Title: Neuromuscular Electrical StimulaTion of the lower limbs: an effective adjunct to Pulmonary Rehabilitation? (NEST-PR)
Funder: Department of Health and Social Care

Abstract: BACKGROUND: Although primarily a disease of the lungs, extra-pulmonary manifestations influence morbidity and mortality in Chronic Obstructive Pulmonary Disease (COPD). In particular quadriceps muscle dysfunction is associated with reduced exercise capacity, impaired quality of life, increased healthcare resource usage and mortality. Pulmonary rehabilitation (PR), a programme of exercise-training and education, is the mainstay of non-pharmacological treatment in COPD, and improves exercise capacity and health related quality of life. However the effects on lower limb muscle strength are more modest, perhaps reflecting the focus on aerobic walking, rather than resistance, exercise in UK PR programmes. Patients may be too breathless to perform whole body exercise at a high enough intensity to influence lower limb muscle function. Neuromuscular electrical stimulation (NMES) is a method of enhancing muscle function which uses a portable device to deliver, via skin electrodes, an electrical current to the thighs causing contraction of the underlying muscles. NMES can be self-administered, providing an opportunity for patients to train their muscles outside of a supervised outpatient pulmonary rehabilitation session. This may be more acceptable than whole body exercise to breathless patients as NMES can be self-administered in the sitting position and requires limited ventilatory demand. Several trials have demonstrated that NMES alone can improve lower limb muscle strength and exercise capacity. However there is little data examining whether it has a role as an adjunct to supervised exercise training, such as pulmonary rehabilitation. Previous data is limited to very small trials in highly selective populations, which were open label and had unblinded assessors. AIMS: 1) To update a Cochrane review evaluating the effectiveness of NMES for improving muscle strength in adults with advanced disease. 2) To perform a randomised placebo controlled trial to determine whether home bilateral NMES of the quadriceps muscles, as an adjunct to an outpatient 8-week pulmonary rehabilitation programme, produces a clinically relevant improvement in lower limb muscle function, exercise capacity and quality of life in patients with COPD. STUDY 1: A systematic review will be performed according to the Cochrane Handbook for Systematic Reviews of Intervention to identify any new and potentially relevant studies investigating the use of NMES in adults suffering from muscle weakness due to advanced disease. The results of comparable outcome measures will be combined and meta-analysis performed.STUDY 2: DESIGN: A prospective, randomised, double-blind, placebo-controlled trial. Patients will be randomised at the individual level with a 1:1 allocation. POPULATION: 108 patients with COPD referred to a pulmonary rehabilitation programme with quadriceps weakness. All patients will undergo an 8-week outpatient pulmonary rehabilitation programme comprising two supervised sessions per week. In addition, patients will be randomised to: INTERVENTION: Active NMES delivered to both quadriceps muscles for 30 minutes a day, five times a week for 8 weeks. CONTROL: Sham NMES delivered to both quadriceps muscles for 30 minutes a day, five times a week for 8 weeks. OUTCOMES: Primary: cycling endurance time at 80% peak workload. Secondary: quadriceps strength/mass, incremental exercise capacity, health related quality of life. These will be performed at baseline and at 8 weeks (pre- and post- pulmonary rehabilitation). Adverse events and compliance will also be recorded. BENEFITS TO PATIENTS AND NHS: Quadriceps weakness is associated with adverse outcomes in COPD including mobility limitation, increased mortality and healthcare utilisation. Reversing quadriceps weakness is an important therapeutic goal. Although small trials have demonstrated that NMES alone improves quadriceps strength in patients with COPD, it is not known whether it provides additional benefit to current gold standard treatment of pulmonary rehabilitation. This trial will be firmly embedded in a NHS service, and will closely monitor safety and feasibility as well as clinical efficacy.

Lay abstract: Chronic Obstructive Pulmonary Disease (COPD) is the commonest lung problem in older people and it affects 3 million people in the UK. Most patients complain of breathlessness, which limits physical activities of daily living. Although COPD is primarily a lung disease, it is now recognised that other body systems are involved which influence patient symptoms and physical abilities. In particular, research has shown that the leg muscles in COPD are weaker than the muscles in healthy people of a similar age. Leg muscle weakness in COPD has been shown to reduce exercise capacity, impair quality of life, increase the need for healthcare resources and reduce survival. This muscle weakness can potentially be reversed, thereby improving both quality of life and physical functioning in patients with COPD. This is, particularly important when the lung disease is largely irreversible. The aim of the project is to review the current evidence for neuromuscular electrical stimulation (NMES) for muscle weakness and to test whether, in addition to pulmonary rehabilitation, NMES of the thigh muscle can increase leg muscle strength and improve function more than pulmonary rehabilitation alone in people with COPD. Pulmonary rehabilitation is a programme of care that consists of supervised exercise training and education delivered by healthcare professionals with a wide range of skills. This programme has been shown to increase exercise capacity and health-related quality of life in people with COPD. However, the effect on leg muscle function is relatively modest. This may be due to a number of different reasons. In the UK, clinical pulmonary rehabilitation is based primarily on walking exercise. People with COPD may be too breathless to exercise at a level high enough to reverse muscle weakness. Furthermore, a significant proportion of pulmonary rehabilitation programmes in the UK are based in the community setting, where specialist muscle-training equipment (for example a leg press) may not be easily accessible; this makes it more difficult to adjust the level of muscle-strengthening exercises. Another drawback is that, although three supervised exercise sessions per week have been shown to be the most effective way of gaining benefits, most UK pulmonary rehabilitation programmes provide only one or two supervised exercise sessions per week. Participants are expected to perform unsupervised exercise at home to supplement the supervised sessions but, without formal monitoring, it is difficult to assess accurately the length of time or the level at which exercise is performed at home by people on pulmonary rehabilitation programmes. Nevertheless, the home setting represents an important part of the overall pulmonary rehabilitation programme in providing additional exercise training to benefit the patient. NMES uses a small battery-operated machine and pads, which are placed over each thigh to produce a comfortable stimulation of the underlying muscles. Several small studies and reviews have demonstrated improvements in lower limb muscle strength with NMES in people with COPD. NMES might be more acceptable to very breathless people with COPD than whole-body exercise such as walking as the equipment is very portable and it can be self-administered at home in the sitting position (for example, whilst watching television). However, there is very little data examining the role of NMES in enhancing the benefits of pulmonary rehabilitation. In our study, 108 people with COPD starting an eight-week pulmonary rehabilitation programme (exercise and education programme) will receive two supervised exercise and education sessions per week, each session lasting two hours, for eight weeks. In addition, participants will be randomly allocated to receive either active or sham (dummy) NMES to be applied at home to the thigh muscles. During the programme, all participants will receive 30 minutes of daily stimulation for 8 weeks at home and the level of stimulation will be set either to allow muscle contraction (active) or to provide skin sensation only (dummy). We will measure cycling time, leg muscle strength, change in thigh-muscle size, walking ability and quality of life before and after pulmonary rehabilitation. Patient representatives have been involved in design of the study. Furthermore, they will be involved in the development of patient information sheets for the study and will help with the data presentation of the study's findings. The information that we get from this trial will help in deciding whether NMES brings any additional benefit to outpatient pulmonary rehabilitation and in advising whether this should be provided routinely by the NHS.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RESPIRATORY