Williams KJ1, Ravikumar R1, Gaweesh AS2, Moore HM1, Lifsitz AD3, Lane TRA1, Shalhoub J1

A Review of the Evidence to Support Neuromuscular Electrical Stimulation in the Prevention and Management of Venous Disease

Williams KJ1, Ravikumar R1, Gaweesh AS2, Moore HM1, Lifsitz AD3, Lane TRA1, Shalhoub J1, Babber A1, Davies AH1.

1 Academic Section of Vascular Surgery, Department of Surgery & Cancer, Imperial College London, UK

2 Department of Vascular Surgery, Faculty of Medicine, University of Alexandria, Egypt

3 Hospital Italiano, Servicio de Cirugía General, Sector Flebolinfología, Buenos Aires, Argentina

Table 1. Introduction Venous disease is common in the general population. Dysfunction of the venous system in the form of obstruction, incompetence or failure of the muscle pump leads to venous hypertension. Chronic venous hypertension manifests as a wide spectrum of venous disorders in the lower extremities, such as varicose veins, oedema, skin changes and ulceration. Up to 20% of the general population suffer from uncomplicated varicose veins, 1.1-14.9% complain of oedema, and up to 5% have skin changes or ulceration1.

Deep venous disease is less prevalent than its superficial counterpart, however morbidity and mortality from deep venous thrombosis (DVT), venous thromboembolism (VTE), and post thrombotic syndrome (PTS) are significant 2. DVT is recognised as an increasingly important and frequent cause of venous disease, has an incidence of 0.2% in the general population, and up to 25% in the hospital population 3. Factors affecting venous flow (e.g. immobility, dehydration, sepsis) predispose to venous thromboembolism, and are commonly seen after long haul flights and hospital inpatient episodes4. Reversal of these risk factors is thought to be protective against venous thromboembolism, and underlies government anti-VTE initiatives in hospitals. Despite this, 1000 people in the UK are diagnosed with DVT every week, and roughly 50% of these will go on to develop pulmonary embolism, a potentially life-threatening condition 5,6. In 2007 nearly 17000 recorded deaths in England and Wales recorded DVT or PE as either the primary cause of death or a contributory factor7.

The muscular pumps of the lower limb (foot, calf and thigh) consist of deep venous plexuses surrounded by muscle groups in tight ensheathing fascia, and are credited with providing approximately 90% of venous return during ambulation 8. The calf muscle pump, first described by William Harvey in 1628, has an ejection fraction of approximately 65% in healthy individuals9,10. In a normal individual, resting standing venous pressure is 80-90mmHg, which drops by more than 50% with calf exercise11. This pumping effect is blunted in patients with venous reflux 11. An effective calf muscle pump in the presence of valvular dysfunction or obstruction plays a compensatory role, and may offset symptoms in chronic venous disease12. Therefore it is not surprising that stimulation of the calf muscle pump has been the target for a number of potential clinical applications in the prevention and management of venous disease. The calf muscle pump can be augmented passively or actively. Applying external pressure to the calf results in passive augmentation of the calf muscle pump. This pressure can be applied continuously (compression stockings) or intermittently (intermittent pneumatic compression – IPC; or calf squeezes). Alternatively, active stimulation can be achieved by voluntary calf muscle exercises.

Neuromuscular Electrical Stimulation (NMES) utilises transcutaneous electrodes to cause muscle contraction either by activating the muscle itself (direct), or the nerve supplying a muscle group (indirect). Electrical stimulation has been used to elicit muscle contraction since the time of Galvani (1791), however has never attained true popularity due to problems associated with electricity supply, peri-operative safety, and portability of equipment13. A wide variety of commercial and medical products are emerging in the market with applications such as strength training, exercise recovery tools, rehabilitation in immobilised patients, and in the management of acute pain (e.g. child birth). The aim of this review is to provide a summary of the available literature on the use of electrical stimulation in the management of venous disease, and its relevance in the modern era.

