Roger Ackroyd

Safety and efficacy of diaphragm pacing in patients with respiratory insufficiency due to amyotrophic lateral sclerosis (DiPALS): a multicentre, open-label, randomised controlled trial.

BACKGROUNDnNon-invasive ventilation is part of the standard of care for treatment of respiratory failure in patients with amyotrophic lateral sclerosis (ALS). The NeuRx RA/4 Diaphragm Pacing System has received Humanitarian Device Exemption approval from the US Food and Drug Administration for treatment of respiratory failure in patients with ALS. We aimed to establish the safety and efficacy of diaphragm pacing with this system in patients with respiratory muscle weakness due to ALS.nnnMETHODSnWe undertook a multicentre, open-label, randomised controlled trial at seven specialist ALS and respiratory centres in the UK. Eligible participants were aged 18 years or older with laboratory supported probable, clinically probable, or clinically definite ALS; stable riluzole treatment for at least 30 days; and respiratory insufficiency. We randomly assigned participants (1:1), via a centralised web-based randomisation system with minimisation that balanced patients for age, sex, forced vital capacity, and bulbar function, to receive either non-invasive ventilation plus pacing with the NeuRx RA/4 Diaphragm Pacing System or non-invasive ventilation alone. Patients, carers, and outcome assessors were not masked to treatment allocation. The primary outcome was overall survival, defined as the time from randomisation to death from any cause. Analysis was by intention to treat. This trial is registered, ISRCTN number 53817913.nnnFINDINGSnBetween Dec 5, 2011, and Dec 18, 2013, we randomly assigned 74 participants to receive either non-invasive ventilation alone (n=37) or non-invasive ventilation plus diaphragm pacing (n=37). On Dec 18, 2013, the Data Monitoring and Ethics Committee (DMEC) recommended suspension of recruitment on the basis of overall survival figures. Randomly assigned participants continued as per the study protocol until June 23, 2014, when the DMEC advised discontinuation of pacing in all patients. Follow-up assessments continued until the planned end of the study in December, 2014. Survival was shorter in the non-invasive ventilation plus pacing group than in the non-invasive ventilation alone group (median 11·0 months [95% CI 8·3-13·6] vs 22·5 months [13·6-not reached]; adjusted hazard ratio 2·27, 95% CI 1·22-4·25; p=0·009). 28 (76%) patients died in the pacing group and 19 (51%) patients died in the non-invasive ventilation alone group. We recorded 162 adverse events (5·9 events per person-year) in the pacing group, of which 46 events were serious, compared with 81 events (2·5 events per person-year) in the non-invasive ventilation alone group, of which 31 events were serious.nnnINTERPRETATIONnAddition of diaphragm pacing to standard care with non-invasive ventilation was associated with decreased survival in patients with ALS. Our results suggest that diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.nnnFUNDINGnThe National Institute for Health Research Health Technology Assessment Programme; the Motor Neurone Disease Association of England, Wales, and Northern Ireland.

DiPALS: Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis - a randomised controlled trial.

BACKGROUNDnAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease resulting in death, usually from respiratory failure, within 2-3 years of symptom onset. Non-invasive ventilation (NIV) is a treatment that when given to patients in respiratory failure leads to improved survival and quality of life. Diaphragm pacing (DP), using the NeuRx/4(®) diaphragm pacing system (DPS)™ (Synapse Biomedical, Oberlin, OH, USA), is a new technique that may offer additional or alternative benefits to patients with ALS who are in respiratory failure.nnnOBJECTIVEnThe Diaphragm Pacing in patients with Amyotrophic Lateral Sclerosis (DiPALS) trial evaluated the effect of DP on survival over the study duration in patients with ALS with respiratory failure.nnnDESIGNnThe DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy.nnnPARTICIPANTSnEligible participants had a diagnosis of ALS (ALS laboratory-supported probable, clinically probable or clinically definite according to the World Federation of Neurology revised El Escorial criteria), had been stabilised on riluzole for 30 days, were aged ≥u200918 years and were in respiratory failure. We planned to recruit 108 patients from seven UK-based specialist ALS or respiratory centres. Allocation was performed using 1u2009:u20091 non-deterministic minimisation.nnnINTERVENTIONSnParticipants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS.nnnMAIN OUTCOME MEASURESnThe primary outcome was overall survival, defined as the time from randomisation to death from any cause. Secondary outcomes were patient quality of life [assessed by European Quality of Life-5 Dimensions, three levels (EQ-5D-3L), Short Form questionnaire-36 items and Sleep Apnoea Quality of Life Index questionnaire]; carer quality of life (EQ-5D-3L and Caregiver Burden Inventory); cost-utility analysis and health-care resource use; tolerability and adverse events. Acceptability and attitudes to DP were assessed in a qualitative substudy.nnnRESULTSnIn total, 74 participants were randomised into the trial and analysed, 37 participants to NIV plus pacing and 37 to standard care, before the Data Monitoring and Ethics Committee advised initial suspension of recruitment (December 2013) and subsequent discontinuation of pacing (on safety grounds) in all patients (June 2014). Follow-up assessments continued until the planned end of the study in December 2014. The median survival (interquartile range) was 22.5 months (lower quartile 11.8 months; upper quartile not reached) in the NIV arm and 11.0 months (6.7 to 17.0 months) in the NIV plus pacing arm, with an adjusted hazard ratio of 2.27 (95% confidence interval 1.22 to 4.25; pu2009=u20090.01).nnnCONCLUSIONSnDiaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure.nnnFUTURE WORKnIt may be that certain population subgroups benefit from DP. We are unable to explain the mechanism behind the excess mortality in the pacing arm, something the small trial size cannot help address. Future research should investigate the mechanism by which harm or benefit occurs further.nnnTRIAL REGISTRATIONnCurrent Controlled Trials ISRCTN53817913.nnnFUNDINGnThis project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 45. See the HTA programme website for further project information. Additional funding was provided by the Motor Neurone Disease Association of England, Wales and Northern Ireland.

