Effects of combined blood flow restriction and neuromuscular electrical stimulation on skeletal muscle hypertrophy in adults: a systematic review and meta analysis

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Mangahas, Lance C. Dalleck, Claire Drummond, Adel Ghorbani, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7173103/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Traditional resistance training is often prescribed to stimulate skeletal muscle hypertrophy in adults, however voluntary mechanical movement is not possible for all individuals. The combination of blood flow restriction and neuromuscular electrical stimulation (C-BFR-NMES) has recently been shown to be a passive intervention to promote skeletal muscle hypertrophy in adults. However, due to various protocols being used in the literature, varying amounts of skeletal muscle hypertrophy have been reported. Purpose: The aim of this systematic review and meta-analysis was to quantitatively investigate the effectiveness of C-BFR-NMES compared to BFR or NMES alone, or no intervention to induce skeletal muscle mass in adults. The secondary aims were to compare muscle hypertrophy outcomes when different measurement devices are used following C-BFR-NMES, and to investigate the C-BFR-NMES protocols used to induce skeletal muscle hypertrophy in adults. Methods: A PRISMA-compliant systematic review and meta-analysis was conducted. PubMed, MEDLINE, Web of Science, Scopus and CINAHL were searched from inception to 28 February 2025 using the following inclusion criteria: (1) untrained healthy adults (between the age of 18 – 64 years), (2) study design allowed comparison between C-BFR-NMES and CONTROL (BFR or NMES alone, or no intervention), (3) lower limb skeletal muscle hypertrophy was assessed pre/post intervention, (4) interventions included study periods ≥14 days , and (5) manuscripts written in English. A random-effects meta-analysis was performed and reported in standardised mean differences. Results: A total of 615 articles were screened, three studies with a total population of N = 37 were included, and seven meta-analyses were conducted. C-BFR-NMES induced significantly greater muscle hypertrophy compared to CONTROL (Z = 2.66, p = 0.008), with a medium pooled effect size (ES) of 0.61 (95% CI 0.11 to 1.6) in favour of C-BFR-NMES. Conclusion: A pooled analysis of current data suggests the C-BFR-NMES promotes a medium effect on skeletal muscle hypertrophy in lower body musculature compared to BFR or NMES alone, or no exercise in healthy adults. Further research is needed to determine the effectiveness of C-BFR-NMES in upper body musculature, as well as different cohorts such as adolescent and older populations. Health sciences/Health care Health sciences/Medical research Biological sciences/Physiology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Key Points The results of the systematic review and meta analysis suggest that combined blood flow restriction (BFR) and neuromuscular electrical simulation (NMES) (C-BFR-NMES) is an effective intervention for increasing skeletal muscle mass in healthy adults. In comparison to BFR or NMES alone, or no intervention, C-BFR-NMES resulted in significantly greater increases in skeletal muscle mass. Incorporating C-BFR-NMES into rehabilitation or early intervention programs provides an opportunity for individuals who are unable to perform voluntary resistance training a passive modality to promote muscle hypertrophy. 1. Introduction Skeletal muscle mass represents a large proportion of whole body mass and is the most prevalent adipose tissue free mass in the human body [1] . It facilitates many fundamental outcomes such as locomotion, vital organ protection, and promotion of optimal metabolic health [2] . In contrast, decline in skeletal muscle mass can result in impaired cardiac output, muscle oxidative capacity, insulin sensitivity, basal metabolic rate, and ultimately an increase in adipose tissue mass [1] . Excessive body fat, which is a notable characteristic of overweight and obese individuals, is a major health risk [3] . An increase in skeletal muscle mass or skeletal muscle hypertrophy has functional and sporting benefits as positive correlations have been found between muscle cross sectional area and muscle strength [4] . When an individual experiences an increase in body fat with a decrease in skeletal muscle mass, such changes in body composition are associated with metabolic syndrome [5] , diabetes mellitus [6] , and cardiovascular disease [7] . Furthermore, sarcopenia, the progressive loss of muscle mass that is associated with aging further exacerbates this dysfunction [8] . Ensuring adults partake in physical activity or exercise, notably resistance training, will assist in the promotion and maintenance of skeletal muscle mass, and reduce the risk of chronic diseases such as diabetes, hypertension, and cardiovascular disease [9] . Physical inactivity is considered to be the fourth leading risk factor in global mortality, accounting for approximately 3.2 deaths annually [10] . Resistance training (RT) is the primary type of exercise prescribed to individuals wanting to increase muscle mass [11] . Skeletal muscle hypertrophy can aid in the prevention of age associated muscle insulin resistance [12] and diminished mitochondrial capacity [13] . The American College of Sports Medicine [14] and Australian Government [15] both recommend that adults aged between 18 – 64 years perform muscle strengthening activities on two or more days per week. Data from Australia in 2022 showed that only 26.6% of adults aged 18 – 64 years performed at least two days of muscle strengthening activities per week [16] . Males are more likely to achieve this guideline compared to females [16] . Notably, the proportion of individuals who performed muscle strengthening activities on one day per week generally decreased as age increased [16] . Traditionally, RT is prescribed at high-intensity (≥70% of one repetition maximum [1RM]) to stimulate muscle hypertrophy [14] . However, high-intensity RT is not practical for some individuals recovering from injury, suffering from chronic health conditions, undergoing periods of immobilisation, or athletes in season when training stress is high. The prescription of ≥70% 1RM is based on previous research [14] , demonstrating that high loads (HL) are necessary to recruit higher threshold motor units (MU) responsible for promoting maximal muscular adaptation. The Heneman’s size principle dictates that when muscle actions are performed, the smallest MUs are activated first, with progressively larger MUs recruited as force production requirements increase [17] . Recently, it has been shown that training with intensities as low as 30% 1RM could ultimately result in complete MU recruitment when exercise is performed to momentary muscular failure [18,19] . It is important to note that when lower intensities are used, individuals are required to perform more repetitions to increase overall workload and ensure sufficient metabolic and mechanical stress are achieved [20] . Whether or not RT is prescribed at high or low volume, these methods still require active voluntary movement to be performed by the individual to stimulate muscle protein synthesis. Blood flow restriction (BFR) in combination with RT has been found to stimulate significant hypertrophy in clinical [21] , athletic [22] , adolescent [11] , adult [23] and elderly populations [24] . A meta-analysis conducted by Lixandrão et al. [25] compared the hypertrophic effects of high-load-RT versus low-load RT combined with BFR. The authors found that both groups elicited similar gains in muscle hypertrophy (ES diff : 0.10 ± 0.10; 95% CI -0.10 to 0.30), suggesting that metabolic and mechanical stress is augmented with BFR. The application of BFR requires the use of a pneumatic tourniquet system, which is placed on the most distal portion of an individual’s upper and/or lower limb [26] . When the cuff is inflated, depending on the width of the cuff used, the circumference of the limb and fat free mass/fat mass composition, partial or full restriction of arterial blood flow can occur to anatomical structures distal to the cuff. Due to the lower blood pressure (BP) of arterial inflow to the periphery and the higher BP return of venous outflow to the right atrium [27] , effective BFR seeks to limit arterial inflow [26] . Momentary occlusion of arterial inflow causes deoxygenated blood pool in the limb distal to the site of the cuff, causing hypoxia [28] . This mechanism increases the amount of metabolic stress experienced by the limb [29,30] , mediating an increase in hypertrophic factors including hormone concentrations [31] , intracellular signalling pathways for muscle protein synthesis [32] , satellite cell activity [33,34] and patterns in muscle fiber type recruitment [35] . When BFR is prescribed with low-load-RT, increases in skeletal muscle mass have been found to be no different to those who performed traditional resistance training with 70% 1RM [21,25] . This is due to the large increase in metabolic stress caused by BFR application combined with the peripheral mechanical stress in the muscle performing the movement. In circumstances where BFR is prescribed as a passive intervention, it has also been found to be an effective countermeasure to attenuate atrophy during immobilisation [37]. However, it is unable to stimulate a positive increase in skeletal muscle mass [36] . This suggests the BFR alone is an ineffective substitute for RT if the overall goal of the individual is to improve muscle hypertrophy. Neuromuscular electrical stimulation (NMES) has been used extensively in rehabilitation to promote muscle hypertrophy as a passive intervention [37,38] . The ability of NMES to stimulate growth is influenced by the amount of electrically evoked stimulation applied [39] . Unlike traditional RT where voluntary contractions are performed at a prescribed percentage of an individual’s 1RM, NMES causes involuntary contraction of a muscle through an electrical stimulus applied directly to the muscle belly via adhesive electrodes placed on the skin [40] . When prescribing NMES, amplitude can be determined as a percentage of an individual’s maximal voluntary contraction or maximum tolerable amplitude [41] . Recruitment of the muscle depends on identification of the motor point of the muscle, thickness of the layer of subcutaneous tissue beneath the surface of the electrodes [42] , and NMES parameters prescribed (frequency, pulse width, amplitude and stimulation time) [43] . MUs closer to the surface of the skin and thus the stimulating electrode are recruited, with deeper MUs recruited as the stimulation amplitude increases [44] . Typically, electrically induced contractions only reach 40-60% of an individual’s maximum voluntary contraction [45] . This is due to the discomfort associated with prescribing higher stimulation amplitudes [45] . When prescribing NMES intensity as the maximum tolerable by the participant, it is possible that insufficient MU recruitment occurs due to the large interindividual differences in pain threshold [41] . Although mechanical stress is achieved, it may not be sufficient to upregulate the mammalian target of rapamycin (mTOR) and its downstream effects on muscle protein synthesis and ultimately skeletal muscle hypertrophy [46] . Emerging evidence indicates that the use of combined BFR and NMES (C-BFR-NMES) may be a passive intervention to increase skeletal muscle mass in adults [47-53] . It is suggested that the metabolic stress created by the hypoxic environment through BFR can amplify the mechanical stress induced by NMES to cause a positive change in muscle hypertrophy [43,47,48,54] . Due to the multifactorial nature of both interventions, there is currently no defined C-BFR-NMES protocol to induce muscle hypertrophy. The aim of this systematic review and meta-analysis was to quantitatively investigate the effectiveness of C-BFR-NMES compared to BFR or NMES alone, or no intervention to induce skeletal muscle mass in adults. The secondary aims were to compare muscle hypertrophy outcomes when different measurement devices are used following C-BFR-NMES, and to investigate the C-BFR-NMES protocols used to induce skeletal muscle mass in adults. 2. Methods 2.1 Search Strategy This systematic review and meta-analysis were conducted according to PRISMA guidelines [55] (PROSPERO registration number: CRD42021260082). To identify relevant studies, a systematic literature search was independently performed by two researchers (JM & AG). The following databases were searched from inception to 28 February 2025: CINAHL, MedLine, Pubmed, Scopus, and Web of Science. The string search was created using three sections. The first included synonyms of “blood flow restriction”, the second string included synonyms of “neuromuscular electrical stimulation” and the third string included synonyms of “muscle hypertrophy”. Boolean operators were used to ensure that the search included at least one search term per string. All synonyms were connected using “OR”, and all string search terms were connected via “AND”. All database searches were performed with no limiters or filters. Two researchers conducted the literature search independently (JM & AG) using the following search terms for all databases: "blood flow restriction" OR "BFR" OR "occlusion training" OR "vascular occlusion" OR "KAATSU" OR "ischemic training" OR "blood flow restricted" OR "partial occlusion" AND "neuromuscular electrical stimulation" OR "NMES" OR "electrical stimulation" OR "electrostimulation" AND "muscle hypertrophy" OR "muscle growth" OR "muscle size" OR "muscle mass" OR "muscle thickness". All citations were exported to a citation manager Endnote, which was used to remove all duplicates before further processing. 2.2 Inclusion and Exclusion Criteria The PICOS (population, intervention, comparison, outcome measures and study design information) was used to determine the inclusion and exclusion for systematic review. Studies were considered if (1) untrained healthy adults (between the age of 18 – 64 years) were included, (2) study design allowed comparison between C-BFR-NMES and CONTROL (BFR or NMES alone, or no intervention), (3) lower limb skeletal muscle hypertrophy was assessed pre/post intervention, (4) interventions included study periods ≥14 days, and (5) manuscripts written in English. Studies were excluded if (1) pharmacological use of legal or illegal ergogenic aids or supplements was involved, and (2) C-BFR-NMES was combined with other exercise methods. The Physical Evidence Database Scale (PEDro) was used to rate the quality of studies included. The scale provides an 11-point checklist to ensure bias congruency on estimates of treatment effectiveness and has been found to be a valid measure when determining the methodological qualities of studies [56] . All articles were assessed independently by JM and AG. 2.3 Data Extraction All identified studies were screened via examining titles and abstracts for study eligibility. Full text of identified studies was then acquired for data extraction and further screening of eligibility criteria. The following information was extracted: (1) population characteristics, (2) primary outcome measures, (3) methods, (4) C-BFR-NMES protocols used, and (5) skeletal muscle hypertrophy measurement protocols used. To quantify the changes in skeletal muscle hypertrophy measured, pre- and post-intervention measurement time points were used. For studies that provided incomplete data, the corresponding author of the manuscript was contacted. If the required data were not provided via correspondence, the study data were excluded. Table 1 shows data of the included studies. Table 2 outlines the methodological quality of each study measured via the PEDro scale. 