Abstract: We included six RCTs, comprising 195 participants with MS. Two RCTs investigated inspiratory muscle training with a threshold device; three RCTs, expiratory muscle training with a threshold device; and one RCT, regular breathing exercises. Eighteen participants (˜ 10%) dropped out; trials reported no serious adverse events. We pooled and analyzed data of 5 trials (N=137) for both inspiratory and expiratory muscle training, using a fixed-effect model for all but one outcome. Compared to no active control, meta-analysis showed that inspiratory muscle training resulted in no significant difference in maximal inspiratory pressure (mean difference (MD) 6.50 cmH2O, 95% confidence interval (CI) −7.39 to 20.38, P = 0.36, I2 = 0%) or maximal expiratory pressure (MD −8.22 cmH2O, 95% CI −26.20 to 9.77, P = 0.37, I2 = 0%), but there was a significant benefit on the predicted maximal inspiratory pressure (MD 20.92 cmH2O, 95% CI 6.03 to 35.81, P = 0.006, I2 = 18%). Meta-analysis with a random-effects model failed to show a significant difference in predicted maximal expiratory pressure (MD 5.86 cmH2O, 95% CI −10.63 to 22.35, P = 0.49, I2 = 55%). These studies did not report outcomes for health-related quality of life. Three RCTS compared expiratory muscle training versus no active control or sham training. Under a fixed-effect model, meta-analysis failed to show a significant difference between groups with regard to maximal expiratory pressure (MD 8.33 cmH2O, 95% CI −0.93 to 17.59, P = 0.18, I2 = 42%) or maximal inspiratory pressure (MD 3.54 cmH2O, 95% CI −5.04 to 12.12, P = 0.42, I2 = 41%). One trial assessed quality of life, finding no differences between groups. For all predetermined secondary outcomes, such as forced expiratory volume, forced vital capacity and peak flow pooling was not possible. However, two trials on inspiratory muscle training assessed fatigue using the Fatigue Severity Scale (range of scores 0-56 ), finding no difference between groups (MD, −0.28 points, 95% CI−0.95 to 0.39, P = 0.42, I2 = 0%). Due to the low number of studies included, we could not perform cumulative meta-analysis or subgroup analyses. It was not possible to perform a meta-analysis for adverse events, no serious adverse were mentioned in any of the included trials. The quality of evidence was low for all outcomes because of limitations in design and implementation as well as imprecision of results. This review provides low-quality evidence that resistive inspiratory muscle training with a resistive threshold device is moderately effective postintervention for improving predicted maximal inspiratory pressure in people with mild to moderate MS, whereas expiratory muscle training showed no significant effects. The sustainability of the favourable effect of inspiratory muscle training is unclear, as is the impact of the observed effects on quality of life.

Plain-language summary: We searched electronic databases for randomized controlled trials (where participants are assigned at random to either a treatment or a control arm) published up to 3 February 2017 that investigated respiratory muscle training in people with MS. In addition, we contacted experts in the field to identify additional studies. We found six trials involving 195 participants with MS. Training consisted of two or three sets of 10 to 15 repetitions, twice a day for at least three days a week, and interventions lasted for six weeks to three months. Follow-up ranged from no follow-up to six months. Two of the included trials investigated inspiratory muscle training with a threshold device (i.e. a portable breathing device that increases airflow resistance while inhaling or exhaling). Three trials investigated expiratory muscle training with a threshold device, and one trial investigated breathing exercises. We found benefits with inspiratory muscle training for improving predicted maximal inspiratory pressure, but not for improving measured maximal inspiratory pressure. We did not find any effects for maximal expiratory pressure. Only one study measured quality of life, but it did not find any effects; two trials measured fatigue and also failed to find a difference between the treatment and control groups. Eighteen participants (˜ 10%) dropped out, and no trials reported any serious adverse events. The six trials that were eligible for inclusion in this review were small, so statistical power was low, making analyses less precise. In addition, studies were heterogeneous in terms of the type of respiratory muscle training, dosing/intensity, and the severity of MS. In addition, we could not analyze the effects of training on, for example, cough efficacy, pneumonia, and quality of life, as the included trials did not report on these outcomes even though they are important for patients, caregivers and healthcare professionals. Altogether, this review provides low-quality evidence that resistive inspiratory muscle training improves predicted inspiratory muscle strength in people with MS. We did not find any effects for resistive expiratory muscle training. More high-quality research in respiratory muscle training in MS is needed.