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Safety of neuromuscular electrical stimulation among critically ill patients: systematic review

ABSTRACT

Objective:

To review the evidence on the safety of neuromuscular electrical stimulation when used in the intensive care unit.

Methods:

A systematic review was conducted; a literature search was performed of the MEDLINE (via PubMed), PEDro, Cochrane CENTRAL and EMBASE databases, and a further manual search was performed among the references cited in randomized studies. Randomized clinical trials that compared neuromuscular electrical stimulation to a control or placebo group in the intensive care unit and reporting on the technique safety in the outcomes were included. Hemodynamic variables and information on adverse effects were considered safety parameters. Articles were independently analyzed by two reviewers, and the data analysis was descriptive.

Results:

The initial search located 1,533 articles, from which only four randomized clinical trials were included. Two studies assessed safety based on hemodynamic variables, and only one study reported an increase in heart rate, respiratory rate and blood lactate, without clinical relevance. The other two studies assessed safety based on reported adverse effects. In one, 15% of patients described a prickling sensation, without any clinically relevant abnormalities. In the other, one patient suffered a superficial burn due to improper parameter configuration.

Conclusion:

Neuromuscular electrical stimulation is safe for critically ill patients; however, it should be applied by duly trained professionals and with proper evidence-based parameters.

Safety; Electric stimulation therapy; Respiration, artificial; Drug-related side effects and adverse reactions; Physical stimulation; Intensive care units

RESUMO

Objetivo:

Revisar as evidências sobre segurança da eletroestimulação neuromuscular quando utilizada em unidade de terapia intensiva.

Métodos:

Revisão sistemática, sendo a busca realizada nas bases de dados MEDLINE (acessado via PubMed), PEDro, Cochrane CENTRAL e EMBASE, além de busca manual de referências em estudos randomizados. Foram incluídos ensaios clínicos randomizados que comparassem aplicação da eletroestimulação neuromuscular com grupo controle ou placebo em unidades de terapia intensiva, e que contivessem informações sobre segurança da técnica nos desfechos, sendo considerado como segurança dados de variáveis hemodinâmicas e informações sobre efeitos adversos.

Resultados:

Os artigos foram analisados por dois revisores independentes, e a análise dos dados foi descritiva. A busca inicial encontrou 1.533 artigos; destes, foram incluídos somente 4 ensaios clínicos randomizados. Dois estudos avaliaram segurança por meio das variáveis hemodinâmicas, e somente um deles mostrou aumento nas frequências cardíacas, respiratória e lactato, porém sem relevância clínica. Os outros dois estudos avaliaram a segurança por meio do relato de efeitos adversos; um expôs que 15% dos pacientes apresentaram sensação de picada, sem alteração clinicamente relevante; o outro relatou apenas que um paciente sofreu queimadura superficial por configuração incorreta dos parâmetros.

Conclusão:

A eletroestimulação neuromuscular é uma técnica segura para ser aplicada em pacientes graves, porém deve ser aplicada por profissional treinado e utilizando parâmetros corretos, baseados em evidências.

Descritores:
Segurança; Estimulação elétrica; Respiração artificial; Efeitos colaterais e reações adversas relacionados a medicamentos; Estimulação física; Unidades de terapia intensiva

INTRODUCTION

The survival rate of critically ill patients has increased over time as a function of technological advances and new techniques used for providing intensive care.(11 Segers J, Hermans G, Bruyninckx F, Meyfroidt G, Langer D, Gosselink R. Feasibility of neuromuscular electrical stimulation in critically ill patients. J Crit Care. 2014;29(6):1082-8.) However, in parallel with such an increase in the survival rate, the therapeutic resources that contribute to such outcomes also cause some comorbidities, such as muscle weakness derived from the loss of muscle mass and strength.(22 Herridge MS, Tansey CM, Matté A, Tomlinson G, Diaz-Granados N, Cooper A, Guest CB, Mazer CD, Mehta S, Stewart TE, Kudlow P, Cook D, Slutsky AS, Cheung AM; Canadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293-304.) In addition to these factors, one might also mention immobility in the bed, which increases muscle catabolism and reduces the synthesis of proteins and muscle mass.(33 Truong AD, Fan E, Brower RG, Needham DM. Bench-to-bedside review: mobilizing patients in the intensive care unit--from pathophysiology to clinical trials. Crit Care. 2009;13(4):216.) These muscle disorders might have a negative impact on the patients' independence and quality of life as well as on their functional capacity after discharge from the hospital.(44 Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016;10:CD009419.)