2.4 Risk of Bias The risk of bias was assessed by two independent authors (JM and AG). The Risk of Bias 2 (RoB 2) tool was used to assess different domains of the reviewed randomised control trials to determine sources of bias that could be introduced into the results (Table 3). The domains included determine: (1) bias arising from the randomisation process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurements of the outcome, and (5) bias in the selection of the reported result. Funnel plots were also assessed for each outcome to interpret any evidence of publication bias. 2.5 Statistical Analysis RevMAN was used to perform statistical analysis of the individual studies (Review Manager, Version 5.3, The Cochrane Collaboration, 2014). Observations were weighted by the inverse of the sampling variance. To calculate the standardised mean difference (SMD), the difference in mean outcome between groups was derived by the standard deviation of outcome among participants. Partially observed considerable between-timepoint differences in SD pre and SD post, SD change was defined as SD change = square root [(SD pre 2 / N pre + (SD post 2 / N post )]. A forest plot was used to present SMD and 95% confidence intervals (CIs) in skeletal muscle mass change between C-BFR-NMES and CONTROL. SMD was chosen as selected study results were presented in different units. To account for interstudy protocol variability and heterogeneity, all analysis that was performed used a random effects model. Pooled effect sizes (ES) were calculated for each comparison. Alpha level was set to p < 0.05. Data were reported as mean ± standard deviation. To report for inter study heterogeneity, the I 2 method was used. This allowed for the quantification of the variation between the studies that is caused by heterogeneity rather than chance alone. An I 2 of 0-40% represents low heterogeneity, 30-60% represents moderate heterogeneity, 50-90% represents substantial heterogeneity, and 75-100% represents considerable heterogeneity [57] . In all analyses, multiple comparisons were included from several studies in order to increase the accuracy and thus generalization of our meta-analysis. This is a common and accepted statistical method for meta-analysis [58] . A sensitivity analysis was performed, by excluding one comparison at a time for each meta-analysis to determine if the effect size and study heterogeneity were influenced by a particular comparison [59] . 3. Results 3.1 Study Selection From our search of five data bases (PubMED, Web of Science, Scopus, Medline, CINAHL), 615 articles were identified (Figure 1). From this, 96 duplicates were removed, and 519 articles were screened for eligibility criteria via titles and abstracts. The full texts of thirteen studies were retrieved for further screening. Following multiple attempts to contact corresponding authors, three studies were excluded from our analysis due to insufficient data for muscle hypertrophy measurements [49,53,60] . An additional two articles were identified through citation searching. One study was excluded due to full text not being available [61] . A sensitivity analysis was conducted, and no significant changes in effect sizes were shown. Two studies were deemed to be “low risk” of bias [50,51] , while one study showed “some concerns” when assessed using the RoB 2 [52] . All included studies scored between 5 and 7 points (mean = 6.3, SD = 1.2) In total, seven meta-analyses were conducted. The first comparison investigated the effects of C-BFR-NMES on muscle hypertrophy compared to CONTROL (no intervention) (Figure 2). The second and third comparisons were performed to investigate the effect of C-BFR-NMES relative to CONTROL on muscle hypertrophy when measured via Brightness mode (B-mode) ultrasound (Figure 3) or dual x-ray absorptiometry (DXA) (Figure 4), respectively. The fourth comparison investigated the effects of C-BFR-NMES compared to CONTROL when focusing on quadricep mass (Figure 5). Comparisons five, six and seven investigated the benefit of varying C-BFR-NMES protocols including individualised BFR cuff pressure (Figure 6), standardised cuff pressure (Figure 7), and NMES intensity prescription (Figure 8), respectively, compared to CONTROL on muscle hypertrophy. 3.2 Effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy Three studies comparing the effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy were included in the meta-analysis [50-52] (Figure 2). From the selected studies, a total of eight comparisons on the effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy. One study applied C-BFR-NMES to the posterior lower leg calf complex to assess changes in gastrocnemius muscle mass [52] . Two studies applied C-BFR-NMES to the anterior portion of the upper leg to assess change in vastus lateralis muscle mass [50,62] . Our results show that C-BFR-NMES induced significantly greater muscle hypertrophy compared to CONTROL (Z = 2.66, p = 0.008), with a medium pooled ES of 0.61 (95% CI 0.11 to 1.6) in favour of C-BFR-NMES. The calculation of I 2 showed significant substantial heterogeneity of 59% ( p = 0.02) 3.3 Effects of C-BFR-NMES versus CONTROL on skeletal muscle mass measured via DXA Two studies with a total of five comparisons investigated determined changes in hypertrophy, measuring muscle mass via DXA [50,51] (Figure 3). Quantitative analysis showed that four out of five included comparisons induced a positive change in muscle mass, with a small pooled ES of 0.32 (95% CI 0.12 to 0.76). However, this effect size did not reach statistical significance (Z = 1.42, p = 0.15). The calculation of I 2 showed moderate heterogeneity of 45% but was not significant ( p = 0.12). 3.4 Effects of C-BFR-NMES versus CONTROL on skeletal muscle thickness Two studies with a total of three comparisons investigated changes in muscle mass assessed through muscle thickness via B-mode ultrasound [50,52] (Figure 4). All three comparisons found C-BFR-NMES elicited a significantly greater hypertrophic effect than BFR, NMES or no intervention when measured via B-mode ultrasound (Z = 3.96, p <0.0001), with large pooled ES of 1.12 (95% CI 0.61 to 1.81). The calculation of I 2 was non-significant ( p = 0.40), showing low heterogeneity of 0%. 3.5 Effects of C-BFR-NMES versus CONTROL on quadricep mass Two studies with a total of seven comparisons investigated the effects of C-BFR-NMES specifically on the quadriceps muscle [50,51] (Figure 5). Across all comparisons, there was a positive change in quadricep mass that reached significance (Z = 2.45, p = 0.01), with a medium pooled ES of 0.62 (95% CI 0.13 to 1.13). The calculation of I 2 was significant ( p = 0.01), showing substantial heterogeneity (64%). 3.6 Effects of C-BFR-NMES versus CONTROL when using individualised cuff pressure One study that included four comparisons applied C-BFR-NMES with an individualised restrictive cuff pressure to the individual [50] (Figure 6). Individual blood flow restriction cuff pressures ranged from 180-290mmHg. These comparisons reached statistical significance (Z = 5.03, p < 0.001), with large pooled ES of 1.26 (95% CI 0.77 to 1.75). The calculation of I 2 was non-significant ( p = 0.87), showed low heterogeneity of 0%. 3.7 Effects of C-BFR-NMES versus CONTROL when using standardised cuff pressure Two studies comprising of four comparisons applied C-BFR-NMES with a standardised restrictive cuff pressure based on previous research [51,52] (Figure 7). Standardised blood flow restriction pressures ranged from 100-220mmHg. These comparisons showed a small ES of 0.08 (95% CI -0.26 to 0.43) which did not reach statistical significance (Z = 0.49, p = 0.62). The calculation of I 2 was non-significant ( p = 0.87), showed low heterogeneity of 0%. 3.8 Effects of C-BFR-NMES versus CONTROL when prescribing NMES as a percentage of maximal voluntary isometric contraction (MVIC) Two studies prescribed C-BFR-NMES using a NMES intensity which was based on a percentage of the individual’s maximal voluntary isometric contraction, measured via knee extension dynamometry [50,52] (Figure 8). Prescription of NMES intensity ranged from 15-20% of MVIC. Studies that utilised this prescription showed a significant positive change in muscle hypertrophy (Z = 4.96, p < 0.001), with a large ES of 1.13 (95% CI 0.68 to 1.58). The calculation of I 2 was non-significant ( p = 0.68), showed low heterogeneity of 0%. 4. Discussion The primary aim of this systematic review and meta-analysis was to investigate the effects of C-BFR-NMES as a passive intervention to increase skeletal muscle mass in adults, compared to BFR or NMES alone, or no intervention. Additional analyses performed explored different protocols used when applying C-BFR-NMES, providing insight into what procedures are most effective in promoting skeletal muscle hypertrophy. The main finding of the present study is that C-BFR-NMES provides positive hypertrophy adaptions in skeletal mass when compared to BFR or NMES alone, or no intervention. The use of DXA and B-mode ultrasound for muscle hypertrophy measurement was also investigated. When muscle thickness was measured via B-mode ultrasound, a significant medium effect was found. Conversely, measurements of muscle thickness via DXA showed no significant effect, likely due to the regional changes in the muscle that DXA is unable to differentiate. Applying C-BFR-NMES to the vastus lateralis found a medium effect, compared to when applied to the gastrocnemius. Further, individualising restriction cuff pressure to the individual, and modulating NMES intensity as a percentage of the participants MVIC facilitated the greatest changes in muscle hypertrophy. The implementation of C-BFR-NMES into rehabilitation or early intervention programs provides an opportunity for individuals who are unable to perform voluntary resistance training a passive modality to promote muscle hypertrophy. The mechanism by which C-BFR-NMES could induce significantly greater muscle hypertrophy relative to CONTROL could be explained by the expected larger increase in metabolic stress caused by the accumulation of metabolic by-products with the combined intervention relative to either intervention alone or no intervention [63] . Metabolic stress is purported to be the primary mechanism through which muscle hypertrophy occurs due to the increase in anabolic hormone release, hypoxia, ROS production and cell swelling [64] . Blood flow plays an important role in providing oxygento the working muscles, and it is well documented that decreasing oxygen availability to the exercising muscles can have significant effects on muscle hypertrophy [65] . The application of BFR can limit or occlude arterial flow into the muscle, whilst venous return is occluded, beginning a cascade of physiological responses that upregulate muscle protein synthesis [35] . The occlusion causes localised pooling of blood and muscle cell swelling, which augments metabolic stress within the muscle [66] . Even without exercise, acute increases in muscle thickness (MT) have been observed in combination with a decrease in plasma volume when BFR is applied [67] . This suggests that the change in MT is not just oedema but there is a fluid shift from the plasma to inside the muscle cell [68] . Volume changes inside the muscle cell are detected by an intrinsic volume sensor, which may lead to the activation of mTOR and MAPK pathways. Previous studies have shown that activation of these pathways can promote skeletal muscle hypertrophy [32,69,70] . The recognised gold standard for determining changes in muscle size in vivo is via magnetic resonance imaging (MRI) [71] . However, due to the costs and accessibility of MRI, alternative measurement methods are utilised to assess muscle size. The studies included in this review found B-mode ultrasound and DXA were used to measure muscle thickness and lean mass respectively [50-52] . Interestingly our meta-analysis showed ES of 1.12 ( p <0.0001) for measurements via B-mode ultrasound, comparatively to ES of 0.32 ( p = 0.15). Although DXA has been found to have a strong association with MRI derived values at a single time point, its ability to detect change following a chronic resistance training intervention is less accurate [72] . Lean mass measurements via DXA are obtained through assessment of the soft tissue compartment of interest. This allows for the regional determination of body composition. As a result, DXA is unable to differentiate between muscle groups and can only quantify the mass of the transverse sections of the body. Further, quantification of lean soft tissue mass includes proteins, glycogen, soft tissue materials, and water [73] . Training interventions will cause acute changes in these substrates which may not reflect structural change caused by hypertrophic growth, limiting the accuracy of DXA measurements over various time points. B-mode ultrasound was used to quantify changes in muscle thickness in two studies [50,52] . A previous study compared MT measurements via B-mode ultrasound to MRI muscle cross section area (mCSA) and muscle volume (MV) of the vastus lateralis over a 12-week resistance training intervention. A significant correlation between percentage increase in MT and mCSA ( r = 0.69, P = 0.001) at mid-thigh was found, however a non-significant relationship was found between MT and MV ( r = 0.33, P = 0.21) [74] . Regional hypertrophy of the VL muscle belly is a result of the type of intervention used, with heterogenous distribution of often occurring as a response [75] . It remains unclear if regional hypertrophy is a response to mechanical stimuli, or simply the proceeding effects of the applied stimuli [76] . Both Adrande et al. [52] and Slysz et al. [50] measured MT at a single site, which could underrepresent the effectiveness of the interventions employed. To obtain a more accurate representation of MT change following a chronic intervention, multiple measurements across the muscle belly should be obtained, rather than a single measurement at 50%, providing a more coherent quantification of structural change of the muscle belly. The inclusion of a multi-site MT protocol (30%, 50% and 70% of the femur length) was utilised by Li et al. [53] following 6 weeks of C-BFR-NMES + RT. When compared to the control group who performed an identical RT protocol, a greater MT increase ( p < 0.05) was reported in the C-BFR-NMES + RT group. This finding suggests that a multi-site