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Background: Invasive mechanical ventilation (IMV) is a life-saving intervention. Following resolution of the condition that necessitated IMV, a spontaneous breathing trial (SBT) is used to determine patient readiness for IMV discontinuation. In patients who fail one or more SBTs, there is uncertainty as to the optimum management strategy. Objective: To evaluate the clinical effectiveness and cost-effectiveness of using non-invasive ventilation (NIV) as an intermediate step in the protocolised weaning of patients from IMV. Design: Pragmatic, open-label, parallel-group randomised controlled trial, with cost-effectiveness analysis. Setting: A total of 51 critical care units across the UK. Participants: Adult intensive care patients who had received IMV for at least 48 hours, who were categorised as ready to wean from ventilation, and who failed a SBT. Interventions: Control group (invasive weaning): patients continued to receive IMV with daily SBTs. A weaning protocol was used to wean pressure support based on the patient’s condition. Intervention group (non-invasive weaning): patients were extubated to NIV. A weaning protocol was used to wean inspiratory positive airway pressure, based on the patient’s condition. Main outcome measures: The primary outcome measure was time to liberation from ventilation. Secondary outcome measures included mortality, duration of IMV, proportion of patients receiving antibiotics for a presumed respiratory infection and health-related quality of life. Results: A total of 364 patients (invasive weaning, n = 182; non-invasive weaning, n = 182) were randomised. Groups were well matched at baseline. There was no difference between the invasive weaning and non-invasive weaning groups in median time to liberation from ventilation {invasive weaning 108 hours [interquartile range (IQR) 57–351 hours] vs. non-invasive weaning 104.3 hours [IQR 34.5–297 hours]; hazard ratio 1.1, 95% confidence interval [CI] 0.89 to 1.39; p = 0.352}. There was also no difference in mortality between groups at any time point. Patients in the non-invasive weaning group had fewer IMV days [invasive weaning 4 days (IQR 2–11 days) vs. non-invasive weaning 1 day (IQR 0–7 days); adjusted mean difference –3.1 days, 95% CI –5.75 to –0.51 days]. In addition, fewer non-invasive weaning patients required antibiotics for a respiratory infection [odds ratio (OR) 0.60, 95% CI 0.41 to 1.00; p = 0.048]. A higher proportion of non-invasive weaning patients required reintubation than those in the invasive weaning group (OR 2.00, 95% CI 1.27 to 3.24). The within-trial economic evaluation showed that NIV was associated with a lower net cost and a higher net effect, and was dominant in health economic terms. The probability that NIV was cost-effective was estimated at 0.58 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year. Conclusions: A protocolised non-invasive weaning strategy did not reduce time to liberation from ventilation. However, patients who underwent non-invasive weaning had fewer days requiring IMV and required fewer antibiotics for respiratory infections. Future work: In patients who fail a SBT, which factors predict an adverse outcome (reintubation, tracheostomy, death) if extubated and weaned using NIV? Trial registration: Current Controlled Trials ISRCTN15635197. 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. 23, No. 48. See the NIHR Journals Library website for further project information.

