Neuromuscular electrical stimulation for thromboprophylaxis: A systematic review.

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Phlebology OnlineFirst, published on January 6, 2015 as doi:10.1177/0268355514567731

Review Article

Neuromuscular electrical stimulation for thromboprophylaxis: A systematic review

Phlebology 0(0) 1–14 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0268355514567731 phl.sagepub.com

S Hajibandeh, S Hajibandeh, GA Antoniou, JRH Scurr and F Torella

Abstract Objective: To evaluate the effect of neuromuscular electrical stimulation on lower limb venous blood flow and its role in thromboprophylaxis. Method: Systematic review of randomised and non-randomised studies evaluating neuromuscular electrical stimulation, and reporting one or more of the following outcomes: incidence of venous thromboembolism, venous blood flow and discomfort profile. Results: Twenty-one articles were identified. Review of these articles showed that neuromuscular electrical stimulation increases venous blood flow and is generally associated with an acceptable tolerability, potentially leading to good patient compliance. Ten comparative studies reported DVT incidence, ranging from 2% to 50% with neuromuscular electrical stimulation and 6% to 47.1% in controls. There were significant differences, among included studies, in terms of patient population, neuromuscular electrical stimulation delivery, diagnosis of venous thromboembolism and blood flow measurements. Conclusion: Neuromuscular electrical stimulation increases venous blood flow and is well tolerated, but current evidence does not support a role for neuromuscular electrical stimulation in thromboprophylaxis. Randomised controlled trials are required to investigate the clinical utility of neuromuscular electrical stimulation in this setting.

Keywords Deep vein thrombosis, pulmonary embolus, venous thromboprophylaxis, neuromuscular electrical stimulation, mechanical prophylaxis

Introduction Deep vein thrombosis (DVT) and pulmonary embolism (PE) are serious but preventable causes of morbidity and mortality.1 The Virchow’s triad of endothelial injury, hypercoagulable state and stasis are the basis for the pathogenesis of venous thromboembolism (VTE).2 Of these factors, endothelial injury is not commonly targeted for the prevention of VTE since venous thrombosis can occur in the absence of any vascular damage,3 e.g. after prolonged immobility. Hypercoagulability is the most commonly addressed factor in the prevention of VTE, reflected by use of anticoagulants. As part of Virchow’s triad, venous stasis plays an important role in thrombus formation;3 therefore, its avoidance is crucial in preventing VTE. Reducing venous stasis can be achieved by applying mechanical methods of prophylaxis, which have been shown to be effective in reducing the risk of DVT and PE.4 Mechanical measures include graduated compression stocking (GCS), intermittent pneumatic compression

devices (IPCD) and neuromuscular electrical stimulation (NMES) systems. GCS and IPCD are the most commonly used methods of mechanical thromboprophylaxis and are effective for DVT prevention.5,6 The use of GCS has been shown to be associated with a reduction in the crosssectional area of the limb7 and increased venous blood flow velocity.8 IPCD increase venous flow velocity, venous volume flow and pulsatility index.9 However, despite their effectiveness and common use, GCS and IPCD have some disadvantages, being associated with poor patient compliance due to discomfort, excessive Liverpool Vascular and Endovascular Service, Royal Liverpool University Hospital, Liverpool, UK Corresponding author: Shahab Hajibandeh, 8C Link, Liverpool Vascular and Endovascular Service, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK. Email: [email protected]

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heat, itchiness, sweating under the inflatable cuffs and the potential for peroneal nerve palsy.10–14 Electrical stimulation of the lower limb muscles and/ or nerves increases blood flow.11,15–17 NMES refers to the application of pulses of electrical current, delivered through surface electrodes, to trigger generation of a neural action-potential-train to induce an artificial muscle contraction.18 NMES for the prevention of VTE may be beneficial for patients in whom pharmacological or standard mechanical prophylaxis methods are contraindicated or regarded as unsafe or impractical. Furthermore, its use may enhance the effectiveness of other preventive measures.19 Despite theoretical advantages, its clinical utility remains unproven. We therefore conducted a systematic review of the published evidence on the effect of NMES on venous stasis and their effectiveness in the prevention of VTE.

