Intramuscular diaphragm stimulation for ventilator-dependent chronic respiratory failure caused by motor neurone disease

In a multicentre randomised controlled trial (RCT) of 74 patients with respiratory failure caused by amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) plus diaphragm pacing (n=37) was compared with NIV alone (n=37). In the NIV plus pacing group 76% (26 out of 37) of patients died and in the NIV-alone group 51% (19 out of 37) of patients died. The causes of death were similar across the groups (mainly respiratory failure, chest infection, ALS and hypothermia). In another multicentre triple-blind RCT in 74 patients with probable or definite ALS, active stimulation (n=37) was compared with sham stimulation (n=37). More patients died in the active stimulation group than in the sham stimulation group (49% [18 out of 37] compared with 19% [7 out of 37]) as a result of chest infection, acute respiratory failure and terminal respiratory insufficiency. Six patients died before NIV in the active stimulation group because of acute respiratory failure in 5 and sudden cardiac death in 1. No deaths were related to treatment.

There were more adverse events reported in the NIV plus pacing group than in the NIV-alone group (162 events [5.9 events per person-year] in 78% [29 out of 37] of patients compared with 81 events [2.5 events per person-year] in 62% [23 out of 37] of patients) in the RCT of 74 patients with respiratory failure caused by ALS. More patients had serious adverse events in the NIV plus pacing group than in the NIV-alone group (73% [27 out of 37] compared with 51% [19 out of 37]; 46 events compared with 31 events). Respiratory events were the most common in both groups (68% [25 out of 37] compared with 38% [14 out of 37]) followed by gastrointestinal events (27% [10 out of 37] compared with 24% [9 out of 37]), symptoms of motor neurone disease (22% [8 out of 37] compared with 8% [3 out of 37]), gastrostomy (percutaneous endoscopic or per-oral image-guided insertion; 14% [5 out of 37] compared with 24% [9 out of 37]), genitourinary events (8% [3 out of 37] in each group), cardiovascular events (11% [4 out of 37] compared with 5% [2 out of 37]) and dermatological problems (8% [3 out of 37] compared with 11% [4 out of 37]).

Serious adverse events (mainly capnothorax or pneumothorax, acute respiratory failure needing mechanical ventilation, venous thromboembolism and gastrostomy tube placement) were reported in 65% [24 out of 37] of the active stimulation group and in 59% [22 out of 37] of the sham stimulation group in the triple-blind RCT of 74 patients. Some patients had more than 1 adverse event. Other serious adverse events reported include dyspnoea (3 patients), loss of walking ability (3 patients), oesophagitis (1 patient), admission to hospital for any cause (3 patients), accidental removal of gastrostomy tube (1 patient), and reopening of the laparoscopy insertion point needing repair (1 patient). Capnothorax was reported in 13% (5 out of 38) of patients with ALS in a case series of 88 patients. Capnothorax was managed successfully by aspiration, drainage or observation.

Suture granuloma causing infection at the superficial wire connection site (treated by externalising the electrodes) was reported in 1 patient with ALS in the case series of 88 patients. Infection at the stimulation cable entry point was noted in 22% (8 out of 37) of patients in the active group (3 patients needed antibiotics) and 19% (7 out of 37) of patients in the control group (5 patients needed antibiotics) in the triple-blind RCT of 74 patients. Respiratory infections (needing antibiotics) were reported in 5 patients in a case series of 16 ALS patients with respiratory insufficiency treated by diaphragm pacing. Superficial wound infection (treated with antibiotics) was reported in 1 patient in the same study. Urinary infection (needing admission to hospital) and severe pulmonary infection were reported in 1 patient each in a case series of 11 patients.

External electrode repairs were needed in 7 patients in the case series of 16 patients with ALS. Wire failure was reported in 14% (5 out of 37) of patients in the NIV plus diaphragm pacing group in the RCT of 74 patients with respiratory failure caused by ALS.

Pain (needing analgesics) was commonly reported in the active stimulation and sham stimulation groups (92% [34 out of 37] compared with 89% [33 out of 37]) in the triple-blind RCT of 74 patients. Pain needing a reduction in the intensity of diaphragm pacing was noted on day 2 in 54% (20 out of 37) of patients in the active stimulation group and none in the sham stimulation group in the same study.

In addition to safety outcomes reported in the literature, specialist advisers are asked about anecdotal adverse events (events which they have heard about) and about theoretical adverse events (events which they think might possibly occur, even if they have never done so). For this procedure, specialist advisers listed the following anecdotal adverse event: excess mortality. They considered that the following were theoretical adverse events: decompensated respiratory failure, breathlessness related to diaphragm pacing and atrophy and progression of diaphragm weakness.