Population	Intervention	Comparison	Outcome
Males and females over the age of 40	NMES	NMES intervention on COPD patients admitted to ICU with a COPD exacerbation	Quadriceps Maximal Voluntary Contraction
COPD patients with a moderate to severe airflow restriction < FEVI < 80% predicted. 30% < FEV1 < 50% predicted. FEV1 is > 30% predicted.		Different NMFS frequency in combination with Pulmonary Rehabilitation (PR)	Quadriceps Endurance
		NMES intervention compared to a non- stimulated lower limb

Table 1:PICO search term

Criterion	Inclusion	Exclusion
Language of article	Published in English	Published in another language other than English
Publication date	A study published less than 13 years ago	Study published more than 13 years ago
Statistical method used	Descpription of the statiscial method used is present	Description of the statistical method used is not present
Patient selection	Information on patient selection needed to be given, with patients having a confirmed moderate to severe COPD and exacerbation	Information on patient selection was not provided study which included mild COPD patients. unconfirmed COPD exacerbation, stable and had neurological or locomotor conditions
Age	Above the age of 40	Under the age of 40
Study design	Randomised control trial with pre-test and post-test experimental design	Systematic Review, Meta-analysis, Non-randomised control trial, Randomised control trial with another experimental design
Outcome measures	The study eximained one or more of the following: Quadriceps strength and endurance	Does not assess any of the primary outcome measures
Intervention period	The acute effects of NMES was investigated throughout length of hospital stay	The chronic effects of NMES in combination of Pulmonary Rehabilitation or in an outpatient setting