Methods This systematic review was performed according to an agreed predefined protocol. The protocol was not registered at the International Prospective Register of Systematic Reviews. We reported this systematic review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards.20

Eligibility criteria We included all experimental, observational and randomised controlled studies on patients or healthy volunteers undergoing any form of NMES for the purpose of increasing venous blood flow of the lower limb and/or VTE prevention.

Outcomes measures The following outcomes were specifically sought and recorded: venous volume flow; (peak) venous velocity; venous cross-sectional area; incidence of DVT (diagnosed by duplex ultrasongraphy, venography, fibrinogen uptake test, phlebography or clinically) and PE; patient compliance and subjective discomfort, including measurements by visual analogue scale scores (VAS) and verbal rating scores (VRS); length of hospital stay; and device-related adverse events.

Search strategy The National Library of Medicine’s Medline database using a web-based search engine (PubMed) from 1966 to the present date (July 2014) and EMBASE for Excerpta Medica Database from 1980 to present date

were used to identify relevant literature. Medical Subject Headings (MeSH) and key terms were combined using Boolean operators to retrieve relevant reports. The keywords ‘electrical nerve stimulation’, ‘neuromuscular stimulation’, ‘electrostimulation’, ‘nmes’, ‘neuromuscular electrical stimulation’ and ‘neuromuscular electrostimulation’ were combined by the Boolean operator OR (search A). Furthermore, the keywords ‘venous thromboembolism’, ‘thromboembolism’, ‘venous stasis’, ‘deep venous thrombosis’, ‘thromboprophylaxis’, ‘chronic venous disease’, ‘venous hemodynamics’, ‘thrombosis’, ‘thromboembolism’, ‘blood velocity’, ‘venous transit time’, ‘pulmonary embolism’ and ‘vte’ were combined by the Boolean operator OR (search B). The resulted literatures from search A and B were combined by the Boolean operator AND in order to narrow the results. Moreover, in order to reduce the possibility of missing relevant articles, the reference lists of selected articles were reviewed. Moreover, Cochrane library and abstracts from vascular society meetings (The Vascular Society of Great Britain and Ireland, The Society for Vascular Surgery and the European Society for Vascular Surgery) were assessed in order to find relevant articles. Abstracts from general surgery meetings were not assessed to identify relevant literature.

Study selection The title, abstract and introduction sections of related articles were assessed independently by two reviewers (Shahab H and Shahin H). The full texts of relevant reports were retrieved and those articles that met the inclusion criteria of the study were selected. Full texts of all relevant reports were available and no studies were excluded due to inaccessible full text. Any discrepancies in study selection were resolved by discussion between the reviewers. If necessary, an independent third (FT) reviewer was consulted.

Data extraction Data from included articles were extracted and recorded on data extraction sheets by two reviewers independently (Shahab H and Shahin H). The extracted information included: publication year, sample size, study design, patient characteristics, type of patients, type of intervention and outcomes. Disagreements were resolved by discussion between the two reviewers. If no agreement could be reached, a third reviewer (FT) made the final decision.

Methodological quality assessment The Scottish Intercollegiate Guidelines Network (SIGN) notes on methodology21 and the



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Newcastle-Ottawa Quality Assessment Scale (NOAS)22 were used for methodological quality assessment of randomised and observational studies, respectively. We did not assess the methodological quality of experimental studies. The SIGN methodology checklist consists of two sections and classifies each study as high quality, acceptable or low quality. The NOAS consists of three sections (selection, comparability and outcome) and each study can be awarded maximum score of 4 for selection, 2 for comparability and 3 for outcome. Methodological quality of the included studies was assessed independently by two reviewers (Shahab H and Shahin H). Disagreements were resolved by discussion between the two reviewers. If no agreement could be reached, a third reviewer (FT) made the final decision.

