Wendy Baird

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.

Conducting qualitative research within Clinical Trials Units: Avoiding potential pitfalls

The value of using qualitative research within or alongside randomised controlled trials (RCTs) is becoming more widely accepted. Qualitative research may be conducted concurrently with pilot or full RCTs to understand the feasibility and acceptability of the interventions being tested, or to improve trial conduct. Clinical Trials Units (CTUs) in the United Kingdom (UK) manage large numbers of RCTs and, increasingly, manage the qualitative research or collaborate with qualitative researchers external to the CTU. CTUs are beginning to explicitly manage the process, for example, through the use of standard operating procedures for designing and implementing qualitative research with trials. We reviewed the experiences of two UK Clinical Research Collaboration (UKCRC) registered CTUs of conducting qualitative research concurrently with RCTs. Drawing on experiences gained from 15 studies, we identify the potential for the qualitative research to undermine the successful completion or scientific integrity of RCTs. We show that potential problems can arise from feedback of interim or final qualitative findings to members of the trial team or beyond, in particular reporting qualitative findings whilst the trial is on-going. The problems include: We make recommendations for improving the management of qualitative research within CTUs.

Supporting public involvement in research design and grant development: a case study of a public involvement award scheme managed by a National Institute for Health Research (NIHR) Research Design Service (RDS)

It is good practice for the public to be involved in developing health research. Resources should be available for researchers to fund the involvement of the public in the development of their grants.

Quality of life in children and adolescents with Osteogenesis Imperfecta: a qualitative interview based study

BackgroundOsteogenesis Imperfecta (OI) is a disease with varying severity affecting physical, social and emotional well-being of the child and their family. There is no existing evidence on how the OI population regard their quality of life (QoL). The main aim of this study was to determine how OI impacts on the quality of life and well-being of children and their family. It is the first stage of a larger project to develop a disease specific quality of life measure for children with OI.MethodsPurposive sampling was used to cover the diversity of the OI population. Twenty-five qualitative interviews were undertaken with children (n = 10), parents (n = 10) and health professionals (n = 5). Interviews were digitally recorded and transcribed verbatim. Significant themes were identified, extracted and organised, undergoing framework analysis.ResultsSix main themes were identified; being safe and careful, reduced function, pain, fear, isolation, independence. There was a large amount of agreement between the three groups of interviewees, although discrepancies did occur between parents and children, with regard to the themes independence and fear.ConclusionsThis data presents the first step in developing items for a disease specific QoL measure for children with OI. Several of the themes uncovered showed similarity to other QoL measures, but the addition of being safe and careful, particularly in relation to fractures, demonstrated the need for a disease specific measure for children with OI.

Involving the public in systematic reviews: a narrative review of organizational approaches and eight case examples

This paper reviews the recent literature on public involvement in the systematic review process. We examine how relevant organizations involve the public in their review processes and how the public are involved in individual reviews. We identified nine surveys or reports of public involvement in systematic reviews at an organizational level and eight examples of public involvement in individual reviews. The public was found to be involved in the following stages of the review process: topic prioritization; refining the scope of the review; suggesting, locating and appraising the literature; interpreting findings; and writing up the review. Numerous tensions, facilitating strategies and recommendations for good practice were identified. Future research directions are delineated.

Can an emergency department-based Clinical Decision Unit successfully utilize alternatives to emergency hospitalization?

Objective To evaluate a Clinical Decision Unit (CDU) designed to utilize alternatives to emergency hospitalization. CDUs are one model of care designed to strengthen the gatekeeper role of Emergency Departments (EDs). Methods This retrospective cohort study was carried out in a UK NHS acute hospital. All 854 patients in the CDU cohort were compared with three age-stratified, historical cohorts from the same clinical centre. The median age was 62 years (range 16–94).The main outcome measures were discharge to general practitioner, outpatient services or hospitalization, the 30-day unplanned reattendance rate for those not hospitalized, and monthly medical admission figures. Results Approximately 511 [59.8%, 95% confidence interval (CI): 56.5–63.1%] to 560 (65.6%, 95% CI: 62.3–68.7%) patients were admitted in the comparison cohorts, compared with only 186 (21.8%, 95% CI: 19.1–24.7%) in the CDU cohort (P≤0.05). Approximately 243 (28.5%, 95% CI: 25.5–31.6%) to 289 (33.8%, 95% CI: 30.7–37.1%) patients were discharged to general practitioner services in the comparison groups, compared with 562 (65.8%, 95% CI: 62.6–68.9%) in the CDU group (P≤0.05). Approximately eight (0.9, 95% CI: 0.5–1.8%) to 17 (2%, 95% CI: 1.2–3.2%) patients in the comparison groups were discharged to outpatient clinics, compared with 82 (9.6%, 95% CI: 7.8–11.8%) in the CDU group (P≤0.05). There was no consistent trend towards statistically significant rises in unplanned reattendance (P>0.05). Monthly medical admissions fell substantially during CDU operation. Conclusion This CDU model was associated with statistically and clinically significant reductions in hospital admissions. The judicious application of this CDU model to other ED environments can be expected to yield similar benefits.