approach to measuring changes in CSA is more sensitive to hypertrophy than single-site measurements. The impact magnitude of C-BFR-NMES on muscle hypertrophy may be dependent on the target muscle. This is likely due to the composition of muscle fiber type within the muscle itself. Fast twitch fibers have approximately 50% greater growth capacity compared to slow twitch fibers, therefore if they can be preferentially recruited individuals will see an enhanced rate of hypertrophy [77] . Previous research has indicated the soleus contains a much larger percentage of type I slow twitch fibers (70%) [78] compared to the vastus lateralis muscle (42%) [79] . This is a likely reason why Andrade et al. [52] did not observe statistically significant changes in soleus hypertrophy following two weeks of C-BFR-NMES application. Due to NMES recruiting muscle fibers in a non-preferential manner [80] , the growth potential of the soleus is limited by its high percentage of type I muscle fiber. Although metabolic stress is believed to be the primary mechanism behind BFR induced hypertrophy, an increase in mechanical tension causes greater fast twitch fiber recruitment [35] . According to the size principle, MU are recruited in a task dependent orderly manner, from smallest to largest [17] . As a result, fast fatiguing, large type II MU are only recruited when necessary to minimise the early onset of muscular fatigue. Conversely, with the application of BFR, there is an increase in FT fiber recruitment to assist in force production at lower thresholds [81] . MU recruitment during NMES is influenced by the positioning of the electrodes on the skin, superficial the muscle belly. As MU are directly recruited by NMES, they are seen to follow a synchronous and repeated activation pattern, different to voluntary MU recruitment [82] . This may contribute to a greater degree of fatigue compared to voluntary efforts, where asynchronous MU cycling allows for periods of recovery [43] . Due to the nature of NMES application, superficial muscle fibers are activated more favourably. Superficial activation occurs due to NMES activating the axons which are underneath the stimulating electrodes. MU recruitment has been seen to decrease proportionally as distance from the electrodes increase [43] . When combined with BFR, it is possible that the superficial muscle fibers are fatigued at a greater rate, increasing metabolic and mechanical stress and undergo preferential hypertrophy. However, if high stimulation frequencies are applied, the addition of BFR can cause a rapid fatigue onset and ultimately reducing the duration of effective muscular tension and limiting adaptive potential [83] . These mechanisms are further reinforced by Li et al. [53] , who observed a discrepancy between the NMES + RT and C-BFR-NMES + RT. Although the NMES + RT group exhibited increased muscle activation (as measured by surface electromyography), similar to the C-BFR-NMES + RT group, it did not achieve the same significant gains in muscle strength observed in the latter ( p = 0.736, p <0.05). This highlights a critical point: while EMS alone effectively recruits motor units and elevates electrical activity, depending on the intensity used, it may lack key physiological conditions required for strength development. These include sufficient mechanical tension to stimulate hypertrophy, coordinated central nervous system involvement, and sustained metabolic stress, factors comprehensively addressed through the addition of BFR. Both Andrade et al. [52] and Slysz and Burr [51] utilized a standardised cuff pressure (100mmHg and 220mmHg) when applying C-BFR-NMES. The disparity between these absolute pressures is due to the physical size of the cuff. A wider cuff, as used by Andrade et al. [52] has been shown to be more effective at lower inflation pressures [84] . Although a wider cuff was used to compensate for a lower pressure, neither study found significant changes in muscle hypertrophy. Conversely, Slysz et al. [50] applied restrictive pressures ranging from 180-290mmHg to achieve full arterial occlusion. A review by Patterson et al. [26] suggested pressures ranging from 40 to 80% of arterial occlusion as sufficient to promote metabolite accumulation in the limb. Interestingly, when combined with lower loads, a higher pressure (at least 80% arterial occlusion pressure) is recommended to augment the stimulus [85] as seen in Slysz et al. [50] . Restricted venous return causes a pooling of blood and hypoxia locally within the muscle, resulting in greater metabolic acid [86] . Due to the chemical changes produced by the metabolic byproducts within the active musculature during BFR exercise, there is a greater stimulation of chemosensitive sensory nerves (Group III and IV afferents) [87] . Continued BFR application throughout rest periods can cause continued activation of group III/IV muscle afferents, which sense mechanical and metabolic (respectively) stimuli arising in the exercise muscle. Innervation of alpha motor neurons results in the contraction of skeletal muscle fibers. Alpha motor neuron stimulation can be attenuated through the activation group III/IV afferents. To overcome this, there is an increase in muscle fiber recruitment to satisfy muscular force requirement and limit a decline in force production and power output [35] . Takarada et al. [88] investigated the effects of BFR when used in isolation (intervention) compared to no occlusive stimulus (control) on disuse atrophy of knee extensor muscles. It was found that BFR resulted in significantly less atrophy in knee extensors and flexors than when compared to the control group, suggesting that muscle swelling plays an important role in increasing metabolic stress. Although arguments can be made for continuous occlusion throughout exercise protocols, no studies have found significant differences between hypertrophy outcomes. Adenosine triphosphate (ATP) production and oxygen (O 2) consumption are a result of mitochondrial respiration. This process also produces reactive oxygen species (ROS) as byproduct [64] . Increases in metabolic and mechanical work is concomitant with ROS production increases. Influx of ROS affects muscle fatigue and the inhibition of sarcoplasmic reticulum Ca 2+ release and microfibril Ca 2+ sensitivity [64] . Further, ROS activates the group IV afferents that primarily transmit information about metabolic stimuli, and directly inhibits motoneurons. An increase in EMG amplitude has been shown during low load resistance training with BFR, and it is likely a similar mechanism occurs when RT is substituted for NMES [89,90] . Group III/IV muscle afferents facilitate ‘central fatigue’ and ultimately an individual’s receptiveness to fatigue and capacity for exercise. Therefore, if restrictive cuff pressure is not adequately applied, the extent to which metabolites will pool within the working muscle are limited and will be insufficient to upregulate muscle protein synthesis. Two studies included in this review utilised a pre-determined restriction pressure which could partially explain the lack of statistically significant changes in muscle hypertrophy [51,52] . Similarly, Li et al. [53] utilised pre-determined pressures based on the thigh circumference. Although it should be noted, the studies include in this review utilised a single-chamber bladder system, Li et al. [53] used a multi-chamber bladder system. Functionally, a single-chamber system encircles the limb, applying consistent pressure when inflated. Conversely, multi-chamber systems consistent of several individual bladders, which can result in non-uniform circumferential pressure when inflated [91] . The latter require significantly higher restrictive pressures to account for the bladder design difference (up to 350 mmHg for the lower body), but also the narrower width of the cuff (5cm). Although standardised pressures can occlude arterial flow, this method does not take into consideration individual differences and can result in varying degrees of blood flow restriction. Optimal cuff pressure is influenced by a combination of cuff width and thigh circumference of the individual [92] . Natsume et al. [49] found that the occlusion pressure required to effectively limit arterial flow is largely influenced by individual thigh circumference. Although fixed occlusion pressures can successfully restrict blood flow, it does not account for individual differences, and this can potentially cause a large variance in acute physiological responses [26] . Previous research also shows that thigh circumference was able to predict AOP equally when compared to measurements thigh composition (mid-thigh muscle [mCSA] and fat [fCSA] cross sectional area [93] . If so, an optimal pressure gradient will inhibit venous blood flow while reducing the arterial inflow of blood, thus a blood pooling will be evident in the muscle tissue [94] . The quantity of pressure follows a dose respsubgonsive manner as the hormesis curve [95] . Due to ambiguity regarding optimal pressure for the proliferation of skeletal muscle hypertrophy, high levels of cuff pressure may result in reductions in muscle activity and safety consequences more detrimental than suboptimal muscle adaptation [93,96] . Practically, high cuff pressures have been found to cause greater discomfort which could be detrimental to exercise adherence and enjoyment. In line with current BFR protocol recommendations, cuff pressure should be prescribed using relative pressure to the AOP [26] . Selection of appropriate amplitude has a direct impact on the number of MU activated via NMES. Increasing current amplitude causes an increase in torque production which occurs through the activation of additional motor units. Prescribing intensity as a percentage of MVIC is often used in NMES protocols as this is a quantifiable intensity relative to the individual’s capabilities. The limiting factor in prescribing higher percentages relative to MVIC is individual discomfort [97,98] . Likewise, where studies prescribed amplitude based on maximum tolerance, it becomes highly dependent on pain thresholds of the individual [99-102] . Early increases in current amplitude result are followed with a steep rise in torque, followed by a plateau at a high level of stimulation [47] . This review found that the literature uses both percentage MVIC and maximum tolerable intensity. A plausible issue with prescribing intensity via the maximum tolerable method is that is individual pain thresholds are likely to vary significantly between individuals, which may result in the intensity inducing insufficient mechanical stress. Therefore, it can be recommended that current amplitude be set at a percentage of MVIC to minimise excessive discomfort to the individual. Further, increasing intensity percentage throughout a chronic intervention in line with progressive overload principles will minimise accommodation to the stimulus [103] . 4.1 Practical Application/Recommendations Due to its passive nature, these results suggest that C-BFR-NMES can be used in adult populations who are unable to perform voluntary resistance training, or to use in conjunction with resistance training as means to stimulate skeletal muscle hypertrophy. When recommending C-BFR-NMES it is important to consider both BFR and NMES variables to elicit the beneficial stimulus to the individual. BFR occlusion pressure should be applied based on individual AOP, rather than standardised cuff pressure. There seems to be a difference in continuous versus intermittent application. Intermittent application, where the cuff is removed during rest periods, is recommended to decrease individual discomfort. NMES amplitude should be calculated as a percentage of an individual’s MVIC (15-20%), with frequencies between 50-100Hz used along with a pulse width between 200-400us. Skeletal muscular adaptions can be seen as early as two weeks combined with a high frequency of application between 4 – 5 days per week. Although no adverse effects were reported throughout the included studies, individuals need to be screened for contraindications of BFR such as circulatory issues, heart disease, hypertension, diabetes or pregnancy; and for NMES use including burns, skin lesions, vascular impairment, or cardiac pacemakers [104] . Further research should be done to determine the effects of C-BFR-NMES in adolescent or elderly populations. 5. Limitations The main limitation of the study was the lack of research implementing C-BFR-NMES. As a result, there is no defined protocol when combining the two modalities to elicit skeletal muscle hypertrophy. The calculation of I 2 showed a heterogeneity of 59% (p = 0.02). This variability might result in differences in training protocols (both BFR and NMES), sample sizes and hypertrophy assessment (muscle thickness vs muscle mass). A number of studies were found stating clinically significant increase in muscle hypertrophy following chronic interventions but were not included as they did not meet our inclusion/exclusion criteria [47-49] . Bergamasco et al. [68] found a 4.6% (p<0.0001) increase in VL CSA following 20 sessions. C-BFR-NMES was compared to LL-BFR that showed an 11.2% (p<0.0001) increase in VL CSA. These results suggest C-BFR-NMES presents an appropriate method to increase muscle CSA when voluntary exercise is not feasible. Gorgey et al. [47] noted a 15% increase in extensor carpi radialis longus (ECLR) CSA (p=0.048) in individuals with incomplete tetraplegia. Natsume et al. (2015) [49] demonstrated an 3.9% increase in quadricep thickness after 2 weeks of C-BFR-NMES training. Li et al. [53] found a significant increase in muscle thickness following 6 weeks of C-BFR-NMES + RT compared to RT ( p < 0.05) and NMES + RT ( p < 0.05). Slysz et al. [50] utilised an unloading period for the entire 2 weeks while C-BFR-NMES was applied. As the aim of their study was to investigate the effectiveness of C-BFR-NMES in attenuating disuse atrophy, if a similar study was performed without immobilisation the results may show further benefit to C-BFR-NMES. Disuse periods as short as five days have been shown to induce significant decreases in muscle mass (3.5%) [105] . As muscle is a highly plastic tissue that responds to environmental stimuli, the removal of weight bearing activities would promote premature muscle loss and limit the results of the intervention. 6. Conclusion A pooled analysis of current data suggests that C-BFR-NMES promotes a medium effect on skeletal muscle hypertrophy in lower body musculature compared to BFR or NMES alone, or no exercise in healthy adults. C-BFR-NMES is an entirely passive intervention that does not require voluntary movement. In populations where individuals are immobilised or unable to perform voluntary exercise, it could provide a significant benefit. Further, C-BFR-NMES provides an opportunity for those with chronically low levels of skeletal muscle mass to increase hypertrophy in a controlled environment. Further research is needed to determine the effectiveness of C-BFR-NMES in upper body musculature, as well as different population groups such as adolescent and elderly. 