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RESEARCH ARTICLE
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Neuromuscular electrical stimulation for preventing skeletal muscle
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weakness and wasting in critically ill patients: a systematic review
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Nicola A Maffiuletti1*, Marc Roig2, Eleftherios Karatzanos3 and Serafim Nanas3
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1Neuromuscular
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2Department
Research Laboratory, Schulthess Clinic, Zurich, Switzerland.
of Exercise and Sport Sciences and Department of Neuroscience and
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Pharmacology, University of Copenhagen, Copenhagen, Denmark. 3First Critical Care
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Department, Evangelismos Hospital and National and Kapodestrian University of
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Athens, Athens, Greece.
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* Corresponding author
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E-mail addresses:
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NAM: nicola.maffiuletti@kws.ch
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MR: markredj@gmail.com
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EK: lkaratzanos@gmail.com
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SN: sernanas@gmail.com
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Abstract
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Background: Neuromuscular electrical stimulation (NMES) therapy may be useful in
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early musculoskeletal rehabilitation during acute critical illness. The objective of this
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systematic review was to evaluate the effectiveness of NMES for preventing skeletal
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muscle weakness and wasting in critically ill patients, in comparison with usual care.
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Methods: We searched Pubmed, CENTRAL, CINAHL, Web of Science and PEDro to
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identify randomized controlled trials exploring the effect of NMES in critically ill
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patients, with a well-defined NMES protocol, providing outcomes related to skeletal
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muscle strength and/or mass, and whose full text was available. Two independent
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reviewers extracted data on muscle-related outcomes (strength and mass), participant
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and intervention characteristics, and assessed the methodological quality of the studies.
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Due to the lack of means and standard deviations, as well as the lack of baseline
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measurements in two studies, it was impossible to conduct a full meta-analysis. When
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means and standard deviations were provided, effect sizes of individual outcomes were
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calculated, otherwise a qualitative analysis was performed.
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Results: The search yielded eight eligible studies involving 172 patients. The
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methodological quality of the studies was moderate to high. Five studies reported
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greater strength or better strength preservation with NMES, with a large effect size for
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one study. Two studies found better preservation of muscle mass with NMES, with small
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to moderate effect sizes, while no significant benefits were found in two other studies.
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Conclusions: NMES added to usual care proved to be more effective than usual care
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alone for preventing skeletal muscle weakness in critically ill patients. However, there is
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inconclusive evidence for the prevention of muscle wasting.
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Keywords: Muscle strength, Muscle mass, Quadriceps femoris, Intensive care, Sepsis,
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Rehabilitation
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Background
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A large majority of patients admitted to the intensive care unit (ICU) after the very acute
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phase of a critical illness exhibit major defects in skeletal muscle strength (weakness)
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and mass (wasting) [1-3]. This so-called ICU-acquired weakness (ICUAW) is generally
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defined as a bilateral deficit of muscle strength in all limbs [4] that is accompanied by a
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profound loss of muscle mass (as high as 5% per day during the first week of ICU [5, 6]),
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and is associated with delayed weaning from mechanical ventilation [7], protracted and
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costly ICU and hospital stay (the average daily ICU cost being approximately €1’000 [8]),
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and elevated mortality rates [9, 10]. ICUAW, whose etiology is multifactorial, has been
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associated to impaired physical function and health status in ICU survivors, that can
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persist even years after hospital discharge [11, 12]. This drastically increases the
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duration of post-ICU treatments (including rehabilitation), and provokes severe social,
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psychological and economic consequences (the average cost per life-year gained being
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approximately €6’000 [8]), thus affecting quality of life and delaying return to physical
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self-sufficiency and return to work of people who have been critically ill.