Results Searches of electronic information sources identified 431 and 171 articles in PubMed and EMBASE, respectively, of which 14 were found to be eligible for this review. Another seven studies were found by checking the

reference lists of the selected articles. In total, 21 studies were included in this review for presentation and analysis (Figure 1). These comprised 10 prospective randomised trials,23–32 two prospective observational studies33,34 and nine single-arm experimental studies.35–43 Of the 10 randomised controlled trials, two trials randomised patients’ legs instead of patients as unit of analysis.31,32 Of the selected studies, nine23,25,35,37–41,43 included healthy volunteers as the population of interest, nine24,26,28,30–34,36 included patients undergoing surgical procedures, one study included trauma patients,27 one study included patients with spinal cord injury29 and one study included patients with chronic venous disorders42 (Table 1). NMES was delivered by several devices and settings, as reported in Table 2. Three studies23,25,39 compared NMES with IPCD. Five24,26,33,34,36 studies compared intraoperative NMES with no intraoperative prophylaxis. Two studies27,28 compared NMES with ‘standard prophylaxis’. Two studies29,30 compared NMES with low-dose heparin. NMES was compared with leg elevation in one study.31 Eight studies32,35,37,38,40–43 compared NMES with baseline measurements without NMES.

Figure 1. Literature search strategy.


United Kingdom

Ireland

India

Ireland

United Kingdom

Warwick et al.35

Broderick et al.36

Goyal et al.26

Breen et al.37

Tucker et al.38

Japan

United Kingdom

Country

United Kingdom

23


Healthy volunteers

Patients who had surgeries around the hip joint Healthy volunteers

Patients who had undergone THA

Healthy volunteers

Healthy volunteers

Patients having TKA under general anaesthesia

Healthy volunteers

Population

Single-arm experimental Single-arm experimental

RCT

Single-arm experimental

Prospective randomised trial Single-arm experimental

RCT

RCT

Design

Organ dysfunction, age < 18 or > 65 years, Haematological disorders, previous DVT/PE, peripheral arterial disease

Not reported

DVT, antithrombotic medication, sustained open fractures and pacemakers

Previous leg fracture, use of any medications in the past 30 days, history or signs of haematological disorders or peripheral arterial disease, family history of DVT, clinically significant varicose veins or ulceration of the lower limb, or venous dysfunction on Doppler screening History of diabetes and peripheral vascular disease

History of heart disease or respiratory disorder, current pregnancy, history of peripheral vascular disease, varicose vein surgery or thromboembolic event, cardiac pacemaker, history of leg fractures or metal implants in the leg and long distance travel within one week prior to the study History of DVT, preoperatively detected DVT, preoperative anticoagulant or antiplatelet therapy, congenital or noncongenital hypercoagulation disorders, drug therapy for unstable angina or congestive heart failure and cardiac pacemaker Not reported

Exclusion

No

No

(continued)

Postoperative oral anticoagulant rivaroxaban in both groups No

No

No

Fondaparinux (1.5 mg) or enoxaparine (2000 IU) 24 h after surgery in both groups

No

Anticoagulation

4

30

10

200

11

10

10

90

10

Sample size

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Jawad et al.25

Izumi et al.24

Williams et al.

Study

Table 1. Characteristics of the included studies.

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Japan

Ireland

United Kingdom

Ireland

USA

Ireland

Broderick et al.40

Griffin et al.41

Moloney et al.42

Velmahos et al.27

Lyons et al.43

Country

Izumi et al.39

Study

Table 1. Continued


10

60

10

Healthy volunteers

Chronic venous disorders Trauma patients with contraindications for receiving prophylactic heparin

Healthy volunteers

Healthy volunteers

Healthy volunteers

Population


Single-arm experimental RCT


Single-arm experimental Single-arm experimental

Design

Not reported

Aged < 18 years, known allergy to contrast material, cardiac pacemakers or other implants containing metal parts within the area of treatment, spastic paralysis, local infection at the site of application and history of, or an existing, DVT

(continued)

Subcutaneous unfractionated or lowmolecular-weight heparin in both groups (when the contraindication for its use was no longer present) No

No

No

No

No

(ankle-brachial pressure index < 0.9), varicose veins or lower limb ulceration, musculoskeletal disorders, recent surgery and recent trauma to lower limb and history of gastrointestinal, hepatic, renal, cardiovascular, endocrine, neurological, dermatological, rheumatological, metabolic psychiatric, haematological, or systemic disease judged to be significant Not reported History of heart or respiratory problems, pregnancy, current use of oral contraceptive pill, current smoker, a history of peripheral vascular disease or previous thromboembolic event, history of leg fractures, presence of metal implants in the leg and long distance travel within one week prior to study Superficial or deep venous disease, previous varicose vein surgery, congestive heart failure, patients with pacemaker, lower limb arterial disease (ABPI < 0.9) or active clinically suspected infection Not reported

