Well, I don't think I can walk any faster…before I couldn't go for a walk up the road. I couldn't get no further than the corner, and I had to turn round and come back. But now I can get up as far as the paper shop, on a good day…I have my good days and my bad days, but I can get as far as the paper shop…go for a little walk round the shops...'' (Man,64 years) ''…improvement in the muscles you're looking at… enable me to get out of the chair easier, um, and with not too many details obviously get off the toilet easier and so forth...I struggle with steps and it made it a little bit easier…'' (Man,65 years frequencies. They could not distinguish between the eff ect of exercise and non-exercise programme components, although no signifi cant diff erences in muscle function outcomes were noted between high-frequency NMES and resistance training groups. When drawing any comparison between NMES and pulmonary rehabilitation, it is important to note the lack of observable eff ect on physical activity level, health status, or quality of life following our programme. Although our trial was not powered to detect small changes in these secondary outcomes, pulmonary rehabilitation would typically lead to changes in these outcomes. 8 The short NMES programme duration and absence of concurrent education and behavioural strategies might explain this limited response. Thus, based on current available data, NMES should not be regarded as a replacement for pulmonary rehabilitation. Instead, it might provide adjunct training, 34 or be an alternative means to improve aspects of physical function in those unable to access pulmonary rehabilitation.
The link between peripheral muscle function and whole-body exercise performance is well described in COPD. 35 The strength of association depends on the type of exercise test 36 and the extent of ventilatory versus muscular impairment, which dictate the limiting factors to exercise performance. 37 Vivodtzev and colleagues 32 highlighted this using NMES training. In their study, the level of improvement in exercise performance was related to stimulation intensity, and subsequent gains in quadriceps strength and reduced ventilatory demand during walking. 32 In this trial, 6MWT distance improved in all but two participants at 6 weeks, although treatment response was heterogeneous. In a post-hoc analysis, we explored baseline FEV 1 , QMVC and NMES amplitude, and treatment compliance as possible mediators of treatment eff ect, but none explained the variation in response. Vivodtzev and colleagues 32 also showed gains in muscle mass following NMES, although we used ultrasonography and detected muscle hypertrophy without time-consuming or costly CT techniques. Because NMES was applied via skin electrodes, our imaging of rectus femoris as the most superfi cial of the quadriceps component muscles might have exaggerated the hypertrophic eff ect of NMES. However, our fi ndings are in keeping with changes noted after 8 weeks of lower limb resistance training. 38 This measure of muscle mass has recently been shown as an independent risk factor of admission to hospital and survival 39 and modifi cation of risk via exercise intervention is an attractive prospect.
Participants perceived and reported specifi c functional benefi ts during daily life, which were not captured by standard questionnaires-eg, fi nding toileting or stair climbing easier, or having improved outdoor mobility. The activities participants cited in the qualitative interviews generally depended on lower limb function, suggesting a link to the NMES therapy. The loss of ability to independently complete activities of daily living is pertinent to the trial population, who had substantial impairment at baseline and relied heavily on informal care. Indeed, 22 (42%) patients were enrolled with quadriceps strength below a functionally relevant cutoff point that precludes the ability to sit-to-stand unaided. 40 The discrete changes in function following NMES might be early signs that the so-called deconditioning spiral is starting to be addressed, and with additional time and support, patients might translate gains in physical capacity into changes in their independence.
To our knowledge, our trial is the fi rst to follow patients after NMES is withdrawn. Disappointingly, improvements in exercise capacity and muscle function waned such that at 12 weeks between-group diff erences were no longer signifi cant. This fi nding supports a causal eff ect of NMES. The transient gain in muscle function points towards neural changes supplementing muscle anabolism, with increased sensitivity of neural synapses and better synchronisation of motor units during contractions. 41 It also underscores the need to carefully time use within clinical practice as a standalone intervention. Potential roles might include preparing patients for supervised rehabilitation or enhancing functional recovery following acute illness. The latter indication has been questioned by the data of Greening and colleagues 42 in which NMES was a key component of an early rehabilitation approach following admission to hospital for an acute exacerbation of chronic respiratory disease. However, in that trial, only modest doses of exercise training could be off ered during the short hospital stays, and compliance to the home-based intervention was poor. Importantly, uptake of formal outpatient pulmonary rehabilitation, off ered to both groups after 3 months, was lower in the intervention group than in the usual care control group. This health behaviour suggests that patients receiving the early intervention might have considered their rehabilitation needs to have already been met. 43 Therefore, when treatments like NMES are introduced into clinical practice, clear communication about their role and what they cannot replace is paramount.
Strengths of this trial include the successful masking of participants and outcome assessors, a feature not identifi ed in other NMES trials. 12 Participant masking is diffi cult for any physical intervention, but the use of an outwardly identical placebo device with a limited output and with careful randomisation conduct and communication ensured this was possible. A breadth of validated outcome measures, off ering volitional and non-volitional assessments of muscle mass and function, provided strong mechanistic data to understand the mechanisms behind our primary fi nding. Our follow-up and qualitative data proved to better understand the clinical role of NMES compared with existing treatments. Finally, the high uptake of participants across multiple sites, low attrition rate, along with the pragmatic delivery of treatment that involved diff erent staff and light supervision, enhances the external validity of our fi ndings. We perceive the delivery of NMES in this trial is closer to how it would be off ered in clinical practice than in previous reports.
There are limitations to consider. We were not able to mask the nurses and physiotherapists who were involved in recording of adverse event data, although events were classifi ed without unmasking of group allocation. We perceive our placebo model to have been successful, but we cannot entirely rule out an anabolic eff ect, and incidental features of NMES such as dedicated time for self-management might have aff ected participant behaviour. Our sample size was informed by eff ect estimate data from a pilot study and an established minimally important diff erence for COPD, and the expected diff erence of 54 m was not reached. Nonetheless, our homogeneous sample and well standardised assessments contributed to betweengroup diff erences that were signifi cant and exceeded updated minimally important diff erences for our primary endpoint. 31 We were not powered to detect small changes in health status that might be expected following this modest intensity training. We noted a small number of hospital admissions during the short trial period. Although the number of exacerbations, hospital admissions, and courses of oral corticosteroids was higher in the placebo group than in the active group, this was unlikely to account for the diff erences in functional exercise capacity, which remained stable, and was enhanced following active NMES. Based on this research, future work should consider trialling longer programmes of NMES, potentially those that use improvements in function to dovetail into pulmonary rehabilitation, or add behaviour change and education components to NMES to enhance health status and quality of life. Once optimised, the eff ect of an NMES-based approach on outcomes pertaining to patient independence and health service use could be evaluated.
In conclusion, a 6-week programme of NMES improved functional exercise capacity in patients with severe COPD by enhancing quadriceps muscle mass and function. These data support a role for NMES in the management of those unable or unwilling to engage with current pulmonary rehabilitation programmes. The short duration of eff ect and little eff ect on health status suggest a need to explore longer programmes, or adding education and behaviour change interventions as part of a broader rehabilitation package.