Table 2:Inclusion and Exclusion Criteria

Author and Year of Publication	Title	Research Design and Data Collection Instrument	Results	Strengths and Limitations
Abdellaoui et al., (2011)	Skeletal muscle effects of electro. stimulation after COPD Exacerbation: A Pilot Study	Patients were randomly assigned to sham or NMES training The Sham group had weekly therapeutic education sessions, daily active–passive mobilisation and sham electrostirnulation. The ICU, atter baseline NMES group followed the same programme but received effective electro- stimulation. The programme started in the evaluations, and continued in an in-patient rehabilitation unit. Tests carried out: Quadriceps Maximal Voluntary Contraction (QMVC), 6- minute walk test (6MWT), dyspnoea using the MRC scale and muscle biopsy	At the end of the study, quadriceps force improvement was statistically different between groups (p50.02), with a significant increase only in the NMES group (median (interquartile range) 10 (4.7– 11.5) kg; p50.01). Changes in the 6-min walking distance increase only in the NMES group (median (interquartile range) 10 (4.7– 11.5) kg; p50.01). Changes in the 6-min walking distance Were statisticallv different between groups (p50.008), with a significant increase in the NMES group (165 (125–203) m; p50.003). NMES did not lead to higher muscle oxidative stress, as indicated by the decrease in total protein carbonylation (p50.02) and myosin heavy chain carbonylation (p50.01) levels. Finally, we observed a significant increase in type i fiber proporties in the NMES group.	Small sample size, Muscle biopsy resulting in COPD exacerbating patients to withdrawn or refuse
Chaplin et al., (2012)	Neuromuscular Stimulation of Quadriceps in Patients Hospitalised during an Exacerbation of COPD: A Comparison of Low (35 Hz) and High (50 Hz) Frequencies	Experimental study - Pilot Study Tests carried out: Quadriceps maximal voluntary contraction and Endurance Shuttle walk test (ESWT)	A total of 10 patients in each treatment group underwent NMES during hospitalisation (mean [SD] age 68.0 [7.4] years, FEV1 0.99 L [0.58], FEV1/FVC 47% [ 27%], MRC 5 [IQR 1]). There were no significant differences in baseline characteristics between groups. Muscle strength (legs combined) increased in both groups regardless of the NMES frequency used (35 Hz - 3.8 ±4.9; 50 Hz - 3.4 ±5.5 keg). 'l his was only significant within the 35 HZ group . The change in ESWT also showed a trend to increase in both groups (35Hz - 109±92.7; 50Hz - 145.6±94.7). There was no sienificant difference between 145.6±94.7). There was no sienificant difference between	Small sample size, and number of assessors recorded the baseline and discharge outcome measures, thus inter- assessor reliability may have been compromised
Giavedoni et al., (2012)	Neuromuscular electrical stimulation prevents muscle function deterioration in exacerbated COPD: A pilot study.	Pilot study Tests carried out: Anthropometric measures, lung function, muscle strength using the QMVC.	Mean quadriceps muscle strength decreased in control legs (DQMVC 2.9 ±5.3 N, p Z ns) but increased in the stimulated legs (DQMVC 19.2 ± 6.1 N, p < 0.01). The difference in DQMVC between groups was statistically signification (p< 0.05). The Effect of NMES was P directly related to the stimulation intensity (mA) applied throughout the 14 sessions (r Z 0.76, p < 0.01). All patients tolerated NMES without any side effect	Abstance of a sham control leg as an unbiased control, relatively small number of subjects of participants while the muscle measuring technique was dependent on the subject effort
Zanotti et al., (2012)	Combination of Pulmonary Rehabilitation and Neuromuscular ElectricalStimulation in COPD Patients: A Randomised Clinical trail of efficacy	Randomised Clinical of efficacy test carried out: Lung function test, BMI, Sit-to-stand test, 6MWT, mMRC and Health related Quality of life (HRQL) using the St. George’s Respiratory Questionnaire	Quadriceps strength was enhanced by SSPR (STST + 7±1.7 repetitions; p≤0.001); NMPRfurther increased strength (+10±1.6 repetitions; p≤0.001) with a significant difference (p≤0.05) between the treatntentsS,SPR sieniticantly increased exercise capacity (6MWD + 85.3±11.5 m; p=0.01); NMPR further increased the distancewalked (6MWD +146.4±32.7 m; p=0.01) with a significant difference (p≤0.05) between the treatments. None of thc two treatments influemced lung function. Quality of life score (SGRQ – 8.3±2.1; p=0.01) and dyspnoea score (mMRC-0.7±0.18; p= 0.001) decreased after SSPR suggesting a positive effect. NMPR did not further improve the score.	The method to measure muscle strength, selection of patients