Anticoagulation

Exclusion

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24

10

10

Sample size


Hajibandeh et al. 5

United Kingdom

United Kingdom

United Kingdom

United Kingdom

Nicolaides et al.33

Browse and Negus34

Doran et al.31

Doran and White32


200

200

110

116

112

104

48

Sample size

Undergoing a variety of operations Undergoing surgical operations of moderate or major severity Patients undergoing any extensive operation Patients undergoing any extensive operation

Neurosurgical patients who had operation under general anaesthesia Patients undergoing major abdominal surgery

Complete and incomplete-preserved motor, non-functional spinal cord injury

Population

Prospective randomised trial


Prospective observational


RCT

RCT

RCT

Design

Not reported

Operations on the legs, aorta-iliac arterial surgery or any operation in which the iliac veins or vena cava were exposed, as well as pre-menopausal women Not reported

Surgery on the legs or thyroid and those who required the lithotomy position

Not reported

Not reported

Not reported

Exclusion

No

No

No

500 ml dextran 40 during surgery for non-stimulation group. No anticoagulation for stimulation group No

Perioperative and postoperative lowdose heparin (5000 unit) for control group and postoperative Dextran infusion for stimulation group No

Anticoagulation

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RCT: randomised controlled trial; TKA: total knee arthroplasty; THA: total hip arthroplasty; DVT: deep vein thrombosis; PE: pulmonary embolism; ABPI: Ankle brachial pressure index

Sweden

Lindstro¨m et al.28

USA

Country

Sweden

29

Bostrom et al.30

Merli et al.

Study

Table 1. Continued


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Table 2. Neuromuscular electrical stimulation in individual studies.

23

Williams et al. Izumi et al.24 Jawad et al.25 Warwick et al.35 Broderick et al.36 Goyal et al.26 Breen et al.37 Tucker et al.38 Izumi et al.39 Broderick et al.40 Griffin et al.41 Moloney et al.42 Velmahos et al.27 Lyons et al.43 Merli et al.29 Bostrom et al.30 Lindstro¨m et al.28 Nicolaides et al.33 Browse and Negus34 Doran et al.31 Doran and White32

Device

Frequency (Hz)

Pulse width

Charge (mA)

Voltage (V)

Geko T-1 SEN-52901 Geko T-1 Geko T-1 Duo-STIM VEINOPLUS NT2000 NR SEN-5201 Duo-STIM VEINOPLUS NT2000 Lymphavision NT2000 NR NR NR Thrombophylactor Type V MkIII or Medelec TS2 NR NR

1 10 1 1 36 NR 35 1–5 10 or 50 36 0.03–2 35 1.75 25–35 10 8 8 0.2–0.25 NR 0.5 NR

70–560 ms NR 70–560 ms 0–400 ms 350 ms NR 350 ms 200 ms 0.5 ms 350 ms NR 300 ms 3 ms 200–300 ms 50 ms 50 ms 50 ms 50 ms 30 ms NR NR

27 NR 27 27 NR NR 220 1–40 NR NR NR NR NR NR NR 40–50 40–50 NR NR NR NR

NR 100 NR NR NR 15–25 85 NR 100 NR NR NR 0–120 NR NR NR NR NR 15–45 120 NR

NR: not reported

Methodological quality Based on SIGN checklist, all studies included in the systematic review were deemed of ‘acceptable’ methodological quality (Table 3). On the NOAS for observational studies, both Nicolaides et al.33 and Browse and Negus34 were awarded 4 points for selection, 1 point for comparability and 3 points for outcome.

Outcomes Deep vein thrombosis. Eight randomised studies24,26–32 and the two prospective observational studies33,34 included DVT as an outcome measure (Table 4). Izumi et al.24 reported a significant difference in the incidence of DVT on the first postoperative day after total knee arthroplasty (TKA) between electrical stimulation and control groups [11% (95% CI ¼ 4.2 2.5) vs. 31% (95% CI ¼ 18.6 46.8)]. In this study, bilateral duplex ultrasonography of the calf and thigh was used to detect DVT. The criteria for the diagnosis of DVT were the presence of intraluminal thrombotic echogenicity and absence of venous compressibility. Goyal et al.26 did not find any significant difference in the incidence of DVT between electrical stimulation and the control groups on the seventh postoperative