Table 2. Methods The MEDLINE and Embase databases were searched to identify all articles relating to application of electrical muscle stimulation in treating venous disease on 15th August 2014. The following search string was applied:

(Electric$) AND (“calf” OR “foot” OR “thigh” OR “buttock” OR “gluteal) AND (“vein” OR “venous” OR “oedema” OR “edema”). English language and human subject limitations were applied.

Studies were included if they contained venous haemodynamic or clinical data for the use of electrical muscle stimulation (regardless of device or protocol involved). The full articles of studies that appeared to meet the demands of the inclusion criteria were then independently assessed using the STROBE statement to verify the methodological quality of the studies 14. Studies were excluded if results did not relate to electrical muscle stimulation and venous flow. Wound healing studies where devices did not cause muscle contraction were also excluded.

Table 3. Results The search strategy returned a total of 265 articles. Articles were screened by title, abstracts and full text (RR and KW). Following screening 46 articles met the inclusion criteria and were included in the review. The search strategy is illustrated in the PRISMA diagram in Figure 1. FIGURE 1: PRISMA flow diagram of systematic review evaluating the role of neuromuscular stimulation in venous disease

PHYSICAL PARAMETERS Although comparison between trials is hindered by variations in protocols and outcome measures, some investigators have made comparisons varying parameters of electrical stimulation. All studies showed an improvement in venous haemodynamics with stimulation of the calf muscle pump compared to rest:

 Volume flow calf increased 50-719% from baseline15 (venous occlusion plethysmography), 60-614% (ultrasound)16-20

 Femoral and popliteal peak velocity by 25-650%16-18,20-24 (ultrasound)

 Time averaged maximum velocity (TAMV) increased by 178-35420.

 Ejection volume due to electrical stimulation was 60-100% of that elicited by voluntary contraction25,26 and popliteal venous velocity “strongly correlated” to force of plantar flexion27.

 Calf vascular resistance was significantly reduced after electrical stimulation26, equivalent to post-exercise (voluntary calf contractions to a metronome).

Kaplan et al found that stimulation of the foot and calf are equivocal in their effect on popliteal flow22.

Effect of electrical parameters on venous haemodynamics

Direct stimulation of the muscle Nicolaides et al report that pulse width 50-100ms and frequency 25mHz (15/min) produced maximal venous velocity without discomfort28. Settings above this were untenable. Griffin et al increased the frequency of stimulation between 2-120 stimulations per minute and found that the popliteal vein peak velocity increased for stimulations up to 10mHz, but decreased towards 2Hz29. Ejected calf volume per minute increased from 20ml/min to 120 ml/min with increasing stimulation frequency.

Indirect stimulation Lyons et al found that pulse duration 300μs and frequency of 35Hz applied to nerve produced the greatest increase in popliteal peak venous velocity with a pulse width 200-300μs, and frequency 24- 35Hz21. Tucker et al found that increasing stimulation frequency from 1-5Hz and pulse amplitude from 1-40mA had a positive correlation with increasing venous volume flow peak venous velocity and microcirculatory flux23.

Izumi et al 17 compared two different electrical stimulation frequencies (10Hz vs 50Hz) using the same stimulator and found that the lower frequency produced a higher peak velocity compared to 50Hz stimulation, however the findings seem to be confounded by a mix of direct and indirect stimulation.

Comparison of NMES to other medical devices Four studies compared the effect of electrical stimulation to IPC 30-33. Both indirect stimulation via the common peroneal nerve, and direct stimulation of calf muscles have been shown to be non- inferior to calf and/or foot IPC. On comparing calf IPC to electrical stimulation via the common peroneal nerve, Williams et al 32 demonstrated that whilst peak venous velocity increased significantly with both methods, only NMES had a significant effect on time averaged mean velocity (TAMV) and volume flow. On comparing foot IPC to calf NMES, Laverick et al demonstrated a greater increase mean venous velocity and peak venous velocity with NMES.

Faghri et al demonstrated increased cardiac stroke volume (24%), cardiac output (26%) and a reduced total peripheral resistance (21%) with electrical stimulation when compared to IPC calf/thigh34.