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Beneath the cuff: Often overlooked and under-reported blood flow restriction device features and their potential impact on practice-A review of the current state of the research. Front Physiol 14 , 1089065, doi:10.3389/fphys.2023.1089065 (2023). Loenneke, J. P. et al. Effects of cuff width on arterial occlusion: implications for blood flow restricted exercise. Eur J Appl Physiol 112 , 2903-2912, doi:10.1007/s00421-011-2266-8 (2012). Loenneke, J. P., Wilson, J. M., Wilson, G. J., Pujol, T. J. & Bemben, M. G. Potential safety issues with blood flow restriction training. Scandinavian Journal of Medicine & Science in Sports 21 , 510-518, doi:https://doi.org/10.1111/j.1600-0838.2010.01290.x (2011). Young, D. B. in Control of Cardiac Output (Morgan & Claypool Life Sciences Copyright © 2010 by Morgan & Claypool Life Sciences., 2010). Loenneke, J. P., Thiebaud, R. S. & Abe, T. Does blood flow restriction result in skeletal muscle damage? A critical review of available evidence. Scandinavian Journal of Medicine & Science in Sports 24 , e415-422, doi:https://doi.org/10.1111/sms.12210 (2014). Jessee, M. B. et al. The Influence of Cuff Width, Sex, and Race on Arterial Occlusion: Implications for Blood Flow Restriction Research. Sports Medicine 46 , 913-921, doi:10.1007/s40279-016-0473-5 (2016). Glaviano, N. R. & Saliba, S. Can the Use of Neuromuscular Electrical Stimulation Be Improved to Optimize Quadriceps Strengthening? Sports Health 8 , 79-85, doi:10.1177/1941738115618174 (2016). Lyons, G. M., Leane, G. E., Clarke-Moloney, M., O'Brien, J. V. & Grace, P. A. An investigation of the effect of electrode size and electrode location on comfort during stimulation of the gastrocnemius muscle. Med Eng Phys 26 , 873-878, doi:10.1016/j.medengphy.2004.08.003 (2004). Alon, C., Kantor, G. & Ho, H. S. Effects of Electrode Size on Basic Excitatory Responses and on Selected Stimulus Parameters. Journal of Orthopaedic & Sports Physical Therapy 20 , 29-35, doi:10.2519/jospt.1994.20.1.29 (1994). Holcomb, W. R. Effect of training with neuromuscular electrical stimulation on elbow flexion strength. J Sports Sci Med 5 , 276-281 (2006). Holcomb, W. R., Golestani, S. & Hill, S. A Comparison of Knee-Extension Torque Production with Biphasic versus Russian Current. Journal of Sport Rehabilitation 9 , 229-239, doi:10.1123/jsr.9.3.229 (2000). Porcari, J. P. et al. Effects of Electrical Muscle Stimulation on Body Composition, Muscle Strength, and Physical Appearance. The Journal of Strength & Conditioning Research 16 , 165-172 (2002). Kraemer, W. J., Ratamess, N. A. & French, D. N. Resistance training for health and performance. Current Sports Medicine Reports 1 , 165-171, doi:10.1007/s11932-002-0017-7 (2002). Lago, A. F. et al. Effects of physical therapy with neuromuscular electrical stimulation in acute and late septic shock patients: A randomised crossover clinical trial. PLoS One 17 , e0264068, doi:10.1371/journal.pone.0264068 (2022). Valenzuela, P. L., Morales, J. S. & Lucia, A. Passive Strategies for the Prevention of Muscle Wasting During Recovery from Sports Injuries. Journal of Science in Sport and Exercise 1 , 13-19, doi:10.1007/s42978-019-0008-5 (2019). Tables Table 1 . Overview of studies included in the systematic review and meta-analysis: MT = muscle thickness, MM = muscle mass Study Subjects N BFR Protocol NMES Protocol Muscle target Duration / Frequency C-BFR-NMES outcomes relative to CONTROL Andrade et al. (2016) [52] Male adults (20 - 26 y) 7 100mmHg pressure Standardised Continuous application Frequency 35 Hz Pulse width 400 us Amplitude 20% MVIC 6s on 2s off Soleus 6 wk; 3 days/wk MT via B-mode ultrasonography BFR NMES: 15.28% ( p = 0.091) Control: -2.58% ( p = 0.141) No statistically significant increase in MT Slysz and Burr (2018) [51] Adults (18 - 45 y) 20 (10 male, 10 female) 220 mmHg pressure Standardised Intermittent application Frequency 50-100 Hz Pulse width 400 us Amplitude maximum tolerable Quadriceps 6 wk; 4 days/wk MM via DXA BFR NMES: 1.29% BFR: 1.42% NMES: 1.29% Control: 0.01% No statistically significant increase in MM Slysz et al. (2021) [50] Adults (19 - 25 y) 30 (14 male, 16 female) 180 - 290 mmHg pressure Individualised Intermittent application Frequency 60 Hz Pulse width 200 us Amplitude 15% MVIC 6s on 15s off Quadriceps 2 wk; 5 days/wk twice daily MT via B-mode ultrasonography MM via DXA MT BFR NMES: 4% MT BFR: -7% MT Control: -7% No statistically significant increase in MT MM BFR NMES: -0.25% MM BFR: -3% MM Control: -4% No statistically significant increase in MM Table 2 . PEDro scale to measure methodological quality Study reporting criterion Study Eligibility criteria were specified Subjects were randomly allocated Allocation was concealed Baseline characteristics of groups were similar Were subjects blinded Were those administering treatment blinded Were assessors who measured key outcomes blinded At least one key outcome measure obtained from more than 85% of subjects Was an intention to treat analysis uses Were between group statistical analysis performed for at least one outcome Were point measures and measures of variability used for at least one key outcome Score Andrade et al. (2016) [52] 1 0 1 0 0 0 0 0 1 1 1 5 Slysz and Burr (2018) [51] 0 1 1 1 0 0 0 1 1 1 1 7 Slys et al., (2021) [50] 0 1 1 1 0 0 0 1 1 1 1 7 Table 3. Risk of bias evalulation of the RCTs using the RoB 2 tool. "+" = low risk, "?" = some concerns, and "-" = high risk. Study Randomisation process Deviations from intended interventions Missing outcome data Measurements of the outcome Selection of the reported result Overall Andrade et al. (2016) [52] _ + + + ? ? Slysz and burr (2018) [51] + + + + + + Slysz et al., (2021) [50] + + + + + + Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 19 Mar, 2026 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 06 Oct, 2025 Reviewers agreed at journal 06 Oct, 2025 Reviews received at journal 04 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviewers agreed at journal 03 Oct, 2025 Reviews received at journal 27 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers invited by journal 12 Aug, 2025 Editor assigned by journal 12 Aug, 2025 Editor invited by journal 29 Jul, 2025 Submission checks completed at journal 26 Jul, 2025 First submitted to journal 26 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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2","display":"","copyAsset":false,"role":"figure","size":49641,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/b2ff2ebae3c18fd87bf78b1a.png"},{"id":89455676,"identity":"3805a3ce-1962-42a4-8681-b4c9aa9e1a6e","added_by":"auto","created_at":"2025-08-20 06:54:21","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":31225,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-B-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy measured via ultrasound\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/0f3ae8398ba2213b67de9c6a.png"},{"id":89457778,"identity":"e430da2b-59fb-4a72-b739-e4c75e7ee3e7","added_by":"auto","created_at":"2025-08-20 07:18:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40791,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-B-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy measured via dual x-ray absorptiometry (DXA)\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/f113085071d893c0fe4bb964.png"},{"id":89455678,"identity":"0ed50493-5375-49f6-926b-35cad46f2a88","added_by":"auto","created_at":"2025-08-20 06:54:21","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":55409,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-B-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy measured in the vastus lateralis muscle\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/76f16216963192fa87d7a6e1.png"},{"id":89455682,"identity":"0191138d-d1f6-4a66-9074-3bf2906ae0dc","added_by":"auto","created_at":"2025-08-20 06:54:21","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":41265,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-B-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy when individualised blood flow restriction cuff pressures are used\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/0ae54f5e4c38bf67a36e0637.png"},{"id":89455685,"identity":"bc35064c-127c-4d66-819d-f09f17045207","added_by":"auto","created_at":"2025-08-20 06:54:21","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":42147,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot describing the effects of C-B-BFR-NMES versus CONTROL (no intervention) on muscle hypertrophy when standardised blood flow restriction cuff pressures are used\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/29e43cdcfcec2a78afdefb0f.png"},{"id":89456282,"identity":"c8c6f35f-ae34-4c35-980a-3e9fd06adeeb","added_by":"auto","created_at":"2025-08-20 07:02:21","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":40213,"visible":true,"origin":"","legend":"\u003cp\u003epercentage MVIC\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/a6d9d5e171777277f27e695e.png"},{"id":105224958,"identity":"9433a49e-ce71-4249-83c7-5c28a77db893","added_by":"auto","created_at":"2026-03-23 16:17:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1208401,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7173103/v1/9fa60917-af36-4a31-a28e-55f8dd6c3e95.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effects of combined blood flow restriction and neuromuscular electrical stimulation on skeletal muscle hypertrophy in adults: a systematic review and meta analysis","fulltext":[{"header":"Key Points","content":"\u003cp\u003eThe results of the systematic review and meta analysis suggest that combined blood flow restriction (BFR) and neuromuscular electrical simulation (NMES) (C-BFR-NMES) is an effective intervention for increasing skeletal muscle mass in healthy adults.\u003c/p\u003e\n\u003cp\u003eIn comparison to BFR or NMES alone, or no intervention, C-BFR-NMES resulted in significantly greater increases in skeletal muscle mass.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIncorporating C-BFR-NMES into rehabilitation or early intervention programs provides an opportunity for individuals who are unable to perform voluntary resistance training a passive modality to promote muscle hypertrophy.\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eSkeletal muscle mass represents a large proportion of whole body mass and is the most prevalent adipose tissue free mass in the human body \u003csup\u003e[1]\u003c/sup\u003e. It facilitates many fundamental outcomes such as locomotion, vital organ protection, and promotion of optimal metabolic health \u003csup\u003e[2]\u003c/sup\u003e. In contrast, \u0026nbsp;decline in skeletal muscle mass can result in impaired cardiac output, muscle oxidative capacity, insulin sensitivity, basal metabolic rate, and ultimately an increase in adipose tissue mass \u003csup\u003e[1]\u003c/sup\u003e. Excessive body fat, which is a notable characteristic of overweight and obese individuals, is a major health risk \u003csup\u003e[3]\u003c/sup\u003e. An increase in skeletal muscle mass or skeletal muscle hypertrophy has functional and sporting benefits as positive correlations have been found between muscle cross sectional area and muscle strength \u003csup\u003e[4]\u003c/sup\u003e. When an individual experiences an increase in body fat with a decrease in skeletal muscle mass, such changes in body composition are associated with metabolic syndrome \u003csup\u003e[5]\u003c/sup\u003e, diabetes mellitus \u003csup\u003e[6]\u003c/sup\u003e, and cardiovascular disease \u003csup\u003e[7]\u003c/sup\u003e. Furthermore, sarcopenia, the progressive loss of muscle mass that is associated with aging further exacerbates this dysfunction \u003csup\u003e[8]\u003c/sup\u003e. Ensuring adults partake in physical activity or exercise, notably resistance training, will assist in the promotion and maintenance of skeletal muscle mass, and reduce the risk of chronic diseases such as diabetes, hypertension, and cardiovascular disease \u003csup\u003e[9]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePhysical inactivity is considered to be the fourth leading risk factor in global mortality, accounting for approximately 3.2 deaths annually \u003csup\u003e[10]\u003c/sup\u003e. Resistance training (RT) is the primary type of exercise prescribed to individuals wanting to increase muscle mass \u003csup\u003e[11]\u003c/sup\u003e. Skeletal muscle hypertrophy can aid in the prevention of age associated muscle insulin resistance \u003csup\u003e[12]\u003c/sup\u003e and diminished mitochondrial capacity \u003csup\u003e[13]\u003c/sup\u003e. The American College of Sports Medicine \u003csup\u003e[14]\u003c/sup\u003e and Australian Government \u003csup\u003e[15]\u003c/sup\u003e both recommend that adults aged between 18 \u0026ndash; 64 years perform muscle strengthening activities on two or more days per week. Data from Australia in 2022 showed that only 26.6% of adults aged 18 \u0026ndash; 64 years performed at least two days of muscle strengthening activities per week \u003csup\u003e[16]\u003c/sup\u003e. Males are more likely to achieve this guideline compared to females \u003csup\u003e[16]\u003c/sup\u003e. Notably, the proportion of individuals who performed muscle strengthening activities on one day per week generally decreased as age increased \u003csup\u003e[16]\u003c/sup\u003e. Traditionally, RT is prescribed at high-intensity (\u0026ge;70% of one repetition maximum [1RM]) to stimulate muscle hypertrophy \u003csup\u003e[14]\u003c/sup\u003e. However, high-intensity RT is not practical for some individuals recovering from injury, suffering from chronic health conditions, undergoing periods of immobilisation, or athletes in season when training stress is high. The prescription of \u0026ge;70% 1RM is based on previous research \u003csup\u003e[14]\u003c/sup\u003e, demonstrating that high loads (HL) are necessary to recruit higher threshold motor units (MU) responsible for promoting maximal muscular adaptation. The Heneman\u0026rsquo;s size principle dictates that when muscle actions are performed, the smallest MUs are activated first, with progressively larger MUs recruited as force production requirements increase \u003csup\u003e[17]\u003c/sup\u003e. Recently, it has been shown that training with intensities as low as 30% 1RM could ultimately result in complete MU recruitment when exercise is performed to momentary muscular failure \u003csup\u003e[18,19]\u003c/sup\u003e. It is important to note that when lower intensities are used, individuals are required to perform more repetitions to increase overall workload and ensure sufficient metabolic and mechanical stress are achieved \u003csup\u003e[20]\u003c/sup\u003e. Whether or not RT is prescribed at high or low volume, these methods still require active voluntary movement to be performed by the individual to stimulate muscle protein synthesis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBlood flow restriction (BFR) in combination with RT has been found to stimulate significant hypertrophy in clinical \u003csup\u003e[21]\u003c/sup\u003e, athletic \u003csup\u003e[22]\u003c/sup\u003e, adolescent \u003csup\u003e[11]\u003c/sup\u003e, adult \u003csup\u003e[23]\u003c/sup\u003e and elderly populations \u003csup\u003e[24]\u003c/sup\u003e. A meta-analysis conducted by Lixandr\u0026atilde;o et al. \u003csup\u003e[25]\u003c/sup\u003e compared the hypertrophic effects of high-load-RT versus low-load RT combined with BFR. The authors found that both groups elicited similar gains in muscle hypertrophy (ES\u003csub\u003ediff\u003c/sub\u003e: 0.10 \u0026plusmn; 0.10; 95% CI -0.10 to 0.30), suggesting that metabolic and mechanical stress is augmented with BFR.