Background: Invasive mechanical ventilation (IMV) is a life-saving intervention. Following resolution of the condition that necessitated IMV, a spontaneous breathing trial (SBT) is used to determine patient readiness for IMV discontinuation. In patients who fail one or more SBTs, there is uncertainty as to the optimum management strategy., Objective: To evaluate the clinical effectiveness and cost-effectiveness of using non-invasive ventilation (NIV) as an intermediate step in the protocolised weaning of patients from IMV., Design: Pragmatic, open-label, parallel-group randomised controlled trial, with cost-effectiveness analysis., Setting: A total of 51 critical care units across the UK., Participants: Adult intensive care patients who had received IMV for at least 48 hours, who were categorised as ready to wean from ventilation, and who failed a SBT., Interventions: Control group (invasive weaning): patients continued to receive IMV with daily SBTs. A weaning protocol was used to wean pressure support based on the patient's condition. Intervention group (non-invasive weaning): patients were extubated to NIV. A weaning protocol was used to wean inspiratory positive airway pressure, based on the patient's condition., Main Outcome Measures: The primary outcome measure was time to liberation from ventilation. Secondary outcome measures included mortality, duration of IMV, proportion of patients receiving antibiotics for a presumed respiratory infection and health-related quality of life., Results: A total of 364 patients (invasive weaning, n  = 182; non-invasive weaning, n  = 182) were randomised. Groups were well matched at baseline. There was no difference between the invasive weaning and non-invasive weaning groups in median time to liberation from ventilation {invasive weaning 108 hours [interquartile range (IQR) 57-351 hours] vs. non-invasive weaning 104.3 hours [IQR 34.5-297 hours]; hazard ratio 1.1, 95% confidence interval [CI] 0.89 to 1.39; p  = 0.352}. There was also no difference in mortality between groups at any time point. Patients in the non-invasive weaning group had fewer IMV days [invasive weaning 4 days (IQR 2-11 days) vs. non-invasive weaning 1 day (IQR 0-7 days); adjusted mean difference -3.1 days, 95% CI -5.75 to -0.51 days]. In addition, fewer non-invasive weaning patients required antibiotics for a respiratory infection [odds ratio (OR) 0.60, 95% CI 0.41 to 1.00; p  = 0.048]. A higher proportion of non-invasive weaning patients required reintubation than those in the invasive weaning group (OR 2.00, 95% CI 1.27 to 3.24). The within-trial economic evaluation showed that NIV was associated with a lower net cost and a higher net effect, and was dominant in health economic terms. The probability that NIV was cost-effective was estimated at 0.58 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year., Conclusions: A protocolised non-invasive weaning strategy did not reduce time to liberation from ventilation. However, patients who underwent non-invasive weaning had fewer days requiring IMV and required fewer antibiotics for respiratory infections., Future Work: In patients who fail a SBT, which factors predict an adverse outcome (reintubation, tracheostomy, death) if extubated and weaned using NIV?, Trial Registration: Current Controlled Trials ISRCTN15635197., 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. 23, No. 48. See the NIHR Journals Library website for further project information., Competing Interests: Gavin D Perkins reports grants and non-financial support from the Intensive Care Foundation during the conduct of the study. Daniel McAuley reports personal fees from consultancy for GlaxoSmithKline (London, UK), SOBI (Swedish Orphan Biovitum; Stockholm, Sweden), Peptinnovate Ltd (Stevenage, UK), Boehringer Ingelheim (Ingelheim am Rhein, Germany) and Bayer AG (Leverkusen, Germany). Outside the submitted work, his institution has received funds from grants from the UK National Institute for Health Research (NIHR), the Wellcome Trust and others, and from GlaxoSmithKline for Daniel McAuley undertaking bronchoscopy as part of a clinical trial. In addition, Daniel McAuley is one of four named inventors on a patent US8962032 covering the use of sialic acid-bearing nanoparticles as anti-inflammatory agents issued to his institution, Queen’s University Belfast ( www.google.com/patents/US8962032 ). Daniel McAuley is a member of the Health Technology Assessment (HTA) General Board. James Varley reports non-financial support from La Jolla Pharmaceutical Company (San Diego, CA, USA) and personal fees from Emas Pharma (Hitchin, UK) outside the submitted work. Nicholas Hart reports grants from Guy’s and St Thomas’ Charity during the conduct of the study, grants from Philips Respironics (Murraysville, PA, USA), non-financial support from Philips Respironics RT Meeting (Myotrace), personal fees from Fisher & Paykel Healthcare (Auckland, New Zealand), grants from ResMed (San Diego, CA, USA), grants from B & D Electromedical (Stratford-upon-Avon, UK), grants from Fisher & Paykel Healthcare. In addition, Nicholas Hart has a patent, Myotrace, pending and he is on the Pulmonary Research Advisory Board for Philips. Nicholas Hart’s Lane Fox Clinical Respiratory Physiology Research Group has received unrestricted grants (managed by Guy’s and St Thomas’ Foundation Trust) from Philips Respironics, Philips, ResMed, Fisher & Paykel Healthcare, and B & D Electromedical. Philips Respironics and Philips Research are contributing to the development of the Myotrace technology.