day in patients who had hip surgery [2% (95% CI ¼ 0.4 7.7) vs. 6% (95% CI ¼ 2.5 13.1)]. All patients were examined daily for clinical signs of DVT and duplex ultrasonography was performed on the seventh postoperative day routinely. Visualization of thrombosis, absence of flow, and lack of compressibility or augmentation were the criteria for diagnosing DVT in this study. There was no difference in the incidence of DVT between the electrical stimulation and control groups in the trial by Velmahos et al.27 [27% (95% CI ¼ 12.4 48.1) vs. 29% (95% CI ¼ 12.2 52.3)]. Bilateral contrast venography was performed routinely between days 7 and 15 of the study and at any time if clinical features or duplex ultrasonography was suggestive of DVT. The venographic criteria for diagnosing DVT were contrast outlining a filling defect, occluded venous segment associated with a convex filling defect or occluded venous segment with acute thrombus in adjacent vein. Lindstro¨m et al.28 showed that the incidence of DVT was not significantly different between NMES and controls among patients undergoing major abdominal surgery [14% (95% CI ¼ 5.1 29.6) vs. 30% (95% CI ¼ 17.1 46.7)]. However, the incidence of DVT in patients with malignant disease was significantly lower


The study addresses an appropriate and clearly focused question The assignment of subjects to treatment groups is randomised An adequate concealment method is used Subjects and investigators are kept ‘blind’ about treatment allocation The treatment and control groups are similar at the start of the trial The only difference between groups is the treatment under investigation All relevant outcomes are measured in a standard, valid and reliable way What percentage of the individuals or clusters recruited into each treatment arm of the study dropped out before the study was completed? All the subjects are analysed in the groups to which they were randomly allocated (often referred to as intention to treat analysis) Where the study is carried out at more than one site, results are comparable for all sites How well was the study done to minimise bias? Code as follows Yes

Yes

Yes

0%

Yes

NA

þ

Yes

Yes

0%

Yes

NA

þ

Yes

Yes

Yes

Yes

Yes

No

Yes

Yes

No

Izumi et al.24

Williams et al.23


þ

NA

Yes

0%

Yes

þ

NA

Yes

Case: 13% Control: 30%

Yes

Yes

Yes

No

Yes

Yes

Yes

Velmahos et al.27

þ

NA

Yes

0%

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Merli et al.29

þ

NA

Yes

Case: 12% Control: 16%

Yes

Yes

Yes

No

No

Yes

Yes

Bostrom et al.30

þ

NA

Yes

0%

Yes

Yes

Yes

No

No

Yes

Yes


þ

NA

Yes

0%

Yes

Yes

Yes

Yes

No

Yes

Yes

Doran et al.31

þ

(continued)

NA

Yes

0%

Yes

Yes

Yes

Yes

No

Yes

Yes

Doran and White32

8

þ

NA

Yes

0%

Yes

Yes

Yes

No

No

Yes

Yes

Goyal et al.26

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Yes

Yes

No

No

Yes

Yes

Jawad et al.25

Table 3. Methodological assessments of randomised studies based on Scottish Intercollegiate Guidelines Network (SIGN) checklist.


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Izumi et al.24 Yes

Yes

Williams et al.23 Yes

Yes


11% (4.2 24.9) 31% (18.6 46.8)

Incidence of DVT

2% (0.4 7.7) 6% (2.5 13.1)

200

RCT

Goyal et al.26

27% (12.4 48.1) 29% (12.2 52.3)

60

RCT

Velmahos et al.27

7% (0.4 33.9) 47% (23.9 71.5)

48

RCT

Merli et al.29

Yes

Yes

Goyal et al.26

13% (4.7 27.6) 10% (3.8 23.0)

104

RCT

Bostrom et al.30

Yes

Yes

Yes

Yes

Yes

Yes

Bostrom et al.30

1.7% (0.1 10.1) 23% (13.4 36.7)

116


Nicolaides et al.33

Merli et al.29

14% (5.1 29.6) 30% (17.1 46.7)

112

RCT


Velmahos et al.27

DVT: deep vein thrombosis; NMES: neuromascular electrical stimulation; RCT: randomised controlled trial; CI: confidence interval

90

Sample size

NMES (95% CI) Non-NMES (95% CI)

RCT

Design

Izumi et al.23

Yes

Yes

Jawad et al.25

8% (4.1 15.4) 21% (14.0 30.0)

110


Browse and Negus34

Yes

Yes


4% (1.5 7.4) 6% (3.3 10.5)

200


Doran et al.31

Yes

Yes

Doran et al.31

3% (0.9 6.1) 10% (6.4 15.2)

200


Doran and White32

Yes

Yes

Doran and White32

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Table 4. Incidence of DVT reported by the included studies.