\u0026nbsp;The application of BFR requires the use of a pneumatic tourniquet system, which is placed on the most distal portion of an individual\u0026rsquo;s upper and/or lower limb\u0026nbsp;\u003csup\u003e[26]\u003c/sup\u003e. When the cuff is inflated, depending on the width of the cuff used, the circumference of the limb and fat free mass/fat mass composition, partial or full restriction of arterial blood flow can occur to anatomical structures distal to the cuff. Due to the lower blood pressure (BP) of arterial inflow to the periphery and the higher BP return of venous outflow to the right atrium\u0026nbsp;\u003csup\u003e[27]\u003c/sup\u003e, effective BFR seeks to limit arterial inflow\u0026nbsp;\u003csup\u003e[26]\u003c/sup\u003e. Momentary occlusion of arterial inflow causes deoxygenated blood pool in the limb distal to the site of the cuff, causing hypoxia\u0026nbsp;\u003csup\u003e[28]\u003c/sup\u003e. This mechanism increases the amount of metabolic stress experienced by the limb\u0026nbsp;\u003csup\u003e[29,30]\u003c/sup\u003e, mediating an increase in hypertrophic factors including hormone concentrations\u0026nbsp;\u003csup\u003e[31]\u003c/sup\u003e, intracellular signalling pathways for muscle protein synthesis\u0026nbsp;\u003csup\u003e[32]\u003c/sup\u003e, satellite cell activity\u0026nbsp;\u003csup\u003e[33,34]\u003c/sup\u003e and patterns in muscle fiber type recruitment\u0026nbsp;\u003csup\u003e[35]\u003c/sup\u003e. When BFR is prescribed with low-load-RT, increases in skeletal muscle mass have been found to be no different to those who performed traditional resistance training with 70% 1RM\u0026nbsp;\u003csup\u003e[21,25]\u003c/sup\u003e. This is due to the large increase in metabolic stress caused by BFR application combined with the peripheral mechanical stress in the muscle performing the movement. In circumstances where BFR is prescribed as a passive intervention, it has also been found to be an effective countermeasure to attenuate atrophy during immobilisation [37]. However, it is unable to stimulate a positive increase in skeletal muscle mass\u0026nbsp;\u003csup\u003e[36]\u003c/sup\u003e. This suggests the BFR alone is an ineffective substitute for RT if the overall goal of the individual is to improve muscle hypertrophy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNeuromuscular electrical stimulation (NMES) has been used extensively in rehabilitation to promote muscle hypertrophy as a passive intervention \u003csup\u003e[37,38]\u003c/sup\u003e. The ability of NMES to stimulate growth is influenced by the amount of electrically evoked stimulation applied \u003csup\u003e[39]\u003c/sup\u003e. Unlike traditional RT where voluntary contractions are performed at a prescribed percentage of an individual\u0026rsquo;s 1RM, NMES causes involuntary contraction of a muscle through an electrical stimulus applied directly to the muscle belly via adhesive electrodes placed on the skin \u003csup\u003e[40]\u003c/sup\u003e. When prescribing NMES, amplitude can be determined as a percentage of an individual\u0026rsquo;s maximal voluntary contraction or maximum tolerable amplitude \u003csup\u003e[41]\u003c/sup\u003e. Recruitment of the muscle depends on identification of the motor point of the muscle, thickness of the layer of subcutaneous tissue beneath the surface of the electrodes \u003csup\u003e[42]\u003c/sup\u003e, and NMES parameters prescribed (frequency, pulse width, amplitude and stimulation time) \u003csup\u003e[43]\u003c/sup\u003e. MUs closer to the surface of the skin and thus the stimulating electrode are recruited, with deeper MUs recruited as the stimulation amplitude increases \u003csup\u003e[44]\u003c/sup\u003e. Typically, electrically induced contractions only reach 40-60% of an individual\u0026rsquo;s maximum voluntary contraction \u003csup\u003e[45]\u003c/sup\u003e. This is due to the discomfort associated with prescribing higher stimulation amplitudes \u003csup\u003e[45]\u003c/sup\u003e. When prescribing NMES intensity as the maximum tolerable by the participant, it is possible that insufficient MU recruitment occurs due to the large interindividual differences in pain threshold \u003csup\u003e[41]\u003c/sup\u003e. Although mechanical stress is achieved, it may not be sufficient to \u0026nbsp;upregulate the mammalian target of rapamycin (mTOR) and its downstream effects on muscle protein synthesis and ultimately skeletal muscle hypertrophy \u003csup\u003e[46]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEmerging evidence indicates that the use of combined BFR and NMES (C-BFR-NMES) may be a passive intervention to increase skeletal muscle mass in adults \u003csup\u003e[47-53]\u003c/sup\u003e. It is suggested that the metabolic stress created by the hypoxic environment through BFR can amplify the mechanical stress induced by NMES to cause a positive change in muscle hypertrophy \u003csup\u003e[43,47,48,54]\u003c/sup\u003e. Due to the multifactorial nature of both interventions, there is currently no defined C-BFR-NMES protocol to induce muscle hypertrophy. The aim of this systematic review and meta-analysis was to quantitatively investigate the effectiveness of C-BFR-NMES compared to BFR or NMES alone, or no intervention to induce skeletal muscle mass in adults. The secondary aims were to compare muscle hypertrophy outcomes when different measurement devices are used following C-BFR-NMES, and to investigate the C-BFR-NMES protocols used to induce skeletal muscle mass in adults.\u0026nbsp;\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e2.1 \u003cem\u003eSearch Strategy\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review and meta-analysis were conducted according to PRISMA guidelines \u003csup\u003e[55]\u003c/sup\u003e (PROSPERO registration number: CRD42021260082). To identify relevant studies, a systematic literature search was independently performed by two researchers (JM \u0026amp; AG). The following databases were searched from inception to 28 February 2025: CINAHL, MedLine, Pubmed, Scopus, and Web of Science. The string search was created using three sections. The first included synonyms of \u0026ldquo;blood flow restriction\u0026rdquo;, the second string included synonyms of \u0026ldquo;neuromuscular electrical stimulation\u0026rdquo; and the third string included synonyms of \u0026ldquo;muscle hypertrophy\u0026rdquo;. Boolean operators were used to ensure that the search included at least one search term per string. All synonyms were connected using \u0026ldquo;OR\u0026rdquo;, and all string search terms were connected via \u0026ldquo;AND\u0026rdquo;. All database searches were performed with no limiters or filters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo researchers conducted the literature search independently (JM \u0026amp; AG) using the following search terms for all databases: \u0026quot;blood flow restriction\u0026quot; OR \u0026quot;BFR\u0026quot; OR \u0026quot;occlusion training\u0026quot; OR \u0026quot;vascular occlusion\u0026quot; OR \u0026quot;KAATSU\u0026quot; OR \u0026quot;ischemic training\u0026quot; OR \u0026quot;blood flow restricted\u0026quot; OR \u0026quot;partial occlusion\u0026quot; AND \u0026quot;neuromuscular electrical stimulation\u0026quot; OR \u0026quot;NMES\u0026quot; OR \u0026quot;electrical stimulation\u0026quot; OR \u0026quot;electrostimulation\u0026quot; AND \u0026quot;muscle hypertrophy\u0026quot; OR \u0026quot;muscle growth\u0026quot; OR \u0026quot;muscle size\u0026quot; OR \u0026quot;muscle mass\u0026quot; OR \u0026quot;muscle thickness\u0026quot;. All citations were exported to a citation manager Endnote, which was used to remove all duplicates before further processing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.2 \u003cem\u003eInclusion and Exclusion Criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe PICOS (population, intervention, comparison, outcome measures and study design information) was used to determine the inclusion and exclusion for systematic review. Studies were considered if (1) untrained \u0026nbsp;healthy adults (between the age of 18 \u0026ndash; 64 years) were included, (2) study design allowed comparison between C-BFR-NMES and CONTROL (BFR or NMES alone, or no intervention), (3) lower limb skeletal muscle hypertrophy was assessed pre/post intervention, (4) interventions included study periods \u0026ge;14 days, and (5) manuscripts written in English.\u003c/p\u003e\n\u003cp\u003eStudies were excluded if (1) pharmacological use of legal or illegal ergogenic aids or supplements was involved, and (2) C-BFR-NMES was combined with other exercise methods. The Physical Evidence Database Scale (PEDro) was used to rate the quality of studies included. The scale provides an 11-point checklist to ensure bias congruency on estimates of treatment effectiveness and has been found to be a valid measure when determining the methodological qualities of studies \u003csup\u003e[56]\u003c/sup\u003e. All articles were assessed independently by JM and AG.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.3 \u003cem\u003eData Extraction\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll identified studies were screened via examining titles and abstracts for study eligibility. Full text of identified studies was then acquired for data extraction and further screening of eligibility criteria. The following information was extracted: (1) population characteristics, (2) primary outcome measures, (3) methods, (4) C-BFR-NMES protocols used, and (5) skeletal muscle hypertrophy measurement protocols used. To quantify the changes in skeletal muscle hypertrophy measured, pre- and post-intervention measurement time points were used. For studies that provided incomplete data, the corresponding author of the manuscript was contacted. If the required data were not provided via correspondence, the study data were excluded. Table 1 shows data of the included studies. Table 2 outlines the methodological quality of each study measured via the PEDro scale.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.4 \u003cem\u003eRisk of Bias\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias was assessed by two independent authors (JM and AG). The Risk of Bias 2 (RoB 2) tool was used to assess different domains of the reviewed randomised control trials to determine sources of bias that could be introduced into the results (Table 3). The domains included determine: (1) bias arising from the randomisation process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurements of the outcome, and (5) bias in the selection of the reported result. Funnel plots were also assessed for each outcome to interpret any evidence of publication bias.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2.5 \u003cem\u003eStatistical Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRevMAN was used to perform statistical analysis of the individual studies (Review Manager, Version 5.3, The Cochrane Collaboration, 2014). Observations were weighted by the inverse of the sampling variance. To calculate the standardised mean difference (SMD), the difference in mean outcome between groups was derived by the standard deviation of outcome among participants. Partially observed considerable between-timepoint differences in SD pre and SD post, SD change was defined as SD change = square root [(SD \u003csub\u003epre\u003c/sub\u003e \u003csup\u003e2\u003c/sup\u003e / N \u003csub\u003epre\u003c/sub\u003e + (SD \u003csub\u003epost\u003c/sub\u003e \u003csup\u003e2\u003c/sup\u003e / N \u003csub\u003epost\u003c/sub\u003e)]. A forest plot was used to present SMD and 95% confidence intervals (CIs) in skeletal muscle mass change between C-BFR-NMES and CONTROL. SMD was chosen as selected study results were presented in different units.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo account for interstudy protocol variability and heterogeneity, all analysis that was performed used a random effects model. Pooled effect sizes (ES) were calculated for each comparison. Alpha level was set to \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05. Data were reported as mean\u0026nbsp;\u0026plusmn; standard deviation. To report for inter study heterogeneity, the \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e method was used. This allowed for the quantification of the variation between the studies that is caused by heterogeneity rather than chance alone. An\u0026nbsp;\u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e of 0-40% represents low heterogeneity, 30-60% represents moderate heterogeneity, 50-90% represents substantial heterogeneity, and 75-100% represents considerable heterogeneity \u003csup\u003e[57]\u003c/sup\u003e. In all analyses, multiple comparisons were included from several studies in order to increase the accuracy and thus generalization of our meta-analysis. This is a common and accepted statistical method for meta-analysis \u0026nbsp;\u003csup\u003e[58]\u003c/sup\u003e. A sensitivity analysis was performed, by excluding one comparison at a time for each meta-analysis to determine if the effect size and study heterogeneity were influenced by a particular comparison \u003csup\u003e[59]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003e3.1 \u003cem\u003eStudy Selection\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrom our search of five data bases (PubMED, Web of Science, Scopus, Medline, CINAHL), 615 articles were identified (Figure 1). From this, 96 duplicates were removed, and 519 articles were screened for eligibility criteria via titles and abstracts. The full texts of thirteen studies were retrieved for further screening. Following multiple attempts to contact corresponding authors, three studies were excluded from our analysis due to insufficient data for muscle hypertrophy measurements \u003csup\u003e[49,53,60]\u003c/sup\u003e. An additional two articles were identified through citation searching. One study was excluded due to full text not being available \u003csup\u003e[61]\u003c/sup\u003e. A sensitivity analysis was conducted, and no significant changes in effect sizes were shown. Two studies were deemed to be \u0026ldquo;low risk\u0026rdquo; of bias \u003csup\u003e[50,51]\u003c/sup\u003e, while one study showed \u0026ldquo;some concerns\u0026rdquo; when assessed using the RoB 2 \u003csup\u003e[52]\u003c/sup\u003e. All included studies scored between 5 and 7 points (mean = 6.3, SD = 1.2)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn total, seven meta-analyses were conducted. The first comparison investigated the effects of C-BFR-NMES on