Lyons et al demonstrated that the effect of electrical stimulation is augmented by a factor of 2 with the addition of graduated compression stockings21.

Nicolaides reported an increased incidence of peri-laparotomy DVT with NMES when compared to a combination of graduated compression stockings and calf/thigh IPC (18% vs 4%)35.

EFFICACY OF CLINICAL APPLICATION

Electrical stimulation as a method of thromboprophylaxis Outcome parameters for DVT detection in these studies are heterogenous, and include presence of clinical symptoms, phlebography, I-125 fibrinogen uptake tests and duplex ultrasound.

Between 1967 and 1973, four case series looked at treatment of one leg with direct muscle stimulation, using the contralateral leg as a no-treatment control. An absolute risk reduction (ARR) of 2-12.7% was seen when compared to control leg36-39.

Randomised trials with subjects undergoing open abdominal surgery, used direct muscle stimulation of the calf versus heparin versus no-treatment controls. This showed a DVT ARR 16-26.3%28,40-42 for NMES, and 26-54% for subcutaneous heparin three times daily. There was a 2.1% declared major haemorrhage rate requiring transfusion for those on heparin, whereas there were no adverse events reported with NMES43. One study reported that NMES gave a DVT ARR 39% over no-treatment control when the laparotomy indication was for malignancy41. One paper reports of NMES use in major trauma, where heparin is contraindicated for VTE prophylaxis – DVT incidence was equivocal (27% NMES versus 29% control, n=47)44. Studies in surgical patients comparing heparinised patients with or without NMES have mixed results, some showing no difference in DVT rates45, whilst other show ARR DVT 22.5% and ARR death 5%46. When combined together, NMES and heparin gave an ARR 40.4% when compared to placebo47.

Figures 2-4 summate meta-analysis of NMES under three conditions. NMES versus no treatment favours NMES, with DVT odds ratio 0.4 (p<0.0001). NMES versus heparin results in DVT odds ratio 1.84 (p=0.03), whilst NMES and heparin versus heparin alone give an odds ratio 0.07 (p<0.001).

FIGURE 2 – Meta-analysis of trials evaluating deep venous thrombosis risk: NMES versus no- treatment control

FIGURE 3 – Meta-analysis of trials evaluating deep venous thrombosis risk: NMES versus heparin

FIGURE 4 – Meta-analysis of deep venous thrombosis risk: dual therapy with NMES and heparin versus heparin alone

Effect of electrical stimulation on leg oedema/chronic venous disease Five studies examined the effect of NMES on oedema, four of which were on healthy individuals18,48- 50 and one study involved patients with evening oedema 51. Healthy volunteers showed significant increase in foot and ankle volume when standing still over 30 minutes, which was abolished with NMES use48. Both leg volume measurements and air plethysmography, in the seated position, demonstrated reversal of fluid pooling in the legs with electrical stimulation of the calf49,50. Broderick tested leg swelling in supine subjects, and unsurprisingly showed no leg swelling over 4 hours bed rest, and no additional effect with NMES18.

In trials on patients with venous disease, 20 minutes of treatment over a 30 day period resolved evening oedema in 59.4% of cases, reduced it in 34.4%, and remained unchanged in 6.2% of cases51. This resulted in a significant reduction in group average supramalleolar circumference, reduced pain score and improved quality of life.

The effect of electrical stimulation in patients with impaired calf muscle pump Patients with neurological disorders affecting the lower limb will suffer from impaired muscle pump activity. In addition to increasing their risk developing deep vein thrombosis, this group of patients are at a higher risk of cardiovascular failure because of autonomic dysfunction and have impaired venous return to the heart. Van Beekvelt et al 52 using strain gauge plethysmography demonstrated that electrical stimulation can improve muscle pump activity in spinal cord injured patients. Although the spinal cord injury patients could tolerate higher current (60mA), their muscle pump action was significantly lower than that of able bodied subjects (21.5% vs 67.7%). Effects of long term treatment were not investigated. Table 4. Discussion