Sillen et al., (2014)	Efficacy of lower limb muscle training modalities in severely dyspnoeic individuals with COPDand quadriceps muscle weakness: results from the DICES trial	A prospective, single- blind, randomised controlled trial was designed.Tests carried out: isokinetic quadriceps muscle function – Biodex, 6MWT, work-rate cycling endurance test (CWRT), Hopsital Anxiety and Depression Scale (HAD Score), St. George’s Repiratory Questionnaire, Canadian Occupational Performance Measure (COPM), BMI, Fat-free mass index, mMRC and Anthropometric measures.	Quadriceps muscle strength increased after HF-NMES (+ 10.8 Newton-metre (Nm)) or strength training (+6.1 Nm; both p<0.01), but not after LF-NMES (+ 1.4 Nm; p=0.43). Quadriceps muscle endurance, exercise performance, lower-limb fat-free mass, exercise-induced symptoms of dyspnoea and fatigue improved significantly cornpared with baseline after HF-NMES, LF- NMES or stren th training .The increase in quadriceps muscle strength and muscle endurance was greater after H F-NN'I ES than after LF- NMES.	Strength: Largest RCT till date and outcome assessors were blinded for group allocation Limitations: underpowered to detect statistically significant differences between HF/LF-NMES and strength training for changes in exercise performance, which did exceed minimal important differences, no control group, high percentage of drop outs, strict inclusion and exclusion criteria
Vieria et al., (2014)	Neuromuscular electrical stimulation improves clinical and physiological function in COPD patient.	A prospective double- blind, randomised, pilot study was conducted to compare the use of NMES to a control intervention. Tests carried out: Fat free mass (FFM) and thigh circumference, spirometry, cardiopulmonary exercises test using an electronically braked cycle ergometer, 6MWT, NF-a and b- endorphin analysisand quality of life using the SGRQ.	Compared with the control group, NMES increased FEV1 and FEV1/FVC, 6-MWD and Tlim (P < 0.01) and reduced BDS and SGRQ (P < 0.01). Additionally, changes in the Tlim were positively correlated with respiratory improvements in FEV1 (rho Z 0.48, P < 0.01). Also, NMES reduced TNF-a and increased b-endorphin levels, compared with the control group (P < 0.001).	N/A
Maddocks et al., (2015)	Neuromuscular electrical stimulation to improve exercise capacity in patients with severe COPD: a randomised double-blind, placebo- controlled trial	A double-blind, placebo- controlled trial. Tests carried out: 6MWT, quadriceps twitch tension (TwQ), isometric quadriceps maximum voluntary contraction (QMVC), rectus femoris cross-sectional area (RFCSA) assessed by ultrasonography, whole- body fat-free mass assessed by bioelectrical impedance analysis, daily step count, time spent upright, number of sit-to-stand transitions, health-related quality of life using the EuroQol 5-dimension (EQ-5D), Chronic Respiratory questionnaire, (CRQ) and the SGRQ.	Change in 6MWT distance was greater in the active NMES group (mean 29·9 [95% CI 8·9 to 51·0]) compared with in the placebo group (–5·7 [–19·9 to 8·4]; mean difference at 6 weeks 35.7 m [95% CI 10·5 to 60·9]; p=0·005). Sensitivity analyses for complete- cases and adjustment for baseline values showed similar results. 6 weeks after stopping the intervention the effect waned (7-3 m [95% CI –32·5 to 47·0]; p=0.50). The proportion of participants who had adverse events was similar between groups (five [20%] in the active NMES group and nine [33%] in the placebo group).	Limitations: not able to mask the nurses and physiotherapists who were involved in recording of adverse event data, although events were classified without unmasking of group allocation
Kucio et al., (2016)	Evaluation of the Effects of Neuromuscular Electrical Stimulation of The Lower Limbs Combined with Pulmonary Rehabilitation on Exercise Tolerance in Patients with Chronic Obstructive Pulmonary Disease	Randomised control trial Tests carried out: Exercise tolerance – 6MWT, Spirometric test and Gasometric test	Pre-intervention the distance walked amounted to 397.2 ± 70.65m and 421.4 ± 69.4 m in the studied groups and did not differ significantly between the groups. Post-intervention, a significant increase of distance walked in the 6MWT was observed only in the NMES+PR group (a median of 6.1% increase in the distance walked). The increase in the distance walked amounted to 24.1m in the NMES+PR group and 10.3 in the PR group. In the PR group, a minor increase in walked distance was noted (2.4%), not differing significantly from the measurements taken before the treatment. The acquired results suggest that NMES of the lower limbs may be applied as an additional form of pulmonary rehabilitation in patients with COPD.	Limitations: Short period of observation of COPD patients, low number of participants.
López- López et al., (2021)	A Feasibility and Efficacy Randomised Controlled Trial of Two Exercise Programs in Severe AECOPD Patients withResting Hypoxemia	A randomised single-blind clinical trial. Tests carried out: Quadriceps strength, balance through the One- leg standing balance test (OLS), Health related QoL through the EuroQol-5D (EQ-5D) and adverse reactions.	At the end of the intervention, there were significant differences in all the variables in favour of the experimental groups (p < 0.05).	Limitations: lack of long-term follow up and a small sample size.