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Because early rehabilitation/mobilization in the ICU has been shown to enhance
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short-term and potentially long-term functional outcomes [13-15], the use of physical
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therapy strategies to counteract skeletal muscle weakness and wasting has been
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frequently promoted in the last few years [16-20]. Neuromuscular electrical stimulation
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(NMES), that consists of generating visible muscle contractions with portable devices
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connected to surface electrodes [21], has been shown to be effective in treating impaired
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muscles [22] as it has the potential to preserve muscle protein synthesis and prevent
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muscle atrophy during prolonged periods of immobilization [23]. ICU-based NMES has
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recently been introduced for the treatment of ICUAW, as it does not require active
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patient cooperation, it has an acute beneficial systemic effect on muscle microcirculation
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[24], and seems to provide some structural and functional benefits to critically ill
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patients [25]. However, due to the heterogeneity of the critically ill patient group but
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also of the NMES procedures implemented in the ICU [18, 26-28], the effectiveness of
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this rehabilitation procedure for ICUAW prevention remains to be clearly proven.
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Previous reviews have analysed the impact of NMES on different muscle outcomes
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in patients with specific chronic diseases such as chronic obstructive pulmonary disease
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(COPD) [22]. Several randomized controlled trials (RCTs) have been completed since
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those reviews were published. Furthermore, a detailed analysis of the effects of NMES in
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critically ill patients is lacking. Results from previous studies suggest that the most
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deconditioned patients obtain the best results when NMES is applied [22]. Given the
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potential use of NMES among patients with a limited capacity to engage in voluntary
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muscle work, the assessment of the evidence behind the use of NMES in critically ill
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patients was much required. We therefore undertook a formal systematic review of the
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literature to determine the rehabilitative effect of NMES on skeletal muscle strength and
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mass in critically ill patients, in comparison with standard care.
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Methods
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Electronic search and information sources
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Two of the authors (EK, SN) performed independently the electronic search on the
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following databases: PubMed (1951-present), Cochrane Controlled Trials Register
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(CENTRAL) (1894-present), Cumulative Index to Nursing and Allied Health Literature
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(CINAHL) (1981-present), Web of Science (1970-present) and Physiotherapy Evidence
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Database (PEDro) (1929-present). Reference lists from articles related to the topic were
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also searched. The search was not language restricted but it was limited to RCTs
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completed on human subjects. The terms used to perform the search were:
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electrotherapy, electrical stimulation, electrical muscle stimulation,
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electromyostimulation, electrostimulation, neuromuscular stimulation and NMES. The
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results of the primary search were combined with the following terms: critically ill
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patients, critical illness, intensive care and ICU. The latest electronic search was
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performed on March 3rd, 2012.
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Study selection and eligibility criteria
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The list of titles and abstracts of articles retrieved in the electronic search were first
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reviewed independently by two of the authors (EK, NAM), who selected only those
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potentially relevant for a more detailed review at full text level. Then both reviewers
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read the full text and applied the following inclusion criteria: (1) RCT exploring the
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effect of NMES in critically ill patients; (2) with a well-defined NMES protocol (i.e., the
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main stimulation parameters were provided) for at least one intervention group; (3)
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with NMES applied to skeletal muscles with an intensity equal to or greater than motor
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threshold (i.e., evoking a visible muscle contraction); (4) including outcomes related to
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muscle strength and/or mass; (5) and whose full text was available. After reviewing the
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articles and applying the inclusion criteria independently, both reviewers held a
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consensus meeting to compare their results and decide which articles should finally be
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included in the review. In case of disagreement, a third reviewer (MR) was included in
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the discussion to reach a final consensus.
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Data collection process
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Two of the authors (EK, MR) extracted independently the data from the studies included
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in the review. Data retrieved included characteristics of patients (i.e., number, gender,
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age, diagnosis and disease severity), interventions (i.e., type, duration, frequency and
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NMES parameters) as well as muscle-related outcomes. When provided, details
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regarding the number of patients excluded or discharged and the compliance with
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treatment were also recorded. After extraction, both reviewers compared their data
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extraction sheets to confirm the accuracy of the data.