NA: not applicable; þ: acceptable; þþ: high quality

Taking into account clinical considerations, your evaluations of the methodology used, and the statistical power of the study, are you certain that the overall effect is due to the study intervention? Are the results of this study directly applicable to the patient group targeted by this guideline?

Table 3. Continued


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in the treatment group [15% (95% CI ¼ 2.7 46.3) vs. 54% (95% CI ¼ 26.1 79.6)]. In this study, a fibrinogen uptake test was used to screen for DVT and, if thrombosis was suspected on the basis of this test, venography was performed whenever possible. Merli et al.29 found a significant reduction in the incidence of DVT in low-dose heparin plus electrical stimulation group [7% (95% CI ¼ 0.4 33.9)] compared to either low-dose heparin (50%) or placebo groups [47% (95% CI ¼ 23.9 71.5%)]. In this study, 125-I fibrinogen scan and impedance plethysmography followed by confirmatory venography were used for diagnosing DVT. Bostrom et al.30 reported no significant difference in the incidence of DVT between the low-dose heparin group and the perioperative electrical stimulation plus postoperative Dextran group [10% (95% CI ¼ 3.8 23.0) vs. 13% (95% CI ¼ 4.7 27.6), respectively]. The 125-I fibrinogen uptake test was used for screening and phlebography was used for verification of DVT. Doran et al.31 found no significant difference in the incidence of DVT between elevated and stimulated legs [6% (95%CI ¼ 3.3 10.5) vs. 4% (95% CI ¼ 1.5 7.4)]. In this study, positive clinical signs of DVT such as persistent deep-calf tenderness and massive oedema were used for diagnosing DVT. Doran et al.32 concluded that the risk of postoperative DVT in the lower limbs is reduced by stimulating the calf muscles electrically during the operation [3% (95% CI ¼ 0.9 6.1) in stimulated legs vs. 10% (95% CI ¼ 6.4 15.2) in unstimulated legs]. Nicolaides et al.33 reported a significantly decreased incidence of DVT with NMES compared to patients not receiving any thromboprophylaxis [1.7% (95%CI ¼ 0.1 10.1) vs. 23% (95% CI ¼ 13.4 36.7)]. In this study, the diagnosis of DVT was made based on isotope scanning before and immediately after surgery, and on the first and on alternate days thereafter up to the 10th postoperative day. DVT was diagnosed if there was a difference of 20% or more of the radioactivity at the same position on two different days or between adjacent positions on the same day if it persisted for more than 24 h. Browse and Negus34 also reported a decreased incidence of DVT in stimulated legs compared to unstimulated legs [8% (95% CI ¼ 4.1 15.4) vs. 21% (95% CI ¼ 14.0 30.0)]. In this study, after surgery, I-fibrinogen was injected intravenously and scintillation counting at 10 cm intervals over the main deep veins of the leg was performed on the first, third and fifth postoperative days. An absolute difference in count rate of more than 15% between adjacent points, or the same point on the other leg, which persisted or increased for more than 24 h was the indication for the presence of underlying venous thrombosis in this study.

