Chin Maguire

SABRE: a multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis

Aim Acute bronchiolitis is the commonest cause for hospitalisation in infancy. Supportive care remains the cornerstone of current management and no other therapy has been shown to influence the course of the disease. It has been suggested that adding nebulised hypertonic saline to usual care may shorten the duration of hospitalisation. To determine whether hypertonic saline does have beneficial effects we undertook an open, multi-centre parallel-group, pragmatic RCT in ten UK hospitals. Methods Infants admitted to hospital with a clinical diagnosis of acute bronchiolitis and requiring oxygen therapy were randomised to receive usual care alone or nebulised 3% hypertonic saline (HS) administered 6-hourly. Randomisation was within 4 h of admission. The primary outcome was time to being assessed as ‘fit’ for discharge with secondary outcomes including time to discharge, incidence of adverse events together with follow up to 28 days assessing patient centred health related outcomes. Results A total of 317 infants were recruited to the study. 158 infants were randomised to HS (141 analysed) and 159 to standard care (149 analysed). There was no difference between the two arms in time to being declared fit for discharge (hazard ratio: 0−95, 95% CI: 0.75−1.20) nor to actual discharge (hazard ratio: 0.97, 95% CI: 0.76−1.23). There was no difference in adverse events. One infant in the HS group developed bradycardia with desaturation. Conclusion This study does not support the use of nebulised HS in the treatment of acute bronchiolitis over usual care with minimal handlings. ClinicalTrials.gov registration number NCT01469845.

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

BACKGROUND Non-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. METHODS We 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. FINDINGS Between 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. INTERPRETATION Addition 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. FUNDING The 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.

BACKGROUND Amyotrophic 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. OBJECTIVE The 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. DESIGN The DiPALS trial was a multicentre, parallel-group, open-label, randomised controlled trial incorporating health economic analyses and a qualitative longitudinal substudy. PARTICIPANTS Eligible 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 ≥ 18 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 1 : 1 non-deterministic minimisation. INTERVENTIONS Participants were randomised to either standard care (NIV alone) or standard care (NIV) plus DP using the NeuRX/4 DPS. MAIN OUTCOME MEASURES The 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. RESULTS In 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; p = 0.01). CONCLUSIONS Diaphragmatic pacing should not be used as a routine treatment for patients with ALS in respiratory failure. FUTURE WORK It 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. TRIAL REGISTRATION Current Controlled Trials ISRCTN53817913. FUNDING This 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.

Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation.

BACKGROUND Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING Six paediatric neuromuscular units. PARTICIPANTS Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient. LIMITATIONS The focus on delivery in hospitals limits generalisability. CONCLUSIONS Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION Current Controlled Trials ISRCTN41002956. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information.

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.

Saline in Acute Bronchiolitis RCT and Economic evaluation: hypertonic saline in acute bronchiolitis – randomised controlled trial and systematic review