For patients unable to perform active movements, neuromuscular electrical stimulation (NMES) might represent a therapeutic option to increase or maintain their muscle strength. NMES programs seem to be acceptable to patients and result in the improvement of muscle function, exercise capacity and quality of life.(55 Dirks ML, Wall BT, Snijders T, Ottenbros CL, Verdijk LB, van Loon LJ. Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans. Acta Physiol (Oxf). 2014;210(3):628-41.) However, estimates of NMES efficacy based on individual studies lack power and precision.(44 Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016;10:CD009419.)

According to some studies, NMES was shown to be effective in the acute stage of a disease,(66 Gerovasili V, Tripodaki E, Karatzanos E, Pitsolis T, Markaki V, Zervakis D, et al. Short-term systemic effect of electrical muscle stimulation in critically ill patients. Chest. 2009;136(5):1249-56.,77 Routsi C, Gerovasili V, Vasileiadis I, Karatzanos E, Pitsolis T, Tripodaki E, et al. Electrical muscle stimulation prevents critical illness polyneuromyopathy: a randomized parallel intervention trial. Crit Care. 2010;14(2):R74.) while in others, it was shown to have no effect in reverting the loss of muscle strength in the acute stage.(88 Gruther W, Benesch T, Zorn C, Paternostro-Sluga T, Quittan M, Fialka-Moser V, et al. Muscle wasting in intensive care patients: ultrasound observation of the M. quadriceps femoris muscle layer. J Rehabil Med. 2008;40(3):185-9.,99 Poulsen JB, Møller K, Jensen CV, Weisdorf S, Kehlet H, Perner A. Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock. Crit Care Med. 2011;39(3):456-61.) Recent studies with variable methodological designs have shown that NMES is safe, feasible and beneficial for patients admitted to the intensive care unit (ICU).(1010 Pohlman MC, Schweickert WD, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Feasibility of physical and occupational therapy beginning from initiation of mechanical ventilation. Crit Care Med. 2010;38(11):2089-94.

11 Bayley P, Thomsen GE, Spuhler VJ, Blair R, Jewkes J, Bezdjian L, et al. Early activity is feasible and safe in respiratory failure patients. Crit Care Med. 2007;35(1):139-45.

12 Morris PE, Goad A, Thompson C, Taylor K, Harry B, Passmore L, et al. Early intensive care unit mobility therapy in the treatment of acute respiratory failure. Crit Care Med. 2008;36(8):2238-43.
-1313 Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, Esbrook CL, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: a randomised controlled trial. Lancet. 2009;373(9678):1874-82.) However, the available data are still inconclusive due to the heterogeneity of protocols and the small sample sizes.

The aim of the present systematic review was to investigate the safety of NMES among critically ill patients by comparison to control or placebo groups.

METHODS

The present systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement(1414 Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336-41. Erratum in: Int J Surg. 2010;8(8):658.) and was registered in the International prospective register of systematic reviews (PROSPERO) on July 18, 2016, under registration number 42016043079.

Eligibility criteria

Randomized clinical trials (RCT) involving patients admitted to the ICU, under invasive mechanical ventilation and subjected to NMES on the peripheral muscles were included. These patients were compared to a control group, composed of patients receiving other types of physical therapy, no intervention or sham NMES.

The outcome assessed was the safety of NMES among critically ill patients, based on the presence/absence of adverse effects and/or hemodynamic parameters.

The exclusion criteria were pilot RCTs and studies with missing data or without control group data.