Pulmonary embolism. This outcome was only reported by one randomised trial,28 which showed a statistically significant difference in the incidence of PE, diagnosed by pulmonary scintigraphy, between the NMES and control groups in favour of the former [16% (95%CI ¼ 6.8 32.7) vs. 35% (95%CI ¼ 21.1 51.7)]. Venous velocity. Peak venous velocity was reported by three randomised trials23,25,27 and all of the single-arm experimental studies35–43 Williams et al.23 reported 103% and 101% increase in peak venous velocity and time-averaged maximum velocity, respectively, in electrical stimulation group which was significantly greater than those achieved in IPC group (51% and 5%, respectively). In this study, duplex ultrasound was used for evaluation of venous blood flow and velocity at left superficial femoral vein. Jawad et al.25 reported 174% and 73% increase in mean venous velocity after NMES at normal clinical setting and at threshold setting, respectively. In this study, colour-flow duplex ultrasound was performed at baseline and after the completion of each program to measure the venous velocity at superficial femoral vein. In contrast, Velmahos et al.27 did not find a significant difference in mean venous velocity between NMES and control groups. In this study, venous velocity was measured on the first day of the study immediately before application of NMES and 20 minutes after its use by duplex scan at three sites (popliteal vein, superficial femoral vein and common femoral vein). In Warwick et al.,35 peak venous velocity was higher in all postural positions when the NMES device was active, both with a plaster cast (mean increase of 97%) and without a plaster cast (mean increase of 63%). In this study, venous blood velocity of the superficial femoral vein during electrical stimulation was measured by duplex ultrasound. In Broderick et al.,36 NMES increased the peak venous velocity in operated and non-operated limbs by 99% and 288%, respectively. Also, it increased the mean venous velocity in operated and non-operated legs by 178% and 354%, respectively. In this study, duplex ultrasound was used to measure venous velocity in the popliteal vein. Breen et al.37 demonstrated that combined stimulation of gastrocnemius and tibialis anterior or soleus and tibialis anterior muscles is as effective as voluntary contraction and results in a statistically significant increase in peak venous velocity compared to the static state (600% and 567%). The popliteal vein was examined by duplex ultrasound. Tucker et al.38 showed that electrical stimulation using 1–40 mA current and 1–5 Hz frequency increased mean peak venous velocity by 50%–260% from baseline.



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Izumi et al.39 reported a 273% improvement in peak venous velocity from baseline. The peak venous velocity was measured using pulsed-wave duplex ultrasonography. In Broderick et al.,40 the stimulation group experienced a 650% increase in peak venous velocity, measured by duplex ultrasound, relative to controls. Griffin et al.41 also reported a 900% increase in peak venous velocity in the stimulation group. Moloney et al.42 reported that electrical stimulation alone or combined with four layer compression bandaging increased median venous velocity, measured by Doppler ultrasound, by 78% and 105% when compared to the stationary state and stationary state plus compression bandaging, respectively. Consistent with this, Lyons et al.43 reported a 266% and 502% increase in peak venous velocity with electrical stimulation alone and electrical stimulation plus compression, respectively. Venous volume flow. This outcome was reported by six studies, all of which used duplex ultrasonography for measuring venous volume flow. Williams et al.23 reported 101% increase in venous volume flow in the stimulation group compared to 3% increase in the IPC group. Jawad et al.25 demonstrated 32% and 4.5% increase in mean venous volume flow at normal clinical setting and at threshold setting, respectively. In Broderick et al.,36 NMES resulted in 159% increase in venous volume flow in the operated limb and 614% increase in non-operated limb. All methods of calf-muscle stimulation in Izumi et al.39 resulted in >2.5 times increase in flow compared with baseline. Consistent with this, a statistically significant increase in venous volume flow compared with baseline was reported by Tucker et al.38 A 301% increase in volume flow was achieved with NMES by Broderick et al.40 Vessel diameter and cross-sectional area. No difference in venous cross-section was found by two studies reporting this outcome.27,35 Tolerability VAS and VRS were used for assessment of patients’ discomfort. In Jawad et al.,25 each device was active for a period of 30 min followed by a 10-min recovery phase and NMES was rated as mild discomfort on VRS. In Warwick et al.,35 the geko device was active for 5 min in each position and the median VAS score and VRS across all positions were 2.5 and 2, respectively. Consistent with these, Broderick et al.36 reported that the mean VAS score at start and end of 4 h electrical stimulation were 2.3 and 3.6, respectively. In Broderick et al.,40 the mean VAS score after 2 h and 4 h of stimulation were 2.7 and 2.8, respectively. Also, Moloney et al.42 reported mean VAS scores of 2.4 after

10 min application of electrical stimulation device. All the reported VAS and VRS scores in the above studies were equivalent to mild pain or discomfort. None of the included studies reported any case in which the leg could not be stimulated.