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Methodological quality
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Two authors (EK, MR) assessed independently the methodological quality of the studies
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using the PEDro scale. This scale, which has been used extensively in the methodological
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evaluation of similar studies [22], and has previously shown good validity and reliability
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[29, 30], is based on 11 items to assess scientific rigor: eligibility criteria, random
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allocation, concealed allocation, baseline comparability, blinded subjects, blinded
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therapists, blinded assessors, follow-up, intention-to-treat, between-group analysis,
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both point estimates and variability. All except one item (eligibility criteria) were used
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to calculate the final score (maximum 10 points). This item was excluded because it
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affects external but not internal or statistical validity. A study was arbitrarily considered
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to be of high quality if PEDro score was greater than 5, of moderate quality if the score
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was 5 or 4, and of low quality if PEDro score was 3 or lower [31]. To minimize errors
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and potential biases in the methodological evaluation, both reviewers compared their
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scores in a consensus meeting. In case of disagreement, a third reviewer (NAM) was
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included in the discussion to reach a final consensus. Consistency between the two
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reviewers that performed the methodological assessment (PEDro scores) was evaluated
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with the Cronbach’s coefficient alpha (α). Overall methodological quality based on the
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PEDro scores was also categorized following the indications provided by Van Tulder et
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al. [32].
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Data analysis
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Outcomes were grouped into two main categories for data analysis: muscle strength and
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muscle mass (thickness and volume). Probably because data were not normally
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distributed, the majority of the studies included in the review reported continuous
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outcomes using medians with interquartile range instead of means with standard
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deviation (SD). We used several statistical approaches ([33], page 156) in an attempt to
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normalize data distribution for the three studies with raw data available [25, 34, 35], but
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we failed to alter the skewed data distribution. We also used the equations proposed by
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Hozo et al. to estimate means and SDs from medians, range and sample size [36].
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However, none of these approaches allowed us to reliably calculate means and SDs. In
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addition, due to the critical status of some subjects, muscle strength was not assessed at
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admission, and therefore baseline strength measurements were not obtained in two
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studies [34, 35]. Given these two important limitations it was not possible to pool the
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data from different studies to conduct a full meta-analysis. Instead, when means and SDs
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were provided, we calculated the effect size (d) of individual outcomes by dividing the
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difference between mean change scores (post-intervention minus pre-intervention
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scores) by the pooled SD [37]. Effect sizes were then categorized according to the
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criteria established by Cohen as large (d > 0.8), moderate (d < 0.8 but > 0.2) or small
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effect (d < 0.2) [37]. When means and SDs at baseline and after the intervention were
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not provided, individual effect sizes were not calculated and, instead, a qualitative
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analysis of the data was performed.
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Results
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Study selection
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The different steps of the electronic search are illustrated in Figure 1. The initial search
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yielded 461 articles that were included in the review process at abstract level. After 113
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duplicates were removed and 348 records were screened, only 10 full-text articles were
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assessed for eligibility (336 records were excluded due to not meeting all the required
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inclusion criteria, and two were excluded because they were conference proceeding
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abstracts and full text was not available [38, 39]). Of those 10 articles, two more studies
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were excluded because one was not a RCT [40], and the other did not report any
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relevant muscle-related outcome [41]. Finally, eight RCTs met all the required criteria
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and were included in the systematic review [25, 34, 35, 42-46]. It should be noted,
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however, that one of the selected articles [34] presented a secondary analysis of a same
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study [35]. Because these two latter studies reported data from different outcomes we
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presented them individually [34, 35].
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Methodological quality
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The PEDro score for each study is reported in Table 1. The mean ± SD PEDro score of the
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studies included in the review was 5.5 ± 1.5, with scores ranging from 4 to 8 (i.e.,
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moderate to high quality). When reviewer's PEDRo scores were compared consistency
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was high (α=0.751; p<0.0001) [47]. The most common methodological weaknesses of
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the studies referred to the blinding of patients (although sham NMES was used in two
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studies [42, 43], which could be considered as a sort of blinding), therapists and
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assessors. The allocation of subjects to different intervention groups was only concealed
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in two studies [42, 45]. In addition, two studies did not report baseline data for muscle
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strength and therefore comparability among groups could not be established [34, 35].