Search strategy

The search was conducted in the following electronic databases: MEDLINE (via PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE. In addition, a manual search of the references cited in published studies was also performed. The search was performed in October 2016 with the following keywords and corresponding synonyms: "critical illness", "intensive care", "intensive care units", "electric stimulation" and "electric stimulation therapy". These terms were associated with a sensitive list of terms to locate RCTs.(1515 Robinson KA, Dickersin K. Development of a highly sensitive search strategy for the retrieval of reports of controlled trials using PubMed. Int J Epidemiol. 2002;31(1):150-3.) The full search strategy used for the PubMed database is described in table 1. The search had no language or date limits.

Table 1
Search strategy used for PubMed

Study selection and data extraction

The titles and abstracts of all the retrieved articles were independently analyzed by two reviewers. Articles whose abstracts did not provide sufficient information were selected for full-text analysis. Following selection based on titles and abstracts, the same reviewers independently selected articles based on full-text analysis; instances of disagreement were solved by consensus.

Data extraction was performed in duplicate by the same two reviewers, who used a standardized form for this purpose. The main outcome was the presence of adverse effects; a second outcome of interest was changes in hemodynamic variables.

Assessment of risk of bias

The methodological quality of the studies was descriptively assessed by two reviewers according to the method formulated by the Cochrane Collaboration.(1616 Carvalho AP, Silva V, Grande AJ. Avaliação do risco de viés de ensaios clínicos randomizados pela ferramenta da colaboração Cochrane. Diagn Tratamento. 2013;18(1):38-44.) The following aspects were considered: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and professionals), detection bias (blinding of outcome assessors), attrition bias (incomplete outcome data), reporting bias (selective reporting) and other sources of bias.

Data analysis

The data were subjected to descriptive and qualitative analysis and are presented in figures and tables.

RESULTS

Description of studies

The initial search located 1,533 articles, out of which 18 were rated as potentially relevant and analyzed in detail. Following full-text analysis, 13 articles were excluded for not addressing the outcomes of interest,(55 Dirks ML, Wall BT, Snijders T, Ottenbros CL, Verdijk LB, van Loon LJ. Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans. Acta Physiol (Oxf). 2014;210(3):628-41.

6 Gerovasili V, Tripodaki E, Karatzanos E, Pitsolis T, Markaki V, Zervakis D, et al. Short-term systemic effect of electrical muscle stimulation in critically ill patients. Chest. 2009;136(5):1249-56.
-77 Routsi C, Gerovasili V, Vasileiadis I, Karatzanos E, Pitsolis T, Tripodaki E, et al. Electrical muscle stimulation prevents critical illness polyneuromyopathy: a randomized parallel intervention trial. Crit Care. 2010;14(2):R74.,99 Poulsen JB, Møller K, Jensen CV, Weisdorf S, Kehlet H, Perner A. Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock. Crit Care Med. 2011;39(3):456-61.,1717 Falavigna LF, Silva MG, Freitas AL, Silva PF, Paiva Júnior MD, de Castro CM, et al. Effects of electrical muscle stimulation early in the quadriceps and tibialis anterior muscle of critically ill patients. Physiother Theory Pract. 2014;30(4):223-8.

18 Gerovasili V, Stefanidis K, Vitzilaios K, Karatzanos E, Politis P, Koroneos A, et al. Electrical muscle stimulation preserves the muscle mass of critically ill patients: a randomized study. Crit Care. 2009;13(5) R161.

19 Hirose T, Shiozaki T, Shimizu K, Mouri T, Noguchi K, Ohnishi M, et al. The effect of electrical muscle stimulation on the prevention of disuse muscle atrophy in patients with consciousness disturbance in the intensive care unit. J Crit Care. 2013;28(4):536.e1-7.

20 Karatzanos E, Gerovasili V, Zervakis D, Tripodaki ES, Apostolou K, Vasileiadis I, et al. Electrical muscle stimulation: an effective form of exercise and early mobilization to preserve muscle strength in critically ill patients. Crit Care Res Pract. 2012;2012:432752.

21 Bouletreau P, Patricot MC, Saudin F, Guiraud M, Mathian B. Effects of intermittent electrical stimulations on muscle catabolism in intensive care patients. JPEN J Parenter Enteral Nutr. 1987;11(6):552-5.

