Title: Standard versus accelerated weaning from non-invasive ventilation (NIV) in chronic obstructive pulmonary disease directed by the NIV outcomes score: a randomised controlled trial
Funder: Department of Health and Social Care

Abstract: Research question: Do daily four-hour, unsupported breathing trials shorten NIV weaning time, compared to standard weaning, in patients with COPD exacerbation and low or medium mortality risk? Background: NIV for ECOPD complicated by respiratory acidaemia saves one life for every 12 patients treated, but it is intrusive and complications are common. Current NIV weaning guidelines are based on limited evidence and inconsistently followed. Our recent 10-centre NIV Outcomes study showed marked variation in duration of NIV (31.5-95.5 hours) and rates of relapse. Aims and objectives: To compare time to successful weaning from NIV in ECOPD using an accelerated versus a standard weaning protocol. We will also assess treatment complications, symptoms, sleep quality, health-related quality of life, readmissions, mortality and health-economic outcomes. Methods Design: A multi-centre, open-label, parallel, randomised controlled trial. Population: Patients with a clinical diagnosis of ECOPD requiring NIV, a low or medium risk NIV Outcome score and meeting clinical criteria for weaning. Patients with an additional indication for level 2/3 support, poor tolerance of NIV, requiring home ventilation or unable to provide informed consent will be excluded. Patients will be identified by daily screening on participating Respiratory Support and Critical Care Units. Intervention: The Standard NIV weaning protocol involves progressively longer intervals without NIV each day, monitored by ABG, and with a final night on NIV after a full day without support. The accelerated weaning protocol involves a daily 4-hour unsupported breathing trial with transcutaneous carbon dioxide tension (PtcCO2) monitoring, and a final ABG. If satisfactory, NIV will be discontinued. For safety, PtcCO2 monitoring will continue for 12 hours in total, and applied to both arms for balance. Randomisation will be performed independently (sealedenvelope.com), using minimisation to ensure balance between groups for size, sites, and predictors of weaning and mortality. Primary outcome: Time to successful weaning. Death on NIV will be captured in a competing risk analysis. Secondary outcomes: Relapse requiring NIV; duration of ventilation; hospital stay; NIV complications; breathlessness, sputum clearance and sleep quality (Richards-Campbell sleep questionnaire) day 1-5; health-related quality of life over 90 days; in-hospital and 90-day mortality, readmission within 30-days, and the cost effectiveness and cost utility of accelerated compared to standard weaning. Exploratory: Responder analysis within the accelerated weaning group. Sample size: Assuming a 5% two-sided type I error, and 80% power, 164 patients are required to detect the minimum clinically important difference in weaning time (24 hours). Timelines for delivery: Develop trial materials and secure ethical approvals to initiate lead site within 3 months, followed by external sites. Recruitment within 24 months with 90 day follow up. Data analysis, write-up, dissemination, and study close within 6 months. Impact and dissemination: Results will be shared with participants, Northumbria Lung Research PPI Group (involved throughout study design and recruitment period), and patients with COPD, presented at conferences and published in medical journals. We will engage the relevant British Thoracic Society Specialist Advisory Groups, British Lung Foundation and NICE. The recent inclusion of the NIV Outcomes score within the National Audit tool will facilitate implementation.

Lay abstract: Why are we planning this study? Every year in the UK, over 141,000 people will be admitted into hospital due to Exacerbations of Chronic Obstructive Pulmonary Disease (ECOPD). Around one-quarter of these patients develop life-threatening respiratory failure, with a build-up of carbon dioxide (waste gas). Non-invasive ventilation (NIV) involves wearing a tightly-fitted mask connected to a ventilator to help patients breathe out more carbon dioxide. NIV halves the risk of dying, but can cause unpleasant side-effects including stomach bloating and skin damage. Once the patient is improving, NIV is gradually removed by giving patients progressively longer periods of time off ventilation. This is called weaning and usually takes 3-4 days. Faster weaning should reduce side-effects and costs. However shorter treatment may be less effective, and respiratory failure (carbon dioxide build-up) may recur. Currently, there is little evidence to guide a safe process for NIV weaning, with concerns highlighted in a National Confidential Enquiry. We recently developed the NIV Outcomes Score, which predicts risk of death in NIV-treated patients. We showed that three in four patients have a low or medium risk, and therefore this group may be suitable for faster weaning. We also noticed big differences between hospitals with respect to duration of weaning and patient relapse rates, highlighting the need for better guidance. What are our aims? To investigate whether patients with ECOPD requiring NIV can be safely weaned off NIV more quickly. How are we planning to do it? Patients hospitalised with ECOPD requiring NIV will be invited to take part. Those who agree will be randomised by computer to a standard or accelerated weaning protocol. The accelerated wean involves a daily 4-hour trial without NIV under close monitoring. If the carbon dioxide levels in the blood are stable and safe, NIV will be stopped early. To ensure our results apply across the NHS, we will include several hospitals and only exclude patients when essential. Our main question is whether the intervention reduces the time required to successfully wean NIV. If NIV is restarted within 48 hours of removal, this will be considered an unsuccessful weaning attempt and will be included in the time to weaning. Patient outcomes, including any increased risk of death will be carefully monitored. We will also assess: side-effects from NIV, relapse, sleep quality, symptoms, quality of life, readmission into hospital, and costs. Who has advised us? Review of this proposal by COPD patients needing NIV confirmed strong support, with input into trial design. How will we share our results? Results will be shared with participants, presented at conferences and published in medical journals. We will engage the relevant British Thoracic Society Specialist Advisory Groups, British Lung Foundation (reaching people with COPD) and NICE.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: RESPIRATORY