Péran et al., (2022)

Effect of neurom uscular electrical stimulation on exercise capacity in patients with severe chronic obstructive pulmonary disease: A randomised controlled trial

Randomised Control Trial: Tests carried out: 1-MSTS, 6MWT, isometric quadriceps maximal voluntary contraction, quadriceps endurance, SGRQ, Borg Scale and spirometry – dynamic hyperinflation.

No significant difference was seen in the evolution of exercise capacity using 1-min sit-to-stand test (3.3 ± 3.8 and 2.6 ± 4.1) and 6- min walk test (37.8 ± 58.4 and 33.1 ± 46.7), in the evolution of quadriceps strength and endurance (9.2 ± 12.9 and 6.6 ± 16.1; 9.0 ± 13.2 and 6.2 ± 17.0), in the evolution of quality of life (St George’s Respiratory Questionnaire: −11.3 ± 11.7 and −8.1 ± 11.6; COPD Assessment Test: −5.7 ± 7.1 and −4.7 ± 7.0), or in the evolution of dyspnea using Dyspnea 12 (−5.5±10.2 and —5.9±8.5) except using modified medical research council scale (95% confidence interval: 0.48 medical research council scale [0.05; 0.91], p = 0.027).

Limitations: Duration of PR was too short, patients feeling during NMES program was not collected, no sham stimulation group,

Table 3:Table of the studies reviewed throughout this literature review

Figure 1: The Acute Exacerbation as illustrated by Buttin et (2011)

Figure 2: The Dyspnoea Spiral adopted from Haas F. et, ( 1993)

Figure 3: The PRISMA Flow Diagram (Page MJ et al.. PRISMA 2020 statement)

Figure 4: Cochrane Risk-of-Bias Tool

Figure 5: Summary of Risk-of-Bias

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is a respira- tory condition characterised by a combination of small airway disease and destruction, features typical of emphysema Ill. De Brandt et al., 12,31 further emphasise that COPD is distinguished by persistent airflow limitation, a significant contributor to global morbidity and disease burden, as noted by Mathur et ale, [41. Maddocks et al 151 report that one in every 8 patients experiencing an exacerbation requires hospitalisation.

In addition to pulmonary changes and respiratory impairments, patients diagnosed with COPD also undergo systemic morphological and biomechanical alterations leading to modified muscle morphology, particularly affecting strength, and physiology, especially in the lower limbs [6]. Bicxhemical changes primarily result from long-term steroid use and Chronic Systemic Inflammatory Syndrome (CSIS) (7) , impacting the patient's physical capacity for activity, as depicted in Figures 1 and 2. Such changes result in more energy expenditure during activities of daily living (ADLs), resulting in short. ness of breath (SOB) following minimal exercises.

Neuro Muscular Electrical Stimulation (NMES) is a non-invasive method of muscle contraction initially introduced for post-muscle injury and surgery rehabilitation and later extended to certain diseases [8]. It is a self-administered device that does not necessitate supervision and imposes a low metabolic load, offering a viable therapy for patients with a high symptom burden [5].

Literature discussing NMES in COPD suggests its applicability during both medically stable and unstable phases [9-11], serving as an alternative to mobilisation and exercise due to its lack of requirement for active patient participation. Hill et al., [12] document how NMES, either alone or combined with conventional exercise training, enhances peripheral muscle condition, exercise capacity, endurance, functional performance, symptom reduction, and health-related quality of life (HRQoL). The additional application of electrical nerve stimulation to an exercise programme has shown to reduce the duration of bed confinement during acute severe stages of the disease [12].

While research on NMES’s effect on lower limb muscle strength spans over two decades, limited research is available on its use during acute exacerbations of COPD (AECOPD), with most studies conducted in a home-based environment. Studies by Abdellaoui et al., [13], Giavedoni et al., [11], Vieira et al., [10] and Kucia et al., [14], recruited small populations, thereby limiting the validity and reliability of outcomes. The primary focus of this review was not directed towards the detailed analysis of NMES protocols. Instead, this aspect is considered an avenue for exploration and investigation in future research projects. This deliberate decision highlights the intention to pave the way for future exploration and in-depth scrutiny of diverse protocols within the scope of research. However, all the articles included had similar NMES protocols, with frequencies ranging from 35Hz to 50Hz. They also stimulated similar groups of muscles and enrolled patients with a similar severity category.

Figure 1

Figure 2

Methodology

A narrative review design was chosen for this study to facilitate comprehensive research. The Population (P), Intervention (I), Comparator (C) and Outcome (O) (PICO) framework guided the inclusion criteria and reporting of study characteristics. Papers were retrieved through thorough searches using Google Scholar, HyDi (Hybrid Discovery), EBSCO, Pubmed, Medline, Cochrane Central Register of Controlled Trials, and Science Direct.

Table 1 illustrates the key PICO search terms. Data extraction and critical appraisal were conducted using the Critical Appraisal Skills Programme (CASP) tool to ensure quality research appraisal, focusing on study characteristics, participant demographics, intervention details, and results.

Table 1

The search strategy yielded over 20,000 research articles following a preliminary search through the selected databases. After eliminating duplicates (n=1740), records marked as ineligible (n=9573), records excluded based on publication date (n=1400), further elimination of excluded articles (n=478), and reports that were not retrieved (n=1432), as well as reports that were excluded (n=5366), a total of 10 full-text randomised-control trials (RCTs) with pre-test and post-test experimental designs were retained as potentially main articles. The PRISMA flow chart (Figure 3) illustrates the search strategy trail, summarising the entire screening process used by the reviewer and resulting in the selection of 10 RCT articles. Studies were then further screened according to the inclusion and exclusion criteria (see Table 2).