Electrical stimulation has been shown to improve venous haemodynamics, however the reporting of stimulation parameters varies greatly between trials. It is not clear from the evidence which are the optimum parameters for stimulation, and it may be that clinical indication will dictate whether direct or indirect stimulation is most suitable. Electrode placement determines the effectiveness of calf muscle stimulation due to the particular nerve or muscle bulk targeted, with direct comparisons being misleading. The contraction relaxation times are variable which would affect venous filling and therefore the calf muscle pump function. Subject position is heterogenous, and comparing studies with standing, seated, prone and supine subjects may be injudicious. Haemodynamic outcome measures include air plethysmography, photoplethysmography, strain gauge plethysmography, venous occlusion plethysmography and venous duplex. The site of duplex scanning varies between the femoral, popliteal, posterior tibial and peroneal veins, whilst assorted haemodynamic parameters are reported, and the clinical significance of each parameter is poorly understood. Similarly, the techniques for detecting DVT in the initial studies lacked the sensitivity and specificity of today’s imaging techniques.

NMES is non-inferior to IPC in terms of venous haemodynamics, and does not carry the complications associated with IPC (mainly excessive heat and sweating under the inflatable cuffs). However some subjects have found NMES untenable53. One of the benefits of electrical stimulation over IPC is that the action increases the activity of the users own muscles, as opposed to a passive compression system. A randomised control trial of intensive care patients demonstrated an improvement in muscle strength with electrical stimulation54. It has been shown that aerobic exercise of any type, even just the arms, has a positive effect on walking distances in claudicants, and may alter metabolic profile55. The cardiovascular benefits from NMES are unknown.

Venous stasis is thought to be a major contributor in the pathogenesis of deep vein thrombosis, and is the main mode of action targeted by electrical stimulation in VTE prevention56. In our meta- analysis, heparin has been shown to be most efficacious in the prevention of DVT when compared to NMES alone. However where heparin is contraindicated, NMES significantly reduces VTE risk. In cases of very high risk, the addition of NMES to a heparin thromboprophylaxis regime increases efficacy. Katz observed a fibrinolytic effect with the use of NMES, and when twinned with increased venous velocities in the deep veins may work in synergy with heparin 57. It must also be kept in mind that there are significant risks associated with heparin, such as major haemorrhage, stroke, exacerbation of post-operative bleeding, heparin-induced thrombocytopaenia, and osteoporosis. There is also a need to adjust dose in extremes of body mass, pregnancy and renal impairment58. These problems are not encountered with NMES. High risk peri-operative patients are likely to benefit from electrical stimulation in addition to low molecular weight heparin. In particular, patients who are regarded as high risk such as those undergoing bariatric surgery and laparoscopic cancer surgery, or immobile patients with spinal cord injuries. The combination of NMES with graduated compression stockings may further enhance the haemodynamic effects. The potential clinical application of electrical stimulation in venous disease is largely unexplored, but given the dependence of the venous system on the calf muscle pump, and the large numbers of people with CVD, this is worth exploring. Given that orthostatic oedema can be reversed with NMES, and the ability of the calf muscle pump to be trained over time, NMES may be very successful in this area. Increased impedance of skin and subcutaneous tissues in the presence of oedema requires higher stimulation settings to achieve muscle contraction, but may be limited by pain threshold. Venous haemodynamic measurements tell part of the story, but we recommend future trials should concentrate on translating these effects into clinical practice. Clinical outcomes (e.g. ulcer healing rates) and quality of life data will be most useful in analyzing NMES as a clinical tool, especially given the success of IPC in this cohort59-63.

The field of electrotherapy is interesting and currently underutilized, despite the emergence of various new devices with improved safety profiles and portability. However, the lack of uniformity of nomenclature impedes comparison between devices. A consensus needs to be achieved on reporting of electrical parameters such as pulse width, frequency of stimulation, intensity and waveform. Research should also investigate the effects of dosing, duration of treatment and long term effects of electrical stimulation in treating venous disease.

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