Bariatric surgery: implications for primary care

Obesity rates in the UK are high with over one-quarter of adults being classified as obese.1 Obesity is associated with a number of medical comorbidities, including type 2 diabetes mellitus, hypertension, obstructive sleep apnoea, and osteoarthritis. Consequently, obesity is linked with increased cardiovascular morbidity and mortality, cancer, functional impairment, and premature death, placing a financial burden on the NHS.nnBariatric surgery has been demonstrated to be the most effective method for substantial and sustained weight loss, with a significant reduction in obesity-related comorbidities and long-term mortality.2 As a result, bariatric surgery rates are increasing in the UK for patients who have failed to respond to non-surgical therapies. GPs will therefore see an increasing number of patients with severe obesity who wish to be referred for surgery.nnGPs play a pivotal role in the management of obesity with early referral of motivated individuals who have failed to achieve substantial weight loss. Further, given the high level of psychosocial disorders in this patient group it is important to make an early assessment and provide support if appropriate. The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) reported that only 29% of patients received psychological input, which mostly occurred following referral.3nnIndications for bariatric surgery have been clearly defined by National Institute for Health and Care Excellence (NICE).4 However, in light of new evidence NICE has recently issued draft guidance on the management of obesity.5 As bariatric surgery has been demonstrated to improve glycaemic control and even remission of type 2 diabetes, NICE recommends that obese patients (body mass index [BMI] 30–34.9) with recent-onset type 2 diabetes (within the past 10 years) may benefit from surgery. Furthermore, patients of Asian origin with recent-onset type 2 diabetes may benefit from bariatric surgery at a lower …

Protocol for diaphragm pacing in patients with respiratory muscle weakness due to motor neurone disease (DiPALS): a randomised controlled trial.

BackgroundMotor neurone disease (MND) is a devastating illness which leads to muscle weakness and death, usually within 2-3 years of symptom onset. Respiratory insufficiency is a common cause of morbidity, particularly in later stages of MND and respiratory complications are the leading cause of mortality in MND patients. Non Invasive Ventilation (NIV) is the current standard therapy to manage respiratory insufficiency. Some MND patients however do not tolerate NIV due to a number of issues including mask interface problems and claustrophobia. In those that do tolerate NIV, eventually respiratory muscle weakness will progress to a point at which intermittent/overnight NIV is ineffective. The NeuRx RA/4 Diaphragm Pacing System was originally developed for patients with respiratory insufficiency and diaphragm paralysis secondary to stable high spinal cord injuries. The DiPALS study will assess the effect of diaphragm pacing (DP) when used to treat patients with MND and respiratory insufficiency.Method/Design108 patients will be recruited to the study at 5 sites in the UK. Patients will be randomised to either receive NIV (current standard care) or receive DP in addition to NIV. Study participants will be required to complete outcome measures at 5 follow up time points (2, 3, 6, 9 and 12 months) plus an additional surgery and 1 week post operative visit for those in the DP group. 12 patients (and their carers) from the DP group will also be asked to complete 2 qualitative interviews.DiscussionThe primary objective of this trial will be to evaluate the effect of Diaphragm Pacing (DP) on survival over the study duration in patients with MND with respiratory muscle weakness. The project is funded by the National Institute for Health Research, Health Technology Assessment (HTA) Programme (project number 09/55/33) and the Motor Neurone Disease Association and the Henry Smith Charity. Trial Registration: Current controlled trials ISRCTN53817913. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the HTA programme, NIHR, NHS or the Department of Health.

Bariatric Surgery in Children

Severe or morbid obesity, with a BMI exceeding 35–40, is often refractory to all therapies other than surgery. Bariatric or weight loss surgery is not generally recommended in childhood as it is fraught with ethical issues and the potential long-term benefits and complications of enteric diversion are not yet fully understood. On the other hand, it has been suggested that bariatric surgery in adolescents may have less complications and a shorter hospital stay than in adults. The long-term implications of bariatric surgery in children are not yet fully understood, and diligent long-term follow-up of all these patients is required to help determine this.