22 Bouletreau P, Patricot MC, Saudin F, Guiraud M, Mathian B. [Effects of intermittent muscle stimulation on muscle catabolism in patients immobilized in the ICU]. Ann Fr Anesth Reanim. 1986;5(4):376-80. French.

23 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.
-2424 Velmahos GC, Petrone P, Chan LS, Hanks SE, Brown CV, Demetriades D. Electro stimulation for the prevention of deep venous thrombosis in patients with major trauma: a prospective randomized study. Surgery. 2005;137(5):493-8.) and one because it was not an RCT.(11 Segers J, Hermans G, Bruyninckx F, Meyfroidt G, Langer D, Gosselink R. Feasibility of neuromuscular electrical stimulation in critically ill patients. J Crit Care. 2014;29(6):1082-8.) The reviewers independently rated four articles as adequate, which together included 162 patients (Table 2, Figure 1).

Table 2
Description of selected studies

Figure 1
Flowchart representing article search and selection. RCT - randomized clinical trial.

Risk of bias

Assessment of the risk of bias based on the method formulated by the Cochrane Collaboration showed that relative to the selection bias aspect of "random sequence generation", two studies exhibited a low risk of bias(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.) and the other two an uncertain risk of bias.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.,2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) Relative to the selection bias aspect of "allocation concealment", all four articles exhibited an uncertain risk of bias.(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.

26 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.
-2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) In regard to performance bias - "blinding of participants and professionals" - three studies exhibited an uncertain risk of bias(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.,2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) and one study presented a low risk of bias.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.)

For detection bias - "blinding of outcome assessors" - two studies exhibited an uncertain risk of bias(2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.,2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) and the other two a low risk of bias.(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) In regard to attrition bias - "incomplete outcome data" - all four studies(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.

26 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.
-2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) exhibited a low risk of bias. Relative to reporting bias - "selective reporting" - all four studies(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.

26 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.
-2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) exhibited a low risk of bias. Concerning other sources of bias, all four studies(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.

26 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.
-2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) exhibited an uncertain risk of bias.

Interventions

The studies included in the present review used different comparator groups: one included a control group,(2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.) another compared NMES to active mobilization,(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) a third used the contralateral side of the body as a control,(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.) and the fourth compared two groups subjected to NMES with different frequencies.(2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) In none of the selected studies was the safety of the technique the primary outcome. In the present review, we used the secondary outcomes and corresponding data (Table 2).

Two out of the four included studies assessed NMES safety based on hemodynamic variables. Stefanou et al.(2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) found significant differences in heart rate, respiratory rate and blood lactate, which were not considered clinically relevant. In contrast, Akar et al.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) did not find any significant differences between the groups.

The other two studies assessed safety based on reported adverse effects. In the study by Abu-Khaber et al.,(2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.) 15% of the participants described a prickling sensation, which was not clinically significant. In the study by Rodriguez et al.,(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.) there was one case of a superficial burn due to the improper configuration of NMES parameters.

DISCUSSION

The present systematic review, based on RCTs, found that as a means to prevent ICU-acquired muscle weakness and in comparison to a control group, NMES is safe provided it is properly applied by a duly trained professional.

None of the studies included in the present review assessed the safety of the technique of interest as the main outcome. However, they assessed variables able to detect risk in the application of NMES.

The ideal dose for use in NMES training protocols has not yet been established, as several systematic reviews on this subject show that there is wide variation in the intensity, duration, number of repetitions and site of application.(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.,2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) On these grounds, one should consider the hypothesis that patients might be undertreated, this being the cause for the lack of reports of adverse effects.

The population in the study by Rodriguez et al.(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.) exhibited sepsis, which is a common occurrence in the ICU associated with systemic inflammation, which is an inducer of protein catabolism. The authors detected one case of skin burn following a session in which the configurations did not comply with the predefined protocol. Other studies conducted with patients with sepsis did not report any adverse effects among the patients subjected to NMES.(99 Poulsen JB, Møller K, Jensen CV, Weisdorf S, Kehlet H, Perner A. Effect of transcutaneous electrical muscle stimulation on muscle volume in patients with septic shock. Crit Care Med. 2011;39(3):456-61.)