muscle hypertrophy compared to CONTROL (no intervention) (Figure 2). The second and third comparisons were performed to investigate the effect of C-BFR-NMES relative to CONTROL on muscle hypertrophy when measured via Brightness mode (B-mode) ultrasound (Figure 3) or dual x-ray absorptiometry (DXA) (Figure 4), respectively. The fourth comparison investigated the effects of C-BFR-NMES compared to CONTROL when focusing on quadricep mass (Figure 5). Comparisons five, six and seven investigated the benefit of varying C-BFR-NMES protocols including individualised BFR cuff pressure (Figure 6), standardised cuff pressure (Figure 7), and NMES intensity prescription (Figure 8), respectively, compared to CONTROL on muscle hypertrophy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3.2\u0026nbsp;Effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy\u003c/p\u003e\n\u003cp\u003eThree studies comparing the effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy were included in the meta-analysis \u003csup\u003e[50-52]\u003c/sup\u003e (Figure 2). From the selected studies, a total of eight comparisons on the effects of C-BFR-NMES versus CONTROL on skeletal muscle hypertrophy. One study applied C-BFR-NMES to the posterior lower leg calf complex to assess changes in gastrocnemius muscle mass \u003csup\u003e[52]\u003c/sup\u003e. Two studies applied C-BFR-NMES to the anterior portion of the upper leg to assess change in vastus lateralis muscle mass \u003csup\u003e[50,62]\u003c/sup\u003e. Our results show that C-BFR-NMES induced significantly greater muscle hypertrophy compared to CONTROL (Z = 2.66, \u003cem\u003ep\u003c/em\u003e = 0.008), with a medium pooled ES of 0.61 (95% CI 0.11 to 1.6) in favour of C-BFR-NMES. The calculation of \u003cem\u003eI\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e showed significant substantial heterogeneity of 59% (\u003cem\u003ep\u003c/em\u003e = 0.02)\u003c/p\u003e\n\u003cp\u003e3.3\u0026nbsp;Effects of C-BFR-NMES versus CONTROL on skeletal muscle mass measured via DXA\u003c/p\u003e\n\u003cp\u003eTwo studies with a total of five comparisons investigated determined changes in hypertrophy, measuring muscle mass via DXA \u003csup\u003e[50,51]\u003c/sup\u003e (Figure 3). Quantitative analysis showed that four out of five included comparisons induced a positive change in muscle mass, with a small pooled ES of 0.32 (95% CI 0.12 to 0.76). However, this effect size did not reach statistical significance (Z = 1.42, \u003cem\u003ep\u003c/em\u003e = 0.15). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e showed moderate heterogeneity of 45% but was not significant (\u003cem\u003ep\u003c/em\u003e = 0.12).\u003c/p\u003e\n\u003cp\u003e3.4\u0026nbsp;Effects of C-BFR-NMES versus CONTROL on skeletal muscle thickness\u003c/p\u003e\n\u003cp\u003eTwo studies with a total of three comparisons investigated changes in muscle mass assessed through muscle thickness via B-mode ultrasound \u003csup\u003e[50,52]\u003c/sup\u003e (Figure 4). All three comparisons found C-BFR-NMES elicited a significantly greater hypertrophic effect than BFR, NMES or no intervention when measured via B-mode ultrasound (Z = 3.96, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt;0.0001), with large pooled ES of 1.12 (95% CI 0.61 to 1.81). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e was non-significant (\u003cem\u003ep\u003c/em\u003e = 0.40), showing low heterogeneity of 0%.\u003c/p\u003e\n\u003cp\u003e3.5\u0026nbsp;Effects of C-BFR-NMES versus CONTROL on quadricep mass\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo studies with a total of seven comparisons investigated the effects of C-BFR-NMES specifically on the quadriceps muscle \u003csup\u003e[50,51]\u003c/sup\u003e (Figure 5). Across all comparisons, there was a positive change in quadricep mass that reached significance (Z = 2.45, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.01), with a medium pooled ES of 0.62 (95% CI 0.13 to 1.13). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u0026nbsp;\u003c/em\u003ewas significant (\u003cem\u003ep =\u0026nbsp;\u003c/em\u003e0.01), showing substantial heterogeneity (64%).\u003c/p\u003e\n\u003cp\u003e3.6\u0026nbsp;Effects of C-BFR-NMES versus CONTROL when using individualised cuff pressure\u003c/p\u003e\n\u003cp\u003eOne study that included four comparisons applied C-BFR-NMES with an individualised restrictive cuff pressure to the individual \u003csup\u003e[50]\u003c/sup\u003e (Figure 6). Individual blood flow restriction cuff pressures ranged from 180-290mmHg. These comparisons reached statistical significance (Z = 5.03, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.001), with large pooled ES of 1.26 (95% CI 0.77 to 1.75). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e was non-significant (\u003cem\u003ep\u003c/em\u003e = 0.87), showed low heterogeneity of 0%.\u003c/p\u003e\n\u003cp\u003e3.7\u0026nbsp;Effects of C-BFR-NMES versus CONTROL when using standardised cuff pressure\u003c/p\u003e\n\u003cp\u003eTwo studies comprising of four comparisons applied C-BFR-NMES with a standardised restrictive cuff pressure based on previous research \u003csup\u003e[51,52]\u003c/sup\u003e (Figure 7). Standardised blood flow restriction pressures ranged from 100-220mmHg. These comparisons showed a small ES of 0.08 (95% CI -0.26 to 0.43) which did not reach statistical significance (Z = 0.49, \u003cem\u003ep\u0026nbsp;\u003c/em\u003e= 0.62). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e was non-significant (\u003cem\u003ep\u003c/em\u003e = 0.87), showed low heterogeneity of 0%.\u003c/p\u003e\n\u003cp\u003e3.8\u0026nbsp;Effects of C-BFR-NMES versus CONTROL when prescribing NMES as a percentage of maximal voluntary isometric contraction (MVIC)\u003c/p\u003e\n\u003cp\u003eTwo studies prescribed C-BFR-NMES using a NMES intensity which was based on a percentage of the individual\u0026rsquo;s maximal voluntary isometric contraction, measured via knee extension dynamometry \u003csup\u003e[50,52]\u003c/sup\u003e (Figure 8). Prescription of NMES intensity ranged from 15-20% of MVIC. Studies that utilised this prescription showed a significant positive change in muscle hypertrophy (Z = 4.96, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), with a large ES of 1.13 (95% CI 0.68 to 1.58). The calculation of \u003cem\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e was non-significant (\u003cem\u003ep\u003c/em\u003e = 0.68), showed low heterogeneity of 0%.\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThe primary aim of this systematic review and meta-analysis was to investigate the effects of C-BFR-NMES as a passive intervention to increase skeletal muscle mass in adults, compared to BFR or NMES alone, or no intervention. Additional analyses performed explored different protocols used when applying C-BFR-NMES, providing insight into what procedures are most effective in promoting skeletal muscle hypertrophy. The main finding of the present study is that C-BFR-NMES provides positive hypertrophy adaptions in skeletal mass when compared to BFR or NMES alone, or no intervention. The use of DXA and B-mode ultrasound for muscle hypertrophy measurement was also investigated. When muscle thickness was measured via B-mode ultrasound, a significant medium effect was found. Conversely, measurements of muscle thickness via DXA showed no significant effect, likely due to the regional changes in the muscle that DXA is unable to differentiate. Applying C-BFR-NMES to the vastus lateralis found a medium effect, compared to when applied to the gastrocnemius. Further, individualising restriction cuff pressure to the individual, and modulating NMES intensity as a percentage of the participants MVIC facilitated the greatest changes in muscle hypertrophy. The implementation of C-BFR-NMES into rehabilitation or early intervention programs provides an opportunity for individuals who are unable to perform voluntary resistance training a passive modality to promote muscle hypertrophy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mechanism by which C-BFR-NMES could induce significantly greater muscle hypertrophy relative to CONTROL could be explained by the expected larger increase in metabolic stress caused by the accumulation of metabolic by-products with the combined intervention relative to either intervention alone or no intervention \u003csup\u003e[63]\u003c/sup\u003e. Metabolic stress is purported to be the primary mechanism through which muscle hypertrophy occurs due to the increase in anabolic hormone release, hypoxia, ROS production and cell swelling \u003csup\u003e[64]\u003c/sup\u003e. Blood flow plays an important role in providing oxygento the working muscles, and it is well documented that decreasing oxygen availability to the exercising muscles can have significant effects on muscle hypertrophy \u003csup\u003e[65]\u003c/sup\u003e. The application of BFR can limit or occlude arterial flow into the muscle, whilst venous return is occluded, beginning a cascade of physiological responses that upregulate muscle protein synthesis \u003csup\u003e[35]\u003c/sup\u003e. The occlusion causes localised pooling of blood and muscle cell swelling, which augments metabolic stress within the muscle \u003csup\u003e[66]\u003c/sup\u003e. Even without exercise, acute increases in muscle thickness (MT) have been observed in combination with a decrease in plasma volume when BFR is applied \u003csup\u003e[67]\u003c/sup\u003e. This suggests that the change in MT is not just oedema but there is a fluid shift from the plasma to inside the muscle cell \u003csup\u003e[68]\u003c/sup\u003e. Volume changes inside the muscle cell are detected by an intrinsic volume sensor, which may lead to the activation of mTOR and MAPK pathways. Previous studies have shown that activation of these pathways can promote skeletal muscle hypertrophy \u003csup\u003e[32,69,70]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe recognised gold standard for determining changes in muscle size in vivo is via magnetic resonance imaging (MRI) \u003csup\u003e[71]\u003c/sup\u003e. However, due to the costs and accessibility of MRI, alternative measurement methods are utilised to assess muscle size. The studies included in this review found B-mode ultrasound and DXA were used to measure muscle thickness and lean mass respectively \u003csup\u003e[50-52]\u003c/sup\u003e. Interestingly our meta-analysis showed ES of 1.12 (\u003cem\u003ep\u003c/em\u003e \u0026lt;0.0001) for measurements via B-mode ultrasound, comparatively to ES of 0.32 (\u003cem\u003ep\u003c/em\u003e = 0.15). Although DXA has been found to have a strong association with MRI derived values at a single time point, its ability to detect change following a chronic resistance training intervention is less accurate \u003csup\u003e[72]\u003c/sup\u003e. Lean mass measurements via DXA are obtained through assessment of the soft tissue compartment of interest. This allows for the regional determination of body composition. As a result, DXA is unable to differentiate between muscle groups and can only quantify the mass of the transverse sections of the body. Further, quantification of lean soft tissue mass includes proteins, glycogen, soft tissue materials, and water \u003csup\u003e[73]\u003c/sup\u003e. Training interventions will cause acute changes in these substrates which may not reflect structural change caused by hypertrophic growth, limiting the accuracy of DXA measurements over various time points.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eB-mode ultrasound was used to quantify changes in muscle thickness in two studies \u003csup\u003e[50,52]\u003c/sup\u003e. A previous study compared MT measurements via B-mode ultrasound to MRI muscle cross section area (mCSA) and muscle volume (MV) of the vastus lateralis over a 12-week resistance training intervention. A significant correlation between percentage increase in MT and mCSA (\u003cem\u003er = 0.69, P = 0.001)\u0026nbsp;\u003c/em\u003eat mid-thigh was found, however a non-significant relationship was found between MT and MV (\u003cem\u003er = 0.33, P = 0.21)\u0026nbsp;\u003c/em\u003e\u003csup\u003e[74]\u003c/sup\u003e. Regional hypertrophy of the VL muscle belly is a result of the type of intervention used, with heterogenous distribution of often occurring as a response \u003csup\u003e[75]\u003c/sup\u003e. It remains unclear if regional hypertrophy is a response to mechanical stimuli, or simply the proceeding effects of the applied stimuli \u003csup\u003e[76]\u003c/sup\u003e. Both Adrande et al. \u003csup\u003e[52]\u003c/sup\u003e and Slysz et al. \u003csup\u003e[50]\u003c/sup\u003e measured MT at a single site, which could underrepresent the effectiveness of the interventions employed. To obtain a more accurate representation of MT change following a chronic intervention, multiple measurements across the muscle belly should be obtained, rather than a single measurement at 50%, providing a more coherent quantification of structural change of the muscle belly. The inclusion of a multi-site MT protocol (30%, 50% and 70% of the femur length) was utilised by Li et al. \u003csup\u003e[53]\u003c/sup\u003e following 6 weeks of C-BFR-NMES + RT. When compared to the control group who performed an identical RT protocol, a greater MT increase (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05) was reported in the C-BFR-NMES + RT group. This finding suggests that a multi-site approach to measuring changes in CSA is more sensitive to hypertrophy than single-site measurements.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe impact magnitude of C-BFR-NMES on muscle hypertrophy may be dependent on the target muscle. This is likely due to the composition of muscle fiber type within the muscle itself. Fast twitch fibers have approximately 50% greater growth capacity compared to slow twitch fibers, therefore if they can be preferentially recruited individuals will see an enhanced rate of hypertrophy \u003csup\u003e[77]\u003c/sup\u003e. Previous research has indicated the soleus contains a much larger percentage of type I slow twitch fibers (70%) \u003csup\u003e[78]\u003c/sup\u003e compared to the vastus lateralis muscle (42%) \u003csup\u003e[79]\u003c/sup\u003e. This is a likely reason why Andrade et al. \u003csup\u003e[52]\u003c/sup\u003e did not observe statistically significant changes in soleus hypertrophy following two weeks of C-BFR-NMES application. Due to NMES recruiting muscle fibers in a non-preferential manner \u003csup\u003e[80]\u003c/sup\u003e, the growth potential of the soleus is limited by its high percentage of type I muscle fiber.