Discussion Prevention of venous stasis by mechanical measures is a mainstay of VTE prophylaxis. We aimed to review the studies investigating NMES as a method of mechanical thromboprophylaxis. Our systematic search identified a very heterogeneous group of studies, and, in particular, only 10 prospective randomised trials on a mixture of patient populations and settings (surgical, trauma, chronic venous disease and neurological). Investigators used a wide variety of devices and settings to deliver NMES; furthermore, the duration and frequency of the stimulation was highly variable. Those studies that reported clinical outcomes used different methods to diagnose VTE, some not always practical or appropriate by modern standards. None of the comparative studies recruited more than 200 patients, and two of these randomised legs instead of patients. Many of the patients receiving treatment in the control groups were managed by methods (i.e. no thromboprophylaxis) that are considered unacceptable in modern medical practice. Despite the heterogeneicity of the studies included in this review, some conclusions can be drawn: venous velocity was the most commonly reported outcome in this review and results suggest that NMES increases venous velocity (and blood flow) in stimulated legs, thus reducing venous stasis. As this is one of the three components of Virchow’s triad, it may be logical to assume that this effect may prove beneficial in VTE prevention. However, velocity is not a surrogate for increased flow. In fact, although intermittent calf contraction can increase velocity briefly, it may not necessarily result in any overall flow increase. Moreover, the use of venous velocity as a surrogate outcome for VTE incidence is controversial since there is no direct evidence that high peak venous velocity results in a lower incidence of DVT.44 Furthermore, it has been argued that very high peak velocity inducing devices might actually increase the risk of DVT.45 These considerations indicate the need for caution in accepting venous velocity and flow as surrogate outcome measures for VTE. Another finding of this review was that modern NMES devices appear to be associated with mild pain and discomfort, as evidenced by acceptable VAS and VRS scores in those studies reporting this outcome.23,25,38,40 In 1970s and 1980s, the devices that were used for calf muscle electrical stimulation



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produced painful stimuli so that they could be used only during general anaesthesia.46 The better tolerability associated with modern devices, as shown in our review, allows them to be used not only during surgery but also during the postoperative period. Due to lack of comparative data, it is unclear, however, whether NMES would result in better compliance in comparison with other methods of mechanical thromboprophylaxis. We could not draw a definite conclusion regarding the efficacy of NMES in thromboprophylaxis because the clinical studies included in this review give conflicting evidence on its effect on the incidence of VTE, with five of them demonstrating no reduction.26–28,30,31 Considering the aforementioned limitations of these studies (different populations, different NMES delivery, different control group treatments, variable VTE diagnostic methods and small sample sizes), it would be unhelpful, and potentially misleading, to attempt a meta-analysis of their results. Two prospective observational studies33,34 reported reduction in the incidence of DVT, but these were not randomised and thus subject to selection bias. More importantly, their NMES devices would no longer be acceptable for use in contemporary practice, and management of the control groups (no thromboprophylaxis), would no longer be acceptable. On this basis, they should be considered of historical interest only. Despite the lack of conclusive evidence in support of NMES for thromboprophylaxis, it is notable that, in England, the National Institute for Health and Care Excellence (NICE) supports the use of the geko device in this setting, for those who are at high risk of VTE and are unable to receive any other mechanical or pharmacological method of prophylaxis.47

Conclusions and future directions Electrical stimulation devices have been experimentally proved to be effective in increasing venous blood velocity and flow. Also, they are now associated with acceptable tolerability that can potentially lead to good patient compliance. NMES thus can reduce venous stasis with, potentially, good acceptance by patients. NMES should be therefore seen as a promising technique for thromboprophylaxis that deserves further investigation. High-quality randomised control trials are required to investigate NMES (delivered by modern tolerable devices) as a reliable method of VTE prophylaxis. The role of this method of mechanical thromboprophylaxis in specific populations, such as patients in whom pharmacological or standard mechanical prophylaxis methods are contraindicated or regarded as unsafe or impractical, also needs to be defined.

The additional effectiveness of NMES combined with other methods of thromboprophylaxis is an area for further research. Finally, if NMES is proven capable of preventing VTE in one or more populations, a robust cost-effectiveness analysis would be necessary prior to recommending its widespread use. Author contributions Shahab Hajibandeh and Shahin Hajibandeh have equally contributed to this paper and joined first authorship is proposed.

Conflict of interest None declared.

Ethical approval Not required.

Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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