A prickling sensation was the only complication described by 15% of the patients subjected to NMES in the study by Abu-Khaber et al.,(2525 Abu-Khaber HA, Abouelela AM, Abdelkarim EM. Effect of electrical muscle stimulation on prevention of ICU acquired muscle weakness and facilitating weaning from mechanical ventilation. Alexandria J Med. 2013;49(4):309-15.) which was included in the present systematic review. According to the authors, this occurrence was no reason to limit the intervention. In turn, Fischer et al.(2828 Fischer A, Spiegl M, Altmann K, Winkler A, Salamon A, Themessl-Huber M, et al. Muscle mass, strength and functional outcomes in critically ill patients after cardiothoracic surgery: does neuromuscular electrical stimulation help? The Catastim 2 randomized controlled trial. Crit Care. 2016;20:30.) detected five cases of patients who reported discomfort during the application of NMES, which was no reason to discontinue the intervention; they did not describe any hemodynamic abnormalities. Pain was the reason why one out of 68 patients dropped out of another study.(2929 Iwatsu K, Yamada S, Iida Y, Sampei H, Kobayashi K, Kainuma M, et al. Feasibility of neuromuscular electrical stimulation immediately after cardiovascular surgery. Arch Phys Med Rehabil. 2015;96(1):63-8.)

One of the factors that aggravates the clinical condition of critically ill patients is the intense inflammation they develop. In addition to the state of hypermetabolism triggered by the inflammation, increased protein catabolism and overload of kidney and heart function also occur. Therefore, all situations that enhance the inflammatory response are undesirable. In a study included in the present review, Akar et al.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) found a reduction of the inflammatory response for the duration of mechanical ventilation among patients who underwent NMES combined with active exercise and the group that received NMES alone. Interleukin 6 levels decreased in the group that underwent NMES combined with exercise, and interleukin 8 levels decreased in the groups that received NMES alone or in combination with exercise. These findings suggest that NMES is not associated with the risk of an increase of the inflammatory response among critically ill patients. However, the authors did not categorize the study participants as per the severity of their clinical condition or the presence of sepsis.

Akar et al.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) further found a significant reduction in heart rate after the intervention. This finding suggests that NMES does not cause cardiac overload. In fact, this finding might denote a clinical improvement and even a cardiovascular adaptation to treatment.(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) In contrast, Stefanou et al.(2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) found an elevation in heart rate in their sample.

In regard to the deaths that occurred in the included studies, there is no indication they were associated with the use of NMES. In the study by Akar et al.,(2626 Akar O, Günay E, Sarinc Ulasli S, Ulasli AM, Kacar E, Sariaydin M, et al. Efficacy of neuromuscular electrical stimulation in patients with COPD followed in intensive care unit. Clin Respir J. 2017;11(6):743-50.) mortality was higher (50%) in the group that did not receive NMES, while relative to the two groups that received NMES, patients out of 20 died.

Among 17 RCTs involving the application of NMES to critically ill patients and subjected to full-text analysis in the present review, only four approached patient safety and were included for review. The fact that the other studies did not make mention of adverse effects suggests that this therapeutic strategy has no unhealthy effects for critically ill patients.

Two observational studies and one pilot study assessed the safety of NMES among critically ill patients.(11 Segers J, Hermans G, Bruyninckx F, Meyfroidt G, Langer D, Gosselink R. Feasibility of neuromuscular electrical stimulation in critically ill patients. J Crit Care. 2014;29(6):1082-8.,2929 Iwatsu K, Yamada S, Iida Y, Sampei H, Kobayashi K, Kainuma M, et al. Feasibility of neuromuscular electrical stimulation immediately after cardiovascular surgery. Arch Phys Med Rehabil. 2015;96(1):63-8.,3030 Parry SM, Berney S, Warrillow S, El-Ansary D, Bryant AL, Hart N, et al. Functional electrical stimulation with cycling in the critically ill: a pilot case-matched control study. J Crit Care. 2014;29(4):695.e1-7.)