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough metabolic stress is believed to be the primary mechanism behind BFR induced hypertrophy, an increase in mechanical tension causes greater fast twitch fiber recruitment \u003csup\u003e[35]\u003c/sup\u003e. According to the size principle, MU are recruited in a task dependent orderly manner, from smallest to largest \u003csup\u003e[17]\u003c/sup\u003e. As a result, fast fatiguing, large type II MU are only recruited when necessary to minimise the early onset of muscular fatigue. Conversely, with the application of BFR, there is an increase in FT fiber recruitment to assist in force production at lower thresholds \u003csup\u003e[81]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMU recruitment during NMES is influenced by the positioning of the electrodes on the skin, superficial the muscle belly. As MU are directly recruited by NMES, they are seen to follow a synchronous and repeated activation pattern, different to voluntary MU recruitment\u0026nbsp;\u003csup\u003e[82]\u003c/sup\u003e. This may contribute to a greater degree of fatigue compared to voluntary efforts, where asynchronous MU cycling allows for periods of recovery \u003csup\u003e[43]\u003c/sup\u003e. Due to the nature of NMES application, superficial muscle fibers are activated more favourably. Superficial activation occurs due to NMES activating the axons which are underneath the stimulating electrodes. MU recruitment has been seen to decrease proportionally as distance from the electrodes increase \u003csup\u003e[43]\u003c/sup\u003e. When combined with BFR, it is possible that the superficial muscle fibers are fatigued at a greater rate, increasing metabolic and mechanical stress and undergo preferential hypertrophy. However, if high stimulation frequencies are applied, the addition of BFR can cause a rapid fatigue onset and ultimately reducing the duration of effective muscular tension and limiting adaptive potential \u003csup\u003e[83]\u003c/sup\u003e. These mechanisms are further reinforced by Li et al. \u003csup\u003e[53]\u003c/sup\u003e, who observed a discrepancy between the NMES + RT and C-BFR-NMES + RT.\u0026nbsp;Although the NMES + RT group exhibited increased muscle activation (as measured by surface electromyography), similar to the C-BFR-NMES + RT group, it did not achieve the same significant gains in muscle strength observed in the latter (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e = 0.736, \u003cem\u003ep\u003c/em\u003e \u0026lt;0.05). This highlights a critical point: while EMS alone effectively recruits motor units and elevates electrical activity, depending on the intensity used, it may lack key physiological conditions required for strength development. These include sufficient mechanical tension to stimulate hypertrophy, coordinated central nervous system involvement, and sustained metabolic stress, factors comprehensively addressed through the addition of BFR.\u003c/p\u003e\n\u003cp\u003eBoth Andrade et al. \u003csup\u003e[52]\u003c/sup\u003e and Slysz and Burr \u003csup\u003e[51]\u003c/sup\u003e utilized a standardised cuff pressure (100mmHg and 220mmHg) when applying C-BFR-NMES. The disparity between these absolute pressures is due to the physical size of the cuff. A wider cuff, as used by Andrade et al. \u003csup\u003e[52]\u003c/sup\u003e has been shown to be more effective at lower inflation pressures \u003csup\u003e[84]\u003c/sup\u003e. Although a wider cuff was used to compensate for a lower pressure, neither study found significant changes in muscle hypertrophy. Conversely, Slysz et al. \u003csup\u003e[50]\u003c/sup\u003e applied restrictive pressures ranging from 180-290mmHg to achieve full arterial occlusion. A review by Patterson et al. \u003csup\u003e[26]\u003c/sup\u003e suggested pressures ranging from 40 to 80% of arterial occlusion as sufficient to promote metabolite accumulation in the limb. Interestingly, when combined with lower loads, a higher pressure (at least 80% arterial occlusion pressure) is recommended to augment the stimulus \u003csup\u003e[85]\u003c/sup\u003e as seen in Slysz et al. \u003csup\u003e[50]\u003c/sup\u003e. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRestricted venous return causes a pooling of blood and hypoxia locally within the muscle, resulting in greater metabolic acid \u003csup\u003e[86]\u003c/sup\u003e.\u0026nbsp;Due to the chemical changes produced by the metabolic byproducts within the active musculature during BFR exercise, there is a greater stimulation of chemosensitive sensory nerves (Group III and IV afferents)\u0026nbsp;\u003csup\u003e[87]\u003c/sup\u003e. Continued BFR application throughout rest periods can cause continued activation of group III/IV muscle afferents, which sense mechanical and metabolic (respectively) stimuli arising in the exercise muscle.\u0026nbsp;Innervation of alpha motor neurons results in the contraction of skeletal muscle fibers. Alpha motor neuron stimulation can be attenuated through the activation group III/IV afferents. To overcome this, there is an increase in muscle fiber recruitment to satisfy muscular force requirement and limit a decline in force production and power output\u0026nbsp;\u003csup\u003e[35]\u003c/sup\u003e. Takarada et al.\u0026nbsp;\u003csup\u003e[88]\u003c/sup\u003e investigated the effects of BFR when used in isolation (intervention) compared to no occlusive stimulus (control) on disuse atrophy of knee extensor muscles. It was found that BFR resulted in significantly less atrophy in knee extensors and flexors than when compared to the control group, suggesting that muscle swelling plays an important role in increasing metabolic stress. Although arguments can be made for continuous occlusion throughout exercise protocols, no studies have found significant differences between hypertrophy outcomes.\u003c/p\u003e\n\u003cp\u003eAdenosine triphosphate (ATP) production and oxygen (O\u003csub\u003e2)\u0026nbsp;\u003c/sub\u003econsumption are a result of mitochondrial respiration. This process also produces\u0026nbsp;reactive oxygen species (ROS) as byproduct \u003csup\u003e[64]\u003c/sup\u003e. Increases in metabolic and mechanical work is concomitant with ROS production increases. Influx of ROS affects muscle fatigue and the inhibition of sarcoplasmic reticulum Ca\u003csup\u003e2+\u003c/sup\u003e release and microfibril Ca\u003csup\u003e2+\u003c/sup\u003e sensitivity \u003csup\u003e[64]\u003c/sup\u003e. \u0026nbsp;Further, ROS activates the group IV afferents that primarily transmit information about metabolic stimuli, and directly inhibits motoneurons. An increase in EMG amplitude has been shown during low load resistance training with BFR, and it is likely a similar mechanism occurs when RT is substituted for NMES \u003csup\u003e[89,90]\u003c/sup\u003e. Group III/IV muscle afferents facilitate \u0026lsquo;central fatigue\u0026rsquo; and ultimately an individual\u0026rsquo;s receptiveness to fatigue and capacity for exercise. Therefore, if restrictive cuff pressure is not adequately applied, the extent to which metabolites will pool within the working muscle are limited and will be insufficient to upregulate muscle protein synthesis.\u003c/p\u003e\n\u003cp\u003eTwo studies included in this review utilised a pre-determined restriction pressure which could partially explain the lack of statistically significant changes in muscle hypertrophy \u003csup\u003e[51,52]\u003c/sup\u003e. Similarly, Li et al. \u003csup\u003e[53]\u003c/sup\u003e utilised pre-determined pressures based on the thigh circumference. Although it should be noted, the studies include in this review utilised a single-chamber bladder system, Li et al. \u003csup\u003e[53]\u003c/sup\u003e used a multi-chamber bladder system. Functionally, a single-chamber system encircles the limb, applying consistent pressure when inflated. Conversely, multi-chamber systems consistent of several individual bladders, which can result in non-uniform circumferential pressure when inflated \u003csup\u003e[91]\u003c/sup\u003e. The latter require significantly higher restrictive pressures to account for the bladder design difference (up to 350 mmHg for the lower body), but also the narrower width of the cuff (5cm). Although standardised pressures can occlude arterial flow, this method does not take into consideration individual differences and can result in varying degrees of blood flow restriction. Optimal cuff pressure is influenced by a combination of cuff width and thigh circumference of the individual \u003csup\u003e[92]\u003c/sup\u003e. Natsume et al. \u003csup\u003e[49]\u003c/sup\u003e found that the occlusion pressure required to effectively limit arterial flow is largely influenced by individual thigh circumference. Although fixed occlusion pressures can successfully restrict blood flow, it does not account for individual differences, and this can potentially cause a large variance in acute physiological responses \u003csup\u003e[26]\u003c/sup\u003e. Previous research also shows that thigh circumference was able to predict AOP equally when compared to measurements thigh composition (mid-thigh muscle [mCSA] and fat [fCSA] cross sectional area \u003csup\u003e[93]\u003c/sup\u003e. If so, an optimal pressure gradient will inhibit venous blood flow while reducing the arterial inflow of blood, thus a blood pooling will be evident in the muscle tissue \u003csup\u003e[94]\u003c/sup\u003e. The quantity of pressure follows a dose respsubgonsive manner as the hormesis curve \u003csup\u003e[95]\u003c/sup\u003e. Due to ambiguity regarding optimal pressure for the proliferation of skeletal muscle hypertrophy, high levels of cuff pressure may result in reductions in muscle activity and safety consequences more detrimental than suboptimal muscle adaptation \u003csup\u003e[93,96]\u003c/sup\u003e. Practically, high cuff pressures have been found to cause greater discomfort which could be detrimental to exercise adherence and enjoyment. In line with current BFR protocol recommendations, cuff pressure should be prescribed using relative pressure to the AOP \u003csup\u003e[26]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eSelection of appropriate amplitude has a direct impact on the number of MU activated via NMES. Increasing current amplitude causes an increase in torque production which occurs through the activation of additional motor units. Prescribing intensity as a percentage of MVIC is often used in NMES protocols as this is a quantifiable intensity relative to the individual\u0026rsquo;s capabilities. The limiting factor in prescribing higher percentages relative to MVIC is individual discomfort \u003csup\u003e[97,98]\u003c/sup\u003e. Likewise, where studies prescribed amplitude based on maximum tolerance, it becomes highly dependent on pain thresholds of the individual \u003csup\u003e[99-102]\u003c/sup\u003e. Early increases in current amplitude result are followed with a steep rise in torque, followed by a plateau at a high level of stimulation \u003csup\u003e[47]\u003c/sup\u003e. This review found that the literature uses both percentage MVIC and maximum tolerable intensity. A plausible issue with prescribing intensity via the maximum tolerable method is that is individual pain thresholds are likely to vary significantly between individuals, which may result in the intensity inducing insufficient mechanical stress. Therefore, it can be recommended that current amplitude be set at a percentage of MVIC to minimise excessive discomfort to the individual. Further, increasing intensity percentage throughout a chronic intervention in line with progressive overload principles will minimise accommodation to the stimulus \u003csup\u003e[103]\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e4.1\u0026nbsp;Practical Application/Recommendations\u003c/p\u003e\n\u003cp\u003eDue to its passive nature, these results suggest that C-BFR-NMES can be used in adult populations who are unable to perform voluntary resistance training, or to use in conjunction with resistance training as means to stimulate skeletal muscle hypertrophy. When recommending C-BFR-NMES it is important to consider both BFR and NMES variables to elicit the beneficial stimulus to the individual. BFR occlusion pressure should be applied based on individual AOP, rather than standardised cuff pressure. There seems to be a difference in continuous versus intermittent application. Intermittent application, where the cuff is removed during rest periods, is recommended to decrease individual discomfort. NMES amplitude should be calculated as a percentage of an individual\u0026rsquo;s MVIC (15-20%), with frequencies between 50-100Hz used along with a pulse width between 200-400us. Skeletal muscular adaptions can be seen as early as two weeks combined with a high frequency of application between 4 \u0026ndash; 5 days per week.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAlthough no adverse effects were reported throughout the included studies, individuals need to be screened for contraindications of BFR such as circulatory issues, heart disease, hypertension, diabetes or pregnancy; and for NMES use including burns, skin lesions, vascular impairment, or cardiac pacemakers \u003csup\u003e[104]\u003c/sup\u003e. Further research should be done to determine the effects of C-BFR-NMES in adolescent or elderly populations.\u0026nbsp;\u003c/p\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eThe main limitation of the study was the lack of research implementing C-BFR-NMES. As a result, there is no defined protocol when combining the two modalities to elicit skeletal muscle hypertrophy. The calculation of I\u003csup\u003e2\u003c/sup\u003e showed a heterogeneity of 59% (p = 0.02). \u0026nbsp;This variability might result in differences in training protocols (both BFR and NMES), sample sizes and hypertrophy assessment (muscle thickness vs muscle mass). A number of studies were found stating clinically significant increase in muscle hypertrophy following chronic interventions but were not included as they did not meet our inclusion/exclusion criteria \u003csup\u003e[47-49]\u003c/sup\u003e. Bergamasco et al. \u003csup\u003e[68]\u003c/sup\u003e found a 4.6% (p\u0026lt;0.0001) increase in VL CSA following 20 sessions. C-BFR-NMES was compared to LL-BFR that showed an 11.2% (p\u0026lt;0.0001) increase in VL CSA. These results suggest C-BFR-NMES presents an appropriate method to increase muscle CSA when voluntary exercise is not feasible. Gorgey et al. \u003csup\u003e[47]\u003c/sup\u003e noted a 15% increase in extensor carpi radialis longus (ECLR) CSA (p=0.048) in individuals with incomplete tetraplegia. Natsume et al. (2015) \u003csup\u003e[49]\u003c/sup\u003e demonstrated an 3.9% increase in quadricep thickness after 2 weeks of C-BFR-NMES training. Li et al. \u003csup\u003e[53]\u003c/sup\u003e found a significant increase in muscle thickness following 6 weeks of C-BFR-NMES + RT compared to RT (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05) and NMES + RT (\u003cem\u003ep\u0026nbsp;\u003c/em\u003e\u0026lt; 0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSlysz et al. \u003csup\u003e[50]\u003c/sup\u003e utilised an unloading period for the entire 2 weeks while C-BFR-NMES was applied. As the aim of their study was to investigate the effectiveness of C-BFR-NMES in attenuating disuse atrophy, if a similar study was performed without immobilisation the results may show further benefit to C-BFR-NMES. Disuse periods as short as five days have been shown to induce significant decreases in muscle mass (3.5%) \u003csup\u003e[105]\u003c/sup\u003e. As muscle is a highly plastic tissue that responds to environmental stimuli, the removal of weight bearing activities would promote premature muscle loss and limit the results of the intervention.