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Only three studies met the follow-up criteria as established by the PEDro scale [42, 44,
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45]. This was because data for at least one key outcome were not obtained in more than
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15% of the patients initially allocated into treatment groups [25, 34, 35], or because the
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number of patients from whom key outcome data were obtained was not explicitly
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stated [43, 46]. Two of the studies used intention-to-treat analysis [34, 35], and in one
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study all patients received treatments as allocated [45]. The rest of the studies did not
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meet the intention-to-treat analysis criterion [25, 42-44, 46]. The results of five out of
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five RCTs that investigated the effect of NMES on muscle strength supported the
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effectiveness of this intervention. Since, two of these studies [42, 45] were of high
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methodological quality (PEDro score ≥ 7) the level of evidence could be categorized as
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moderate to strong. In contrast, since only two [25, 43] of the four studies that
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investigated the effect of NMES on muscle mass found a positive outcome, the evidence
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in support of this technique to improve muscle mass can be considered as conflicting.
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Participants
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Characteristics of the patients included in the review are shown in Table 2. Only
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information of patients whose data for at least one of the outcomes of interest was
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provided was included in the review (at the study level). Data from 172 patients (46
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females and 126 males) were retrieved. Of those 172 patients, 74 were allocated to the
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NMES group, 76 to the control group and 22 patients received NMES on one side of the
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body while the contralateral side acted as control. The most common diagnoses at
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admission were sepsis, COPD and trauma, although patients were also hospitalized due
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to neurological problems, cancer or post-surgery complications. The severity of the
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disease was categorized with the Simplified Acute Physiology Score III (SAPS III) [25, 34,
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35], the Sequential Organ Failure Assessment (SOFA) as well as the Acute Physiology
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and Chronic Health Evaluation II (APACHE II) [25, 34, 35, 44, 45]. No severity scores
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were reported in one study [43]. In addition, two studies reported the number of
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patients diagnosed with critically illness polyneuromyopathy [34, 35], and three other
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studies the number of days in the ICU [44-46]. Two studies that investigated the effects
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of NMES on patients with COPD reported spirometry and blood gas values as measures
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of disease severity [42, 46]. According to international guidelines [48], those patients
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would be categorized as patients with severe to very severe COPD.
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Interventions
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The characteristics of the interventions are shown in Table 3. The duration of the NMES
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protocol ranged from 7 days up to 6 weeks. Patients in the control group received usual
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care and, in some studies, assisted limb mobilization with [42] or without sham NMES
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[46], or sham NMES alone [43]. NMES was delivered while the patient was relaxed on
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the following muscle groups: glutei [46], quadriceps [25, 34, 35, 42-46], hamstrings [42],
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peroneus longus [25, 34, 35], and biceps brachii [45]. Specific details of the stimulation
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parameters are shown in Table 3. In all studies, the criterion to establish the minimum
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intensity of NMES was a visible muscle contraction, which corresponds to the motor
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threshold [49]. NMES intensity during the treatment was progressively adjusted to the
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patients’ tolerance or set as a percentage (150%) of the motor threshold [44].
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Stimulation frequencies ranged from 8 to 100 Hz and pulse durations from 250 to 400
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μs. Five studies reported the use of symmetric biphasic pulses [25, 34, 35, 42, 45], and
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one the use of asymmetric currents [46]. The shape (rectangular) of the stimulation
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pulse and ramp-up and ramp-down times were reported only in three studies [34, 35,
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44]. In general, compliance (percentage of sessions completed) with NMES treatment
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was quite high (81-100%), even though it was not reported in two studies [43, 46]. No
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adverse events or complications in relation to NMES safety or tolerability were reported
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in all but one study included in the systematic review [44]. Specifically, superficial skin
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burn and excessive pain were respectively observed in one and two patients (out of 14)
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by Rodriguez et al. [45].
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Outcomes
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Muscle strength
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Five studies assessed the effects of NMES on strength of different muscle groups (Table
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3) [34, 35, 42, 45, 46]. Four studies evaluated muscle strength using the Medical
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Research Council (MRC) scale [34, 35, 45, 46]. One study found a significantly larger
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MRC score increase in the NMES group compared to the control group [46], with a large
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effect size (d = 1.44). Two studies reported greater MRC scores in NMES than in control
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patients [34, 35], although baseline measurements were not provided. Another study
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found significantly higher MRC scores on the stimulated side compared to the
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contralateral side [45]. One study, in which quadriceps muscle strength was assessed
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with dynamometry [42], reported a significantly larger strength increase in the NMES
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group compared to the control group.