Figure 3

Different CASP checklists are utilised for different research designs. In this narrative review, an RCI' CASP (2020) was deemed suitable as all the reviewed articles were RCTs. CASP enables a thorough and methodical assessment of the quality of selected studies, highlighting their methodological strengths and weaknesses while elucidating the significance of their conclusions (15).

Table 2

A total of 10 articles were reviewed. Table 3 summarises these articles, discussing the effects of NMES as an adjunct to chest and mobility exercises, breathing exercises, and breathing and chest mobility exercises during the acute phase.

Results

The identified studies focus on 7 outcome measures which in- clude the Quadriceps Maximal Voluntary Contraction (QMVC), 1 -minute Sit-to-stand (IMSTS), 6-minute walk test (6MWT), St- George's Respiratory Questionnaire (SGRQ), Medical Research Council (MRC) scale and lung function test. FEVI/FVC ratio or prediction was investigated in all 10 studies and QMVC was investigated in 7 studies (Abdellaouui et Chaplin et al., [16] [p< 0.04], Zanotti et al., [17] [p< 0.001], Sillen et al., [18] [p< 0.01], Maddocks et al., [5] [p=0.028], López- López et al., [19] [p< 0.001] and Péran et al., [20] [p< 0.001]). e 1-minute Sit-to-stand was investigated in 2 studies (Sillen et al., [18] [p≤0.05] and Péran et al., [20] [p< 0.01]), the 6MWT was investigated in 6 studies (Abdellaoui et al., [13] [p=0.008], Sillen et al., [18] [p< 0.01], Vieria et al., 2014 [p< 0.01], Maddocks et al., [5] [p=0.005], Kucio et al., [14] [p=0.001], López- López et al., [19] [p< 0.001] and Péran et al., [20] [p< 0.001]). The Endurance Shuttle walk test (ESWR) and work-rate cycling endurance test (CWRT) were investigated in 1 study respectively (Chaplin et al., [16] [p=0.001] and Sillen et al., [18] [p< 0.01]). Five studies investigated the St. George’s Respiratory Questionnaire (Zanotti et al., [17] [p=0.01], Sillen et al., [18] [p< 0.01], Vieria et al., [10] [p< 0.01], Maddoks et al., [5] [p=0.78] and Péran et al., [20] [p< 0.001]). Health-related quality of life was also investigated by 2 more studies using the EuroQol-5D questionnaire (Maddocks et al., [5] [p< 0.05]) and López- López et al., [19] [p< 0.05]) and the Canadian Occupational Performance Measure COPM (Sillen et al., [18] [p< 0.05] with no statistical difference between the groups. MRC was investigated in 1 study (Chaplin et al., [16] [p< 0.75] for both the experimental and control groups) while Modified Medical Research Council (mMRC) was investigated in 2 studies (Zanotti et al., [17] [p=0.01] and Sillen et al., [18] [p< 0.01]).

Table 3

All studies included had an unclear risk of bias and limitations in reporting quality when assessed using the Cochrainerisk of bias 2.0 toll (Cochrane RoB2) for randomized trials. All studies reported adequate random sequence generation. Two studies used an appropriate method of patient allocation concealment while the other 8 studies were judged at unclear risk of bias because they failed to provide details about allocation concealment. In seven of the studies included, blinding of participants and personnel was described, leaving 4 studies that did not describe despite the use of sham control, thus making it unclear whether the lack of blinding would have affected outcomes. All of the articles had published protocols, therefore, the selective outcomes reporting domain was judged at a low risk of bias (Figures 4 and 5). Information about patient allocation procedures and concealment, together with sham controls are important when evaluating data due to researcher - patient influences on outcomes. Despite this procedure not being clearly outlined in some of the included articles, the majority of those reporting outcomes from NMES in the management of COPD discuss this in depth, allowing for reliability of results as well as repeatability of the intervention.