\u0026nbsp;\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eA pooled analysis of current data suggests that C-BFR-NMES promotes a medium effect on skeletal muscle hypertrophy in lower body musculature compared to BFR or NMES alone, or no exercise in healthy adults. C-BFR-NMES is an entirely passive intervention that does not require voluntary movement. In populations where individuals are immobilised or unable to perform voluntary exercise, it could provide a significant benefit. Further, C-BFR-NMES provides an opportunity for those with chronically low levels of skeletal muscle mass to increase hypertrophy in a controlled environment. Further research is needed to determine the effectiveness of C-BFR-NMES in upper body musculature, as well as different population groups such as adolescent and elderly.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original data generated and analysed during the current study are available from the corresponding author upon request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJM and JSR conceptualised and designed the study. JM analysed and interpreted the data, and wrote the initial draft; JM and AG performed data extraction; LCD, CD, AG and KW contributed to data interpretation and analysis, and provided critical feedback. JSR is the guarantor of the study. All authors reviewed and approved the final manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWolfe, R. R. The underappreciated role of muscle in health and disease. \u003cem\u003eAm J Clin Nutr\u003c/em\u003e \u003cstrong\u003e84\u003c/strong\u003e, 475-482, doi:10.1093/ajcn/84.3.475 (2006).\u003c/li\u003e\n\u003cli\u003eBrook, M. S.\u003cem\u003e et al.\u003c/em\u003e Synchronous deficits in cumulative muscle protein synthesis and ribosomal biogenesis underlie age-related anabolic resistance to exercise in humans. \u003cem\u003eJ Physiol\u003c/em\u003e \u003cstrong\u003e594\u003c/strong\u003e, 7399-7417, doi:10.1113/jp272857 (2016).\u003c/li\u003e\n\u003cli\u003eOh, Y. 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F.\u003cem\u003e et al.\u003c/em\u003e Effects of physical therapy with neuromuscular electrical stimulation in acute and late septic shock patients: A randomised crossover clinical trial. \u003cem\u003ePLoS One\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, e0264068, doi:10.1371/journal.pone.0264068 (2022).\u003c/li\u003e\n\u003cli\u003eValenzuela, P. L., Morales, J. S. \u0026amp; Lucia, A. Passive Strategies for the Prevention of Muscle Wasting During Recovery from Sports Injuries. \u003cem\u003eJournal of Science in Sport and Exercise\u003c/em\u003e \u003cstrong\u003e1\u003c/strong\u003e, 13-19, doi:10.1007/s42978-019-0008-5 (2019).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003cstrong\u003e.\u003c/strong\u003e Overview of studies included in the systematic review and meta-analysis: MT = muscle thickness, MM = muscle mass\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eSubjects\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBFR Protocol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eNMES Protocol\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eMuscle target\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eDuration / Frequency\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eC-BFR-NMES outcomes relative to CONTROL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eAndrade et al. (2016) \u003csup\u003e[52]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eMale adults (20 - 26 y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e100mmHg pressure\u003cbr\u003e\u0026nbsp;Standardised\u003cbr\u003e\u0026nbsp;Continuous application\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFrequency 35\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eHz\u003cbr\u003e\u0026nbsp;Pulse width 400 us\u003cbr\u003e\u0026nbsp;Amplitude 20% MVIC\u003cbr\u003e\u0026nbsp;6s on 2s off\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eSoleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 wk; 3 days/wk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMT via B-mode ultrasonography\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBFR NMES: 15.28% (\u003cem\u003ep\u003c/em\u003e = 0.091)\u003cbr\u003eControl: -2.58% (\u003cem\u003ep\u003c/em\u003e = 0.141)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo statistically\u0026nbsp;\u003cbr\u003e\u0026nbsp;significant increase in MT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSlysz and Burr (2018) \u003csup\u003e[51]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdults (18 - 45 y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e20\u003cbr\u003e\u0026nbsp;(10 male,\u003cbr\u003e\u0026nbsp;10 female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e220 mmHg pressure\u003cbr\u003e\u0026nbsp;Standardised\u003cbr\u003e\u0026nbsp;Intermittent application\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFrequency 50-100 Hz\u003cbr\u003e\u0026nbsp;Pulse width 400 us\u003cbr\u003e\u0026nbsp;Amplitude maximum tolerable\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eQuadriceps\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6 wk; 4 days/wk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMM via DXA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eBFR NMES: 1.29%\u003cbr\u003e\u0026nbsp;BFR: 1.42%\u003cbr\u003e\u0026nbsp;NMES: 1.29%\u003cbr\u003e\u0026nbsp;Control: 0.01%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo statistically\u0026nbsp;\u003cbr\u003e\u0026nbsp;significant increase in MM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSlysz et al. (2021) \u003csup\u003e[50]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eAdults (19 - 25 y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e30\u003cbr\u003e\u0026nbsp;(14 male,\u003cbr\u003e\u0026nbsp;16 female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e180 - 290 mmHg pressure\u003cbr\u003e\u0026nbsp;Individualised\u003cbr\u003e\u0026nbsp;Intermittent application\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eFrequency 60 Hz\u003cbr\u003e\u0026nbsp;Pulse width 200 us\u003cbr\u003e\u0026nbsp;Amplitude 15% MVIC\u003cbr\u003e\u0026nbsp;6s on 15s off\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003eQuadriceps\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2 wk; 5 days/wk\u003cbr\u003e\u0026nbsp;twice daily\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMT via B-mode ultrasonography\u003cbr\u003e\u0026nbsp;MM via DXA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMT BFR NMES: 4%\u003cbr\u003e\u0026nbsp;MT BFR: -7%\u003cbr\u003e\u0026nbsp;MT Control: -7%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo statistically significant increase in MT\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMM BFR NMES: -0.25%\u003cbr\u003e\u0026nbsp;MM BFR: -3%\u003cbr\u003e\u0026nbsp;MM Control: -4%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eNo statistically significant increase in MM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. PEDro scale to measure methodological quality\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"975\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"12\" valign=\"top\" style=\"width: 900px;\"\u003e\n \u003cp\u003eStudy reporting criterion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 67px;\"\u003e\n \u003cp\u003eEligibility criteria were specified\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eSubjects were randomly allocated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eAllocation was concealed\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eBaseline characteristics of groups were similar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWere subjects blinded\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWere those administering treatment blinded\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWere assessors who measured key outcomes blinded\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eAt least one key outcome measure obtained from more than 85% of subjects\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWas an intention to treat analysis uses\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWere between group statistical analysis performed for at least one outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eWere point measures and measures of variability used for at least one key outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 75px;\"\u003e\n \u003cp\u003eScore\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eAndrade et al. (2016) \u003csup\u003e[52]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eSlysz and Burr (2018) \u003csup\u003e[51]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eSlys et al., (2021) \u003csup\u003e[50]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e\u0026nbsp; \u0026nbsp;Risk of bias evalulation of the RCTs using the RoB 2 tool. \u0026quot;+\u0026quot; = low risk, \u0026quot;?\u0026quot; = some concerns, and \u0026quot;-\u0026quot; = high risk.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eStudy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eRandomisation process\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eDeviations from intended interventions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eMissing outcome data\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eMeasurements of the outcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eSelection of the reported result\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003eOverall\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eAndrade et al. (2016) \u003csup\u003e[52]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e_\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e?\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e?\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eSlysz and burr (2018) \u003csup\u003e[51]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 133px;\"\u003e\n \u003cp\u003eSlysz et al., (2021) \u003csup\u003e[50]\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133px;\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7173103/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7173103/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTraditional resistance training is often prescribed to stimulate skeletal muscle hypertrophy in adults, however voluntary mechanical movement is not possible for all individuals.\u003cstrong\u003e \u003c/strong\u003eThe combination of blood flow restriction and neuromuscular electrical stimulation (C-BFR-NMES) has recently been shown to be a passive intervention to promote skeletal muscle hypertrophy in adults. However, due to various protocols being used in the literature, varying amounts of skeletal muscle hypertrophy have been reported.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eThe aim of this systematic review and meta-analysis was to quantitatively investigate the effectiveness of C-BFR-NMES compared to BFR or NMES alone, or no intervention to induce skeletal muscle mass in adults. The secondary aims were to compare muscle hypertrophy outcomes when different measurement devices are used following C-BFR-NMES, and to investigate the C-BFR-NMES protocols used to induce skeletal muscle hypertrophy in adults.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eA PRISMA-compliant systematic review and meta-analysis was conducted. PubMed, MEDLINE, Web of Science, Scopus and CINAHL were searched from inception to 28\u003csup\u003e \u003c/sup\u003eFebruary 2025 using the following inclusion criteria: (1) untrained healthy adults (between the age of 18 – 64 years), (2) study design allowed comparison between C-BFR-NMES and CONTROL (BFR or NMES alone, or no intervention), (3) lower limb skeletal muscle hypertrophy was assessed pre/post intervention, (4) interventions included study periods ≥14 days , and (5) manuscripts written in English. A random-effects meta-analysis was performed and reported in standardised mean differences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 615 articles were screened, three studies with a total population of N = 37 were included, and seven meta-analyses were conducted. C-BFR-NMES induced significantly greater muscle hypertrophy compared to CONTROL (Z = 2.66, \u003cem\u003ep\u003c/em\u003e = 0.008), with a medium pooled effect size (ES) of 0.61 (95% CI 0.11 to 1.6) in favour of C-BFR-NMES.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eA pooled analysis of current data suggests the C-BFR-NMES promotes a medium effect on skeletal muscle hypertrophy in lower body musculature compared to BFR or NMES alone, or no exercise in healthy adults. Further research is needed to determine the effectiveness of C-BFR-NMES in upper body musculature, as well as different cohorts such as adolescent and older populations.\u003c/p\u003e","manuscriptTitle":"Effects of combined blood flow restriction and neuromuscular electrical stimulation on skeletal muscle hypertrophy in adults: a systematic review and meta analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-20 06:54:17","doi":"10.21203/rs.3.rs-7173103/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-06T11:47:35+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"64000974728943351716214419631337258126","date":"2025-10-06T08:48:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-04T21:26:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"163240428900479945171519535316563112927","date":"2025-10-03T15:28:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"33761487699104637882964931023554607826","date":"2025-10-03T15:10:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-27T12:47:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"264770320985878726436360440610228649013","date":"2025-08-12T13:55:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-12T13:41:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-12T13:38:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-29T12:04:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-26T07:13:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-07-26T07:09:55+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e85deab-b985-4d94-870b-686ac12fa9fb","owner":[],"postedDate":"August 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":53232873,"name":"Health sciences/Health care"},{"id":53232874,"name":"Health sciences/Medical research"},{"id":53232875,"name":"Biological sciences/Physiology"}],"tags":[],"updatedAt":"2026-03-23T16:17:44+00:00","versionOfRecord":{"articleIdentity":"rs-7173103","link":"https://doi.org/10.1038/s41598-026-42672-z","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-03-19 15:58:57","publishedOnDateReadable":"March 19th, 2026"},"versionCreatedAt":"2025-08-20 06:54:17","video":"","vorDoi":"10.1038/s41598-026-42672-z","vorDoiUrl":"https://doi.org/10.1038/s41598-026-42672-z","workflowStages":[]},"version":"v1","identity":"rs-7173103","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7173103","identity":"rs-7173103","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}