Iwatsu et al.(2929 Iwatsu K, Yamada S, Iida Y, Sampei H, Kobayashi K, Kainuma M, et al. Feasibility of neuromuscular electrical stimulation immediately after cardiovascular surgery. Arch Phys Med Rehabil. 2015;96(1):63-8.) followed up with 61 patients throughout the postoperative period following heart surgery and analyzed the safety of NMES. Frequencies of 200Hz and 20Hz were alternated, and the intensity of the current was defined in the postoperative period, with patients receiving 10% to 20% of the maximum torque. Safety outcomes were hemodynamic parameters, pacemaker function and arrhythmias. None of these parameters exhibited any abnormalities, which allowed the authors to conclude that NMES does not increase the cardiovascular workload, and thus is safe for the target population.

In an observational study, Segers et al.(11 Segers J, Hermans G, Bruyninckx F, Meyfroidt G, Langer D, Gosselink R. Feasibility of neuromuscular electrical stimulation in critically ill patients. J Crit Care. 2014;29(6):1082-8.) assessed blood pressure, heart rate, respiratory rate, oxygen saturation and skin reactions as safety outcomes of the application of NMES to critically ill patients. The participants received the intervention five times per week, with an intensity up to 80mA, pulse duration up to 500ms and frequency of 50Hz. No significant change was detected in the investigated variables; only skin hyperemia occurred in 50% of the patients following removal of the electrodes, which disappeared gradually. There were no reports of pain limiting the intervention.

In a pilot study that compared a group of patients with sepsis under mechanical ventilation who received NMES combined with ergometric cycling versus a control group, Parry et al.(3030 Parry SM, Berney S, Warrillow S, El-Ansary D, Bryant AL, Hart N, et al. Functional electrical stimulation with cycling in the critically ill: a pilot case-matched control study. J Crit Care. 2014;29(4):695.e1-7.) selected safety parameters to determine continuation or discontinuation of NMES: heart rate below 50 or over 140bpm, mean arterial pressure below 65mmHg, need of fraction of inspired oxygen over 80%, need of positive end-expiratory pressure (PEEP) over 15mmHg, respiratory rate over 35 bpm, oxygen saturation below 85% or a 10% fall, and self-reported pain score over 7 on a visual analog scale. The authors did not detect any serious adverse effects, just one case of desaturation 30 minutes after the intervention. Thus, they concluded that NMES was safe among critically ill patients.

One of the main limitations of the present study derives from the methodological diversity among the included studies. The use of the contralateral lower limb as a control in the study by Rodriguez et al.(2323 Rodriguez PO, Setten M, Maskin LP, Bonelli I, Vidomlansky SR, Attie S, et al. Muscle weakness in septic patients requiring mechanical ventilation: protective effect of transcutaneous neuromuscular electrical stimulation. J Crit Care. 2012;27(3):319.e1-8.) does not allow the assessment of possible systemic abnormal changes following the application of NMES. In turn, Stefanou et al.(2727 Stefanou C, Karatzanos E, Mitsiou G, Psarra K, Angelopoulos E, Dimopoulos S, et al. Neuromuscular electrical stimulation acutely mobilizes endothelial progenitor cells in critically ill patients with sepsis. Ann Intensive Care. 2016;6(1):21.) performed one single NMES session, which does not allow assessment of the effects of continued use or the progressive increase of intensity on muscle mass and the cardiovascular system.

CONCLUSION

Neuromuscular electrical stimulation is a safe technique for application to critically ill patients by duly trained professionals and with proper evidence-based parameters. New randomized clinical trials should be conducted, with the safety of neuromuscular electrical stimulation among critically ill patients as the primary outcome.

  • Registered in the International prospective register of systematic reviews (PROSPERO) on July 18, 2016, under registration number 42016043079.

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Edited by

Responsible editor: Alexandre Biasi Cavalcanti

Publication Dates

  • Publication in this collection
    Apr-Jun 2018
  • Date of issue
    June 2018

History

  • Received
    08 July 2017
  • Accepted
    05 Feb 2018
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