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Muscle mass
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Four studies assessed the effects of NMES on muscle thickness [25, 43, 45], or volume
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[44] (Table 3). Muscle thickness was measured with ultrasound and muscle volume was
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obtained from the analysis of computerized tomography images. In one study, muscle
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thickness decreased less in the NMES group than in the control group [25], and effect
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sizes (d) ranged from 0.11 to 0.39 depending on the muscle group assessed. Another
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study investigated the effects of NMES on quadriceps muscle thickness in acute (<7 days
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hospitalized) and long-term (>14 days hospitalized) patients and found that thickness
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increased only for long-term patients (d = 0.36) but not for acute and sham patients
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[43]. The two other studies found no significant changes in muscle thickness in both the
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stimulated and contralateral biceps brachii [45], and no differences in muscle volume
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loss between the stimulated and contralateral quadriceps [44].
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Discussion
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Neuromuscular electrical stimulation added to usual care, in comparison with usual care
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alone or sham stimulation, was associated with better muscle strength outcomes in ICU
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patients, with moderate to strong evidence. In contrast, the level of evidence was weaker
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and conflicting for outcomes related to muscle mass, with small to moderate effect sizes
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or no effects. These findings suggest that NMES may have the potential to prevent
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skeletal muscle weakness in critically ill patients, which could confer many important
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physical, psychosocial, and economic benefits after discharge from ICU. It remains,
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however, to be ascertained whether NMES therapy can also prevent muscle wasting
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associated with critical illness.
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The high inconsistency among studies in ICU patient characteristics was not
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surprising (as attested by non-normal data distribution and lack of means and SDs),
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however this affected the methodological quality of the included studies, which
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prevented us from completing a meta-analysis. Therefore, the main results of this
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systematic review could only be interpreted with a thorough qualitative analysis.
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Although it is extremely challenging to perform large and well-controlled RCTs in this
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patient population, future NMES studies should consider stratifying patients for main
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diagnosis and eventually also for disease severity, as this latter has been identified as an
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independent risk factor for ICUAW incidence [10, 50]. It is conceivable that the benefits
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of NMES are greater for ICU patients with respiratory (as suggested by the large effect
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sizes observed in COPD patients) [46], or neurological complications, as compared with
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sepsis or trauma patients. For example, inflammation-mediated electrolyte changes and
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also edema may seriously affect conductivity and thus electrical current diffusion [51],
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which could lessen any systemic effect of NMES in these patient samples.
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The questionable validity and heterogeneity of NMES protocol characteristics
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adopted in the eight studies included in this systematic review further complicate the
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interpretation of the present results. The strength of the contraction induced by NMES
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(i.e., evoked tension), that is the main determinant of NMES effectiveness [52], has not
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been reported in any of the included studies. Quantifying this parameter, rather than
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simple current intensity/voltage, is crucial as it would also permit to discriminate
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responders from non-responders [53, 54], and eventually ascertain the optimal NMES
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characteristics for ICU patients on an individual basis. Also, evoked tension should be
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maximized, whenever possible, by selecting appropriate current parameters
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(stimulation frequency of 50-100 Hz [55] and highest tolerable stimulation intensity,
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while minimizing fatigue with long relaxation phases), joint position (long muscle
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length) and methodological precautions such as the accurate determination of muscle
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motor points [56].
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Assessing voluntary muscle strength in the ICU setting is extremely difficult. Despite
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potential limitations of manual muscle testing such as poor validity and inaccuracy of
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subjective ratings [57, 58], especially when assessors are not blinded, voluntary strength
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has been evaluated using the MRC score in the majority of the included RCTs, and only
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one study adopted dynamometry [42]. Considering the limited or null cooperation of
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ICU patients at admission, as well as the considerable influence of central factors
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(including motivation) on maximal voluntary efforts [59], evaluation of muscle function
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in these patients would better rely on artificially-evoked muscle responses. Therefore,
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alternative methods that are independent of patient cooperation such as peripheral
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magnetic stimulation [60], which can also be used to evaluate respiratory muscle
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function [60], electrical impedance myography [61], myotonometry [62], and
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mechanomyography [63], would improve the validity of muscle testing in ICU.