Figure 4

Figure 5

Discussion

This review outlines the effects of NMFS in conjunction with physiotherapy, demonstrating favourable improvements in quadriceps strength, endurance and HRQoL among patients experiencing moderate to severe COPD exacerbations. Previous systemic reviews have primarily focused on investigating the impact of NMES on various outcome measures, including quadriceps maximal voluntary contraction (QMVC), the endurance shuttle walk test (ESWT), work-rate cycling endurance test (CWRT), anthropometric measures, fat-free mass (FFM), one-leg standing balance, electronically braked cycle ergometer, quadriceps twitch tension (TwQ), Biodex, Bioelectrical impedance analysis, lung function test and spirometry, 1-minute sit-to-stand, 6MWT, muscle biopsy, rectus femoris ultrasonography, SGRQ, EQ-5D, HAD Score, COPM, the Borg dyspnoea scale and the Medical Research Council or the Modified Medical Research Council. As a result of the small number of studies, limited sample size, difference in NMES treatment and parameters used and methodological approaches used, and unclear risk of bias, potential improvements reported should be carefully rellected upon.

Improvements in quadriceps strength have been attributed to the additional stimulation of the quadriceps muscles, leading to changes in muscle tissue morphology, such as a shi towards type-1 muscle fibers. This was observed through various assessments, including ultrasonography, biodex, bioelec trical impedance analysis, and thigh circumference measurements. Studies consistently reported significant improvements in quadriceps strength across different NMES parameters and frequencies, suggesting its efficacy in mitigating muscle atrophy during an AECOPD (Abdellaouui et al., [13] [p< 0.001], Chaplin et al., [16] [p< 0.04], Zanotti et al., [17] [p≤0.001], Sillen et al., [18] [p< 0.01], Maddocks et al., [5] [p=0.028], López- López et al., [19] [p< 0.001] and Péran et al., [20] [p< 0.001]).

Studies also demonstrated improvements in other outcome measures, such as endurance, balance, and overall HRQoL. NMES was associated with significant enhancements in the 6MWT, the 1MSTS, ESWT and endurance. These improvements are particularly significant given the observed decline in quadriceps strength and endurance among patients with moderate to severe COPD with an exacerbation, which can further limit mobility and decrease overall functional capacity.

The integration of NMES with other physiotherapy modalities, primarily chest physiotherapy or Pulmonary Rehabilitation, yielded better outcomes compared to control groups. By increasing both quadriceps strength and endurance, NMES interventions facilitated improvements in functional capacity and HRQoL without exacerbating breathlessness. Moreover, NMES was well tolerated with no reported adverse reactions, further supporting its safety and feasibility in the management of AECOPD [5,11,13,16,18]

Despite these promising findings, limitations in the reviewed studies, such as small sample populations, strict inclusion criteria, and limited observational periods, warrant cautious interpretation of the results. Additionally, challenges in maintaining inter-rater reliability and blinding of personnel may have introduced bias in outcome assessments. Future research should address these limitations and explore the optimal use of NMES interventions in AECOPD management through large-scale trials.

Conclusion

In conclusion, this review provides compelling evidence for the beneficial effects of NMES in patients with acute exacerbations of COPD. Integration of NMES into comprehensive management strategies holds promise for improving quadriceps strength, endurance and HRQoL. Despite recommendations for high-frequency NMES, which showed better outcomes in the literature, further research to explore the optimal parameters is required. Varying more than one parameter might produce a likelihood that the intervention may wrongly appear to be benficial irrespective of which parameters were used. Larger sample sizes should be used to obtain more reliable results. Investigation of patient perspectives and acceptability of this intervention would also be recommended for future research in order to evaluate the holistic outcome from this intervention.

1. NMES demonstrates favourable improvements in quadriceps strength during acute exacerbations of COPD.
2. NMES contributes to enhanced endurance and functional capacity when integrated into pulmonary rehabilitation programmes.
3. NMES interventions are associated with improvements in overall HRQoL following AECOPD.
4. NMES is well tolerated and produces no adverse reactions in patients with COPD
5. Future research should explore the optimal parameters and effects of NMES interventions through larger-scale trials.

Funding

This research did not receive a specific grant from any public, commercial, or not-for-profit agency.

Contributions

All authors were involved in the literature search and review process, manuscript preparation and review of all dra and final version of this paper.

Conflict of Interest

The authors report no conflict of interest.

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