BACKGROUND Acute bronchiolitis is the most common cause of hospitalisation in infancy. Supportive care and oxygen are the cornerstones of management. A Cochrane review concluded that the use of nebulised 3% hypertonic saline (HS) may significantly reduce the duration of hospitalisation. OBJECTIVE To test the hypothesis that HS reduces the time to when infants were assessed as being fit for discharge, defined as in air with saturations of > 92% for 6 hours, by 25%. DESIGN Parallel-group, pragmatic randomised controlled trial, cost-utility analysis and systematic review. SETTING Ten UK hospitals. PARTICIPANTS Infants with acute bronchiolitis requiring oxygen therapy were allocated within 4 hours of admission. INTERVENTIONS Supportive care with oxygen as required, minimal handling and fluid administration as appropriate to the severity of the disease, 3% nebulised HS every ± 6 hours. MAIN OUTCOME MEASURES The trial primary outcome was time until the infant met objective discharge criteria. Secondary end points included time to discharge and adverse events. The costs analysed related to length of stay (LoS), readmissions, nebulised saline and other NHS resource use. Quality-adjusted life-years (QALYs) were estimated using an existing utility decrement derived for hospitalisation in children, together with the time spent in hospital in the trial. DATA SOURCES We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and other databases from inception or from 2010 onwards, searched ClinicalTrials.gov and other registries and hand-searched Chest, Paediatrics and Journal of Paediatrics to January 2015. REVIEW METHODS We included randomised/quasi-randomised trials which compared HS versus saline (± adjunct treatment) or no treatment. We used a fixed-effects model to combine mean differences for LoS and assessed statistical heterogeneity using the I (2) statistic. RESULTS The trial randomised 158 infants to HS (n = 141 analysed) and 159 to standard care (n = 149 analysed). There was no difference between the two arms in the time to being declared fit for discharge [median 76.6 vs. 75.9 hours, hazard ratio (HR) 0.95, 95% confidence interval (CI) 0.75 to 1.20] or to actual discharge (median 88.5 vs. 88.7 hours, HR 0.97, 95% CI 0.76 to 1.23). There was no difference in adverse events. One infant developed bradycardia with desaturation associated with HS. Mean hospital costs were £2595 and £2727 for the control and intervention groups, respectively (p = 0.657). Incremental QALYs were 0.0000175 (p = 0.757). An incremental cost-effectiveness ratio of £7.6M per QALY gained was not appreciably altered by sensitivity analyses. The systematic review comprised 15 trials (n = 1922) including our own. HS reduced the mean LoS by -0.36 days (95% CI -0.50 to -0.22 days). High levels of heterogeneity (I (2) = 78%) indicate that the result should be treated cautiously. CONCLUSIONS In this trial, HS had no clinical benefit on LoS or readiness for discharge and was not a cost-effective treatment for acute bronchiolitis. Claims that HS achieves small reductions in LoS must be treated with scepticism. FUTURE WORK Well-powered randomised controlled trials of high-flow oxygen are needed. STUDY REGISTRATION This study is registered as NCT01469845 and CRD42014007569. FUNDING DETAILS This project was funded by the NIHR Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 19, No. 66. See the HTA programme website for further project information.

Role of habit in treatment adherence among adults with cystic fibrosis

Among adults with cystic fibrosis (CF), medication adherence is low and reasons for low adherence are poorly understood. Our previous exploratory study showed that stronger ‘habit’ (ie, automatically experiencing an urge to use a nebuliser) was associated with higher nebuliser adherence. We performed a secondary analysis of pilot trial data (n=61) to replicate the earlier study and determine whether habit–adherence association exists in other cohorts of adults with CF. In this study, high adherers also reported stronger habit compared with low adherers. Habit may be a promising target for self-management interventions. Trial registration number ACtiF pilot, ISRCTN13076797.

Pragmatic criteria to define chronic pseudomonas aeruginosa infection among adults with cystic fibrosis

Despite changes in the epidemiology of respiratory bacteriology among adults with cystic fibrosis (CF), Pseudomonas aeruginosa remains the most common chronic lung pathogen [1]. P. aeruginosa status is important in CF because it influences clinical segregation decisions, choices of preventative inhaled therapy as well as the choice of antibiotics to treat pulmonary exacerbations [2–4]. However, there is currently no Bgold standard^ to define P. aeruginosa status in CF. The Leeds criteria are commonly used in CF research settings [2]. This set of criteria is highly specific in identifying chronic P. aeruginosa infection but lack sensitivity when compared against polymerase chain reaction (PCR) techniques, with a tendency to under-diagnose chronic P. aeruginosa infection as intermittent infection [5, 6]. Not surprisingly, clinical trials evaluating treatments specifically for adults with chronic P. aeruginosa infection generally avoided using the Leeds criteria as part of the eligibility criteria. Instead, a myriad of different definitions are used. For example, the trial evaluating Ciprofloxacin dry powder inhaler used BA positive sputum or throat swab culture for P. aeruginosa within the previous 12 months^ as one of the eligibility criteria [7], whilst the Aztreonam nebuliser trial used BPA-positive sputum culture within the previous 3 months^ [8]. The Leeds criteria were developed in a paediatric population whereby chronic P. aeruginosa is not particularly common [9] and P. aeruginosa status is still quite fluctuant. Avery specific test for chronic P. aeruginosa infection, such as the Leeds criteria, works well in a paediatric population. In an