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The major risk factors for ICUAW are immobilization, multiple organ failure,
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systemic inflammatory response syndrome, gram-negative sepsaemia [10],
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hyperglycemia [3, 64], and medications such as aminoglycosides, colistin and
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corticosteroids. All these elements should be viewed as important confounding factors
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that could distort accurate interpretations of our findings. For example, patients with a
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recent exacerbation of COPD (most of them are prescribed corticosteroids, which can
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induce myopathy) were excluded in one instance [46], while another study examined
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the effects of NMES after COPD exacerbation (some patients received corticosteroids)
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[42]. Immobilization days, disease severity scores (organ specific and physiological) and
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medication use must always be carefully controlled.
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Even though physical therapy practices vary widely across ICU, there is growing
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interest in early rehabilitation strategies that have the potential to prevent skeletal
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muscle weakness and wasting in critically ill patients [20]. These interventions range
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from passive stretching [5] and early mobilization therapy [3] to bed-side cycling
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ergometry [13]. Interestingly, NMES added to usual care has recently been shown to be
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effective in reducing ICUAW incidence [35]. The present systematic review confirms
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these preliminary findings, highlighting the potential role of NMES as a preventive
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countermeasure against ICUAW. Compared to the other rehabilitation strategies, the
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unique aspects of NMES are that: it is relatively cost-effective (one multiple-user NMES
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unit costs less than €400), it does not require patients cooperation (it can be applied to
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sedated patients), it can be implemented during the first few days after ICU admission, it
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does not require patient stability in cardiac and respiratory function, it provokes
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considerable central effects, both acute and chronic [65], which could also contribute to
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preventing the occurrence of muscle weakness in critically ill patients. Moreover,
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besides muscle-related outcomes, NMES has been shown to be more effective than
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conventional care or sham stimulation for improving pulmonary function [35, 42, 46],
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including accelerated weaning from mechanical ventilation [35], physical function (6-
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min walking distance [42] and bed-chair transfer [46]), and for reducing the incidence of
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critical illness polyneuromyopathy [35]. However, the effects of NMES on the
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pathophysiological mechanisms of ICUAW are poorly known and NMES cannot be easily
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used with all critically ill patients (e.g., those with skin lesions, traumatic fractures,
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complete lower motor neuron lesions and cardiac pacemakers), so that there is still no
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consensus among intensivists on its real value.
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Conclusions
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This systematic review provides evidence that adding NMES therapy to usual care is
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more effective than usual care alone or sham NMES to prevent ICUAW. Nevertheless,
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there is inconclusive evidence regarding the effectiveness of NMES for the preservation
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of muscle mass in ICU patients. The effects of NMES we observed were probably
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underestimated due to the non-stratification of patients according to main diagnosis and
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disease severity. More studies are needed to explore the long-term effects of NMES
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therapy during ICU stay on physical function and quality of life in ICU survivors, to
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identify the optimal NMES dosage for ICUAW prevention (both in terms of frequency,
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intensity and volume), and to describe the feasibility, safety and cost-effectiveness of
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NMES in different subpopulations of critically ill patients.
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List of abbreviations
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COPD: chronic obstructive pulmonary disease; ICU: intensive care unit; ICUAW:
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intensive care unit acquired weakness; MRC: Medical Research Council; NMES:
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neuromuscular electrical stimulation; RCT: randomized controlled trial; SD: standard
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deviation.
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Competing interests
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The authors declare that they have no competing interests.
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Authors’ contributions
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NAM and MR made substantial contribution to conception and design of the review. All
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authors made substantial contribution to data acquisition, analysis and interpretation.
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All authors were involved in drafting the manuscript and critically revising it. All authors
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approved the final manuscript.
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Author details
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1Neuromuscular
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2Department
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Pharmacology, University of Copenhagen, Copenhagen, Denmark. 3First Critical Care
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Department, Evangelismos Hospital and National and Kapodestrian University of
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Athens, Athens, Greece.
Research Laboratory, Schulthess Clinic, Zurich, Switzerland.
of Exercise and Sport Sciences and Department of Neuroscience and
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395
Acknowledgements
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None.
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Figure 1 Flow diagram of search strategy.
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