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.

Factors influencing decision-making in relation to timing of gastrostomy insertion in patients with motor neurone disease

Objectives This study aimed to explore the decision-making process leading up to gastrostomy insertion from the perspective of the patients and their informal carers. Gastrostomy feeding is commonly used to support motor neurone disease patients with dysphagia. However, there is no robust evidence to suggest the optimal timing for gastrostomy insertion. Methods Retrospective qualitative exploration using semistructured interviews with paired patients and carers in order to elicit their perceptions in relation to gastrostomy timing. Results 27 patients consented to the study; of these, 23 underwent a successful gastrostomy. Approximately 3 months following a successful gastrostomy, 10 patients and 8 carers were interviewed. Decision-making in relation to the timing of gastrostomy was described as being a difficult process with individual variations and wishes. A range of factors acted as triggers for taking the decision to proceed with gastrostomy such as prolonged, tiring and effortful meals; the task of food preparation; choking and aspiration; and weight loss. Factors such as the reluctance to give up oral feeding, not realising the potential benefits and negative perceptions of gastrostomy influenced a decision to delay the procedure. A tendency for late insertion was identified despite the opposite advice by health professionals. Conclusions The advice for early insertion does not outweigh the personal perceptions and psychosocial factors for patients and their carers. Understanding the factors which influence decision-making on an individual basis is important for information and care provision by healthcare professionals in aiding patients, and their carers, to make informed decisions in relation to gastrostomy timing.

The use of non-invasive ventilation at end of life in patients with motor neurone disease: A qualitative exploration of family carer and health professional experiences

Background: Non-invasive ventilation improves quality and quantity of life in patients with motor neurone disease who have respiratory failure. Use of non-invasive ventilation may, however, result in complex clinical issues for end-of-life care, with concerns as to whether and how it should be withdrawn. Aim: This study aimed to describe carer and health professional experiences of end-of-life care of motor neurone disease patients using non-invasive ventilation. Design/participants: This article reports data from qualitative interviews with family carers and professionals following the death of patients with motor neurone disease who were using non-invasive ventilation in the final phase of the disease. Results: Ten of the 20 patients initiated on non-invasive ventilation were using it in the end-of-life phase of their disease, with 5 using it for 24 h/day. Interviews were carried out with nine family carers and 15 professionals. Nine recurring themes were identified in the data. Both carers and health-care professionals perceived that the terminal phase of motor neurone disease was unexpectedly rapid and that this often led to unplanned interactions with the emergency services. Carers of patients who used non-invasive ventilation perceived non-invasive ventilation as aiding patient comfort and anxiety at the end of life. Conclusions: The use of non-invasive ventilation was described as beneficial and was not perceived by carers or most professionals to have adversely impacted patient’s end-of-life experience. This study highlights variation in patient wishes regarding usage towards the end of life, uncertainty regarding appropriate management among professionals and the importance of disseminating end-of-life wishes.

Factors that influence the dental attendance pattern and maintenance of oral health for people with multiple sclerosis

Objective To determine the impact of multiple sclerosis (MS) on patient attendance at dental practices and maintenance of oral health.Design A cross-sectional postal questionnaire-based study.Setting Leicestershire, United Kingdom.Subjects and methods People with MS in Leicestershire identified from local health authority records (n = 476).Main outcome measures Number registered at dental practice, frequency of attendance, issues and perspectives relating to attendance and maintenance of oral health.Results A response rate of 61% (n = 289) was obtained. When compared to the general population, a higher number of people with MS were registered with a dentist (49%:88%) and displayed more frequent practice attendance (71%:81%) in the past year. People with MS reported difficulties in attending a dentist and maintaining oral health, which were exacerbated by deterioration in general health. Problems relating to reduced personal mobility had the greatest impact on attendance.Conclusions MS has a negative impact on perceived patient attendance and maintenance of oral health. Patients with a progressive disability could benefit greatly from the provision of preventive oral health care. The importance of seeking care earlier rather than later needs to be emphasised to both professionals and patients alike. Further efforts are required to increase awareness of the importance of oral health to the quality of life of people with MS and ensure that individuals with physical disabilities receive